What changed in this filing

/stocks — the workspaceLOADING

Item 1. Business

2024-04-11 compared with 2023-03-09 · 2231 added, 3043 removed, 68 unchanged (99% of the section changed)

We are a biotechnology company focused on the

research and development of transformational vaccines to prevent infectious diseases worldwide.

We hold exclusive, global rights to novel

technology licensed from renowned research institutions around the world, including St.

Jude Children’s Research Hospital, the University

of Oxford, Cincinnati Children’s Hospital Medical Center, and the University of Texas Health at San Antonio.

We believe that our

pipeline and vaccine platform are synergistic for developing next generation preventive vaccines to improve both health outcomes and quality

of life globally.

We seek to develop vaccines that provide long-lasting

immunity to harmful viral and bacterial pathogens that cause infections in patient populations with high unmet needs.

Our most advanced

vaccine candidate is a live-attenuated, intranasally delivered, serotype independent Streptococcus pneumoniae vaccine to prevent

middle ear infections, also known as acute otitis media (AOM), and pneumococcal pneumonia.

AOM is a significant burden globally, particularly

in young children, and pneumococcal pneumonia primarily impacts the elderly population.

Additionally, we believe that this attenuated

bacterium can serve as a platform to protect against other infectious agents that cause acute otitis media, such as non-typeable Haemophilus

influenzae and Moraxella catarrhalis , by anchoring antigens from these pathogens on the surface of BWV-201, our attenuated

Streptococcus pneumoniae bacterial vaccine.

We hold a global, exclusive license to this technology, which was generated from the

laboratory of Jason Rosch, Ph.D., of St.

Jude Children’s Research Hospital.

Our influenza programs are based on technology developed

by Sunetra Gupta, Ph.D.

at the University of Oxford, for which we hold a global, exclusive license for use of epitopes of limited variability,

ELVs, to develop novel influenza vaccine candidates.

Identified through a proprietary computational research and discovery process, we

believe a vaccine formulated with these epitopes from different influenza strains will produce a viable universal influenza vaccine candidate.

We are exploring the development of these influenza ELVs utilizing our norovirus shell and protrusion (S&P) nanoparticle vaccine platform,

licensed from Cincinnati Children’s Hospital Medical Center, or CHMC.

We are also utilizing this platform to develop a vaccine for

the prevention of gastroenteritis caused by norovirus or rotavirus, as well as novel vaccines for malaria and monkeypox.

The final candidate

in our vaccine pipeline is a live-attenuated, orally delivered vaccine to prevent Chlamydia, for which we have a global, exclusive license

to this technology originated from the University of Texas Health at San Antonio.

We leverage the expertise of each of our collaborators

to pursue the discovery and development of vaccines for these diseases, each of which represent high unmet needs globally.

In addition, we have expertise in identifying

business development opportunities for our platform vaccines technologies and portfolio.

This allows for both internal pipeline expansion

and the ability to generate non-dilutive revenue from potential licensing partners to utilize our discovery engine vaccine platform.

is potential for adjunctive or next generation therapeutic exploration to enhance current standard of care options.

Vaccination has been used as an effective method

of protecting individuals against harmful diseases by utilizing the body’s natural defense system to develop resistance or immunity

to infections (World Health Organization, https://www.who.int/news-room/q-a-detail/herd-immunity-lockdowns-and-covid-19 ).

immune system naturally creates antibodies and cell — mediated immunity to defend against foreign pathogens.

Vaccines introduce

or present these foreign pathogens, prompting the body’s immune system produce a response protective against the pathogen without

exposing the body to the relevant lethal or harmful infection (World Health Organization, https://www.who.int/news-room/q-a-detail/herd-immunity-lockdowns-and-covid-19 ).

While vaccines are generally able to provide resistance against disease, many infectious diseases can evolve or mutate leading to shortcomings

of traditional vaccines, such as yearly reformulations.

We believe our vaccine candidates can provide an alternative to the current standards

of care by harnessing durable and long-lived immune response to specific or multiple antigens.

The global vaccine market has recently experienced

significant growth caused by rising awareness of the importance of immunization and vaccination benefits in emerging markets as well as

by projects to fuel further global market expansion.

For instance, The World Health Organization (WHO) has undertaken initiatives to increase

immunization awareness through its Global Vaccine Action Plan and Global Immunization Vision and Strategy.

As such, market research professionals project the global vaccine market

size to reach $73.78 billion by 2028, representing a compounded annual growth rate (CAGR) of 7.3% over the forecast period, driven by

rising prevalence of infectious diseases, increasing government funding for vaccine production and growing emphasis on becoming immunized.

This market acceleration has been coupled with

various strategic transactions in the sector, including consolidations and mergers and acquisitions in recent years.

Major market participants

have strategically acquired start-ups and mid-sized companies to broaden their products portfolios and service offerings.

For instance,

in February 2019, Bharat Biotech acquired Chiron Behring Vaccines, one of the leading manufacturers of rabies vaccines across the globe.

Additionally, in October 2018, Emergent BioSolutions, a multinational specialty biopharmaceutical company, acquired PaxVax for $270 million,

and in July 2017 Sanofi acquired Protein Sciences for $650 million.

In the pneumococcal disease market specifically, for which we are

targeting for our Streptococcus pneumoniae vaccine candidate, GlaxoSmithKline acquired Affinivax for up to $3.3 billion in May

The appetite of these companies to buttress their vaccine programs and pipelines reflects the increasing importance of vaccines

in the healthcare sector, both nationally and worldwide.

Centers for Disease Control, or CDC,

its Advisory Committee on Immunization Practices, or ACIP, and similar international advisory bodies develop vaccine recommendations for

both children and adults.

New pediatric vaccines that receive ACIP preferred recommendations are almost universally adopted, and adult

vaccines that receive a preferred recommendation are widely adopted.

We believe that our vaccine candidates will be well-positioned to

obtain these preferred recommendations, by virtue of their longer and more durable immunity, which could drive rapid and significant market

Our vaccine candidates are being developed in

a manner that is scalable, designed to be cost-effective and provide long term benefit to patients from infectious agents.

The FDA regulatory approval process is lengthy

and time -consuming , and we may experience significant delays in the clinical

development and regulatory approval of our vaccine candidates.

Our vaccine candidates are in early stages of development and may fail

in development or suffer delays that materially and adversely affect their commercial viability.

We may be unable to complete development

of or commercialize our vaccine candidates or experience significant delays in doing so due to regulatory or other uncertainties.

We aim to identify, discover and develop novel

preventive vaccines for infectious diseases.

Key elements of our strategy include:

in advancing the development of our novel vaccine pipeline programs through IND-enabling activities and Phase I clinical studies.

plan to advance our main vaccine programs:

pneumoniae induced AOM and pneumococcal pneumonia, influenza, norovirus-rotavirus,

malaria, and Chlamydia.

in-licensed vaccine candidates are carefully selected based on the following criteria:

area of significant unmet medical need for preventive

long-term vaccine;

strong scientific rationale and established clinical and regulatory pathways;

defined competitive landscape and potential

future commercial opportunity;

and license exclusivity.

● Prioritizing

the research and development for our lead vaccine candidate, BWV-201, through Phase I.

We plan to develop an intranasally delivered, serotype independent

Streptococcus pneumoniae vaccine, capable of protecting young children against acute otitis media, also known as middle ear infections,

and the elderly against pneumococcal pneumonia.

In collaboration with St.

Jude Children’s Research Hospital, we are exploring the

potential to anchor antigens from additional otopathogens to the surface of this vaccine, including non-typeable Haemophilus influenzae

and Moraxella catarrhalis.

and utilize the value of our collaborators and third-party vendors.

will combine disciplined business strategies to further expand the potential synergies with current collaborators.

and expand our proprietary norovirus S&P nanoparticle platform.

immunogenic multi-purpose vaccine platform technologies can be utilized with an array of infectious disease agents to access multiple

development pathways and allow for potential next-generation life cycle management to expand our pipeline and pursue business development

opportunities.

There is potential for the platform to pursue adjunctive therapies to currently available drugs, and for current therapies

to be re-optimized and formulated to protect against multiple antigens.

We plan to utilize this platform to explore the potential to

formulate our influenza vaccine candidates by presenting patented epitopes of limited variability within the platform.

Company Overview

We are a commercial stage

biotechnology company focused on the research, development, and commercialization of innovative solutions for men’s health and oncology.

Through our recent acquisition of Proteomedix, we own Proclarix, an in vitro diagnostic test for prostate cancer originally developed

by Proteomedix and approved for sale in the European Union under the In Vitro Diagnostic Regulation (“IVDR”), which we anticipate

will be marketed in the U.S.

as a lab developed test through our license agreement with LabCorp.

We also own ENTADFI, an FDA-approved,

once daily pill that combines finasteride and tadalafil for the treatment of BPH, a disorder of the prostate.

is an easy-to-use next generation protein-based blood test that can be done with the same sample as a patient’s regular Prostate-Specific

Antigen (“PSA”) test.

The PSA test is a well-established prostate specific marker that measures the concentration of PSA molecules

in a blood sample.

A high level of PSA can be a sign of prostate cancer.

However, PSA levels can also be elevated for many other reasons

including infections, prostate stimulation, vigorous exercise or even certain medications.

PSA results can be confusing for many patients

and even physicians.

It is estimated over 50% of biopsies with elevated PSA are negative or clinically insignificant resulting in an overdiagnosis

and overtreatment that impacts the physician’s routine, our healthcare system, and the quality of patients’ lives.

helps doctors and patients with unclear PSA test results through the use of our proprietary Proclarix Risk Score which delivers clear

and immediate diagnostic support for further treatment decisions.

No additional intervention is required, and results are available quickly.

Local diagnostic laboratories can integrate this multiparametric test into their current workflow because Proclarix assays use

the enzyme-linked immunosorbent assay (ELISA) standard, which most diagnostic laboratories are already equipped to process.

ENTADFI allows men to receive

treatment for their symptoms of BPH without the negative sexual side effects typically seen in patients on finasteride alone.

a recent business strategy shift towards the field of men’s health and oncology and deprioritizing of preclinical vaccine programs,

we are building additional assets in therapeutics, diagnostics, and clinician services for men’s health and oncology.

Since our inception in October

2018 until April 2023, when we acquired ENTADFI, we devoted substantially all of our resources to performing research and development,

undertaking preclinical studies and enabling manufacturing activities in support of our product development efforts, hiring personnel,

acquiring and developing our technology and now deprioritized vaccine candidates, organizing and staffing our company, performing business

planning, establishing our intellectual property portfolio and raising capital to support and expand such activities.

Prior to the acquisition of

ENTADFI, we managed one distinct business segment, which was research and development.

Beginning in the second quarter of 2023, as a result

of the acquisition of ENTADFI, for which we are working towards commercial launch, we operated in two business segments:

development and commercial.

During the third quarter of 2023, we deprioritized our vaccine discovery and development programs, and accordingly,

we now operate in one segment:

Our recent acquisition of Proteomedix during the fourth quarter of 2023 and its related diagnostic

product Proclarix was determined to be within our commercial segment.

The research and development segment was our historical business,

and was dedicated to the research and development of various vaccines to prevent infectious diseases.

The commercial segment was new in

the second quarter of 2023 and is dedicated to the commercialization of our products approved for sale, namely ENTADFI in the U.S.

Proclarix in Europe.

On December 15, 2023, the Company closed its acquisition of Proteomedix

and introduced Onconetix, Inc.

as the new name for the combined company.

The closing of the acquisition of Proteomedix for all stock consideration

provides Proteomedix shareholders with an initial 16.4% ownership stake of Onconetix, and Series B Preferred Stock convertible into 269,672,900

shares of Onconetix Common Stock, subject to Onconetix stockholder approval of the same (“Stockholder Approval”).

In light of (i) the time

and resources needed to continue pursuing commercialization of ENTADFI, and (ii) the Company’s cash runway and indebtedness, the

Company has determined to temporarily pause its commercialization of ENTADFI, as it considers strategic alternatives.

The Company expects

to appoint a new Chief Executive Officer in the second quarter of 2024, after which the new CEO and the Board will reassess its ENTADFI

program in light of the foregoing and other relevant factors.

We are currently focusing

our efforts on commercializing Proclarix.

Given Proclarix is CE-marked

for sale in the European Union, we expect to generate revenue from sales of Proclarix by 2025.

Although we anticipate these sales to offset

some expenses relating to commercial scale up and development, we expect our expenses will increase substantially in connection with our

ongoing activities, as we:

commercialize Proclarix;

hire additional personnel;

operate as a public company;

obtain, maintain, expand and protect our intellectual property portfolio.

To the extent that we resume

the commercialization of ENTADFI, we also expect to incur significant commercialization expenses related to marketing, manufacturing and

distribution for ENTADFI.

We rely and will continue to rely on third parties for the manufacturing of ENTADFI and Proclarix.

internal manufacturing capabilities, and we will continue to rely on third parties, of which the main suppliers are single-source suppliers,

for commercial products.

We do not have any products

approved for sale, aside from Proclarix, from which we have generated only minimal amounts of development revenue since its acquisition,

and ENTADFI, from which we have not generated any revenue from product sales, and for which we have determined to temporarily pause commercialization

To date, we have financed our operations primarily with proceeds from our sale of preferred securities to seed investors,

the initial public offering (“IPO”), the April 2022 Private Placement (as defined below), the August 2022 Private Placement

(as defined below), the proceeds received from a warrant exercise in August 2023, and the proceeds received from the issuance of debt

in January 2024.

We will continue to require significant additional capital to commercialize Proclarix and ENTADFI (if we decide to resume

its commercialization), and to fund operations for the foreseeable future.

Accordingly, until such time as we can generate significant

revenue, if ever, we expect to finance our cash needs through public or private equity or debt financings, third-party (including government)

funding and to rely on third-party resources for marketing and distribution arrangements, as well as other collaborations, strategic alliances

and licensing arrangements, or any combination of these approaches, to support our operations.

We have incurred net losses

since inception and expect to continue to incur net losses in the foreseeable future.

Our net losses may fluctuate significantly from

quarter-to-quarter and year-to-year, depending in large part on the timing of our preclinical studies, clinical trials and manufacturing

activities, our expenditures on other research and development activities and commercialization activities.

As of December 31, 2023, the

Company had a working capital deficit of approximately $11.4 million and an accumulated deficit of approximately $56.8 million.

need to raise additional capital within the next 12 months to sustain operations.

In addition, if Stockholder Approval is not obtained

by January 1, 2025, the Company may be obligated to cash settle the Series B Preferred Stock.

Based on the closing price of $0.166 for

the Company’s stock as of April 5, 2024, the Series B Preferred Stock would be redeemable for approximately $44.8 million.

Until we generate revenue

sufficient to support self-sustaining cash flows, if ever, we will need to raise additional capital to fund our continued operations,

including our product development and commercialization activities related to our current and future products.

There can be no assurance

that additional capital will be available to us on acceptable terms, or at all, or that we will ever generate revenue sufficient to provide

self-sustaining cash flows.

These circumstances raise substantial doubt about our ability to continue as a going concern.

The accompanying

consolidated financial statements of Onconetix, as of and for the year ended December 31, 2023, included elsewhere in this Report do not

include any adjustment that might be necessary if the Company is unable to continue as a going concern.

Because of the numerous risks

and uncertainties associated with our business, we are unable to predict the timing or amount of increased expenses or when or if we will

be able to achieve or maintain profitability.

Additionally, even if we are able to generate revenue from Proclarix or ENTADFI, we may

not become profitable.

If we fail to become profitable or are unable to sustain profitability on a continuing basis, then we may be unable

to continue our operations at planned levels and may be forced to reduce our operations.

Management and History

Onconetix, Inc.

Blue Water Vaccines Inc.

was founded in October

2018 by our Chief Executive Officer, or CEO, Joseph Hernandez, with the initial goal of developing a transformational universal flu vaccine

to treat and prevent infections in patients globally.

Our initial technology, licensed from the University of Oxford, provides a novel

approach to developing a universal influenza vaccine.

Subsequently, our team has identified other program candidates and technologies

to broaden and diversify our vaccine pipeline.

Hernandez, our Chairman and CEO, is a veteran entrepreneur, philanthropist,

and operator with a broad skillset of founding, building, and selling companies, as well as executing business development transactions

and securing private and public capital, including Digene, Noachis Terra and Blue Water Acquisition Corp.

Hernandez was responsible

for our initial $7 million seed funding round from investors including CincyTech.

In addition to his position as our Chairman and CEO,

Hernandez also served on the board of directors for Clarus Therapeutics, Inc.

CRXTQ) until August 2022, and serves on the

board of certain private companies.

Subsequently, a team of veteran industry executives and advisors were assembled, bringing valuable

expertise to our growing infectious disease company.

Jon Garfield, our Chief Financial Officer, has

over 20 years of financial leadership experience, including with healthcare companies.

Garfield regularly provides consulting services

to private equity funds and privately held companies and served as the CEO of Unity MSK from February 2021 to January 2023, and served

as interim Chief Financial Officer of Blue Water Vaccines Inc.

from September 2021 until the consummation of our initial public offering

in February 2022, upon which he became our full-time Chief Financial Officer.

Erin Henderson, who serves as our Chief Business Officer

and Corporate Secretary, has over 20 years of leading strategic transactions, governmental and stakeholder relations and corporate expansion.

Previously, since 2010, she was the Managing Principal at The Aetows Group, a management consulting firm serving both the public and private

Andrew Skibo is our Head of Biologic Operations and was recently Head of Global Biologics Operations at MedImmune/AstraZeneca

and previously worked for Amgen and Genentech (now Roche), where he was responsible for operations, engineering, construction, and validation

for large-scale capital projects related to bio-pharmaceutical manufacturing.

Ali Fattom, Ph.D.

is our Head of Science and Discovery and

was recently Chief Scientific Officer at BlueWillow Biologics, where he led their efforts to develop viral vaccines for various infectious

diseases, including HSV, RSV, and influenza, and previously worked for Nabi Biopharmaceutical and The National Institutes of Health.

Fattom is also an Adjunct Professor at the University of Michigan.

Additionally, members of our Board of Directors

have extensive expertise in the fields of life sciences, business, and finance.

In addition to Mr.

Hernandez, our directors include Vuk

Jeremić, previous Chair of the Council of Europe’s Committee of Ministers and previous President of the United Nations General

Assembly, Simon Tarsh, a retired Deloitte Consulting Managing Director with experience in Life Sciences, Timothy Ramdeen, who has nearly

a decade of experience in private equity and hedge fund investing, capital markets, and company formation, and James Sapirstein, R.Ph.,

M.B.A, President, CEO and Chairman of First Wave BioPharma, Inc.

(Nasdaq:FWBI).

Our Scientific Advisory Board includes Sunetra Gupta,

Professor of Theoretical Epidemiology at The University of Oxford, a leading voice in infectious disease globally;

and John Rice,

Ph.D., Managing Director at CincyTech, with more than 30 years of biotechnology advising experience.

Subject to certain non-compete restrictions, our

chief executive officer, Joseph Hernandez, and other key personnel may pursue other business or investment ventures while employed with

Accordingly, they may have conflicts of interest in allocating time among various business activities and potentially competitive

fiduciary and pecuniary interests that conflict with our interests.

See “Risk Factors — Our Chief Executive Officer, Joseph

Hernandez and our Chief Financial Officer, Jon Garfield, hold certain management positions and directorships of other companies and may

allocate their time to such other businesses, which may cause conflicts of interest in their determination as to how much time to devote

to our affairs and potentially competitive fiduciary and pecuniary interests that conflict with our interests.” For a complete discussion

of the business affairs of our officers, directors and other personnel, please see “Management — Executive Officers and Directors.”

Any such additional business activities or ventures may present conflicts to our interests.

We do not believe that any such potential

conflicts would materially affect our ability to conduct our operations.

Our Infectious Disease Vaccine Candidates

Infectious diseases are one of the leading causes

of death worldwide.

Infectious disease is caused by microorganisms or pathogens, including viruses, bacteria, fungi, and parasites that

infect an individual and cause disease.

Diseases often cause high fever, inflammation, or other symptoms.

While some diseases can be treated

with drugs or therapeutics, some infectious agents evolve to become resistant to commonly used drugs, such as antibiotics, and can become

difficult to control.

Infectious diseases can be passed from person to person or transmitted by insects or other animals.

In many cases,

vaccines are used to elicit a protective immune response in the absence of an infection to render an individual immune to a particular

infectious disease.

Streptococcus pneumoniae (S.

pneumoniae) Vaccine

Our BWV-201 vaccine candidate is an intranasally

delivered, live-attenuated, serotype-independent vaccine, for which early data supports further investigation to pursue a long-term preventive

intranasal vaccine for S.

pneumoniae induced acute otitis media, or AOM, and pneumococcal pneumonia.

We in-licensed the novel live-attenuated

pneumoniae strain from St.

Jude Children’s Research Hospital, or St.

Jude, as a potential serotype independent vaccine.

Researchers from St.

Jude developed a strain of

pneumoniae that contains greatly reduced virulence, yet can transiently colonize the nasopharyngeal cavity, inducing immune

responses to significantly decrease the incidence of AOM and sinusitis as demonstrated in animal models.

Our vaccine production is a straightforward

process, utilizing the entire attenuated bacterium with purification and concentration steps only in the downstream process, thereby reducing

the time and cost of production significantly compared to commonly used polysaccharide or conjugate vaccines.

There is potential for this vaccine to provide

a long-term, leading alternative treatment for AOM and pneumococcal pneumonia and subsequent introduction of a novel preventative standard

The development of a novel vaccine could eradicate potential short-term pain and/or long-term harmful side effects from contracting

the bacteria, as well as eliminate or decrease the need for antibiotic treatment.

Complications from AOM include sensorineural hearing

loss, or SNHL, in adults but are more relevant for the endangerment of children, while pneumococcal pneumonia primarily impacts elderly

adults and can lead to hospitalization and other subsequent infections.

Based on information from the American Academy

of Pediatrics, over 5 million cases of AOM are reported annually in the U.S., resulting in approximately 30 million medical care visits

and over 10 million antibiotic prescriptions, representing approximately $4.3 billion spent on treatment in the U.S.

most common condition treated with antibiotics in the United States and increasing antibiotic resistance among the organisms responsible

for AOM is of concern to researchers and public health officials globally.

Additional statistics supporting the need for

a novel preventive vaccine:

global AOM rate is 10.85%, or 709 million cases per year, with 51% occurring in children under 5 years old (Tong et al.

BMC Health Serv

3 years of age, 80% of children globally are expected to have at least one episode of AOM.

(Vergison A, Lancet Infect Dis.

2010 Mar;10(3):195-203.

10.1016/S1473-3099(10)70012-8.

treatment for AOM is by antibiotic prescription, with more than 80% of all consultations resulting in a prescription.

J Pediatr 170, 323 – 332 (2011).

https://doi.org/10.1007/s00431-010-1286-4 ).

with the introduction of the pneumococcal conjugate vaccine (PCV13) in 2010, 26-36% of cases of AOM in U.S.

were caused by S.

(Casey JR, Kaur R, Friedel VC, Pichichero ME.

Acute otitis media otopathogens during 2008 to 2010 in Rochester, New York.

Infect Dis J .

2013;32(8):805-809.

Doi:10.1097/INF.0b013e31828d9acc).

cases of AOM due to S.

pneumoniae is estimated to be 30-50%.

(Bergenfelz C, Hakansson AP.

Curr Otorhinolaryngol Rep.

and Blue Water Biotech, Inc.) was founded in October 2018.

The Company’s initial goal was to develop a

transformational universal flu vaccine to treat and prevent infections in patients globally.

After deprioritizing our vaccine programs,

the Company subsequently shifted its focus toward building a foundation of therapeutic, diagnostic, and service products in the field

of men’s health and oncology.

Our Interim Chief Executive

Ralph Schiess, has extensive experience with life sciences companies.

Schiess co-founded Proteomedix, a private commercial-stage

diagnostics oncology company that the Company acquired in December 2023 (as further described below) and served as its Chief Executive

Officer from Proteomedix’s inception until December 2019, as Proteomedix’s Chief Scientific Officer from January 2020 to May

2023, and again as Chief Executive Officer since June 2023.

Bruce Harmon, our Chief Financial

Officer, has more than 40 years of experience in financial positions with life sciences companies and various other industries.

has served in a variety of roles, including chief financial officer, controller, chief executive officer, and audit committee chairman.

He has been an independent consultant since 2008 through his business, Lakeport Business Services, Inc., and served in the outsourced

CFO capacity for multiple publicly traded companies.

During this time, Mr.

Harmon was CFO of Marizyme Inc.

from 2020 to 2021, CFO of bioAffinity

Technologies Inc.

in 2022, a director of Dale Biotech LLC since 2017, and a director of Patriax Industries since 2023.

He has extensive

experience with fundraising, public offerings, mergers and acquisitions, and turnarounds.

Earlier in his career, he was a member of a

team that, at the invitation of the Environmental Programmé, presented a green building product to delegates at the United Nations.

He earned a Bachelor of Science degree in accounting from Missouri State University.

Additionally, members of

our Board of Directors have extensive expertise in the fields of life sciences, business and finance.

Our directors include Simon Tarsh,

a retired Deloitte Consulting managing director with experience in life sciences, Timothy Ramdeen, who has nearly a decade of experience

in private equity and hedge fund investing, capital markets, and company formation, and James Sapirstein, R.Ph., M.B.A, President, CEO

and Chairman of First Wave BioPharma, Inc.

Corporate Name Change and Amendment to Bylaws

On April 21, 2023, the Company

filed an amendment to its Amended and Restated Certificate of Incorporation with the Secretary of State of Delaware to change its corporate

name from “Blue Water Vaccines Inc.” to “Blue Water Biotech, Inc.” The name change was effective as of April 21,

In connection with the name change, the Company amended the Company’s bylaws to reflect the corporate name “Blue Water

Biotech, Inc.,” also effective on April 21, 2023.

On December 15, 2023, the

Company filed an amendment to its Amended and Restated Certificate of Incorporation with the Secretary of State of Delaware to change

its corporate name from “Blue Water Biotech, Inc.” to “Onconetix, Inc.”

In connection with the name

change, the Company also amended the Company’s bylaws to reflect the new corporate name.

On May 31, 2023, the Board

amended the Company’s bylaws to reduce the quorum requirement at meetings of the Company’s stockholders from a majority of

the voting power of the outstanding shares of stock of the Company entitled to vote, to one-third of the voting power of the outstanding

shares of stock of the Company entitled to vote, effective immediately.

No other changes were made to the bylaws.

Nasdaq Compliance

On September 18, 2023, we

received notice from Nasdaq staff indicating that, based upon the closing bid price of the Common Stock for the prior 30 consecutive business

days, we were not in compliance with the requirement to maintain a minimum bid price of $1.00 per share for continued listing on Nasdaq,

as set forth in Nasdaq Listing Rule 5550(a)(2) (the “Bid Price Rule”).

On March 13, 2024, we submitted a plan of compliance

to Nasdaq to discuss our plans to evidence compliance with the Bid Price Rule and we received an additional 180-day period, or until September

16, 2024, to regain compliance with the Bid Price Rule.

On August 22, 2023, we received

a notice from Nasdaq that we were not in compliance with Nasdaq Listing Rule 5250(c)(1), which requires listed companies to timely file

all required periodic financial reports with the SEC, given our failure to timely file our quarterly report on Form 10-Q for the quarter

ended June 30, 2023.

On October 20, 2023, we filed our Form 10-Q for the period ended June 30, 2023, and on November 1, 2023, we announced

that we had regained compliance with Nasdaq Listing Rule 5250(c)(1).

Recent Acquisitions

December 15, 2023, Onconetix entered into a Share Exchange Agreement (the “Share Exchange Agreement”), by and among (i) Onconetix,

(ii) Proteomedix, (iii) each of the holders of outstanding capital stock, convertible securities, or stock options of Proteomedix

named therein (collectively, the “Sellers”) and (iv) Thomas Meier, in the capacity as the representative of Sellers in

accordance with the terms and conditions of the Share Exchange Agreement.

Pursuant to the Share Exchange Agreement, subject to the terms and

conditions set forth therein, the Sellers agreed to sell to Onconetix, and Onconetix agreed to buy, all of the issued and outstanding

voting equity interests of Proteomedix in exchange for newly issued shares of Common Stock and newly issued shares of Series B Preferred

Stock (the “Share Exchange”).

consummation of the Share Exchange (the “Share Exchange Closing”) was subject to customary closing conditions and the execution

of the Subscription Agreement entered into with Altos Ventures, a shareholder of Proteomedix prior to the closing of the Share Exchange

(the “PMX Investor”).

The Share Exchange closed on December 15, 2023 (the “Share Exchange Closing Date”).

in 2010, Proteomedix develops, markets and sells non-invasive diagnostic tests accompanied by decision support systems to detect

and assess the prognosis of cancer.

Proteomedix’s lead product, Proclarix ® , is an in vitro diagnostic test for prostate

Proteomedix is working to address all stages in cancer management by developing tools for both more accurate detection and more

efficient treatment of cancer including (i) diagnostic tests to early detect and define the stage of cancer;

(ii) prognostic tools for

the identification of patients with aggressive disease;

and (iii) stratification biomarkers to match patients with therapies that are

more likely to be safe and effective.

prostate cancer stands as the most prevalent and second most fatal cancer type affecting men.

The widespread utilization of PSA screening

since it became broadly available in the 1980s helped reduce the occurrence of metastatic prostate cancers by over half, but also led

to a notable increase in overdiagnosis, sometimes resulting in excessive treatment, severe complications, and potential psychological

There exists a considerable population of men each year who are notified of their heightened risk for prostate cancer based

on elevated PSA levels, with limited options beyond invasive needle biopsies for managing their cancer risk.

addresses the unsolved problem of prostate cancer overdiagnosis, which can lead to negative prostate biopsies that increase costs for

the healthcare system and uncertainty for patients.

Proclarix is approved for sale in the European Union under the IVDR.

Proclarix was

first CE marked under the IVD Directive in Europe in January 31, 2019.

On October 7, 2022, Proclarix gained CE marking under the IVD Regulation

(IVDR) and was registered in the United Kingdom and Switzerland under applicable regulations.

Clinical studies have confirmed that Proclarix

accurately identifies clinically significant prostate cancer through a risk score derived from a clinical decision support system and

could help avoid many unneeded biopsies.

Proclarix as a clinical support system is designed to aggregate multimodal information in an

effort to develop a patient-centric diagnostic approach.

We intend to add more information to the risk score in the future, such as other

biomarkers or magnetic resonance imaging data, to provide an even more powerful tool to guide the patient’s diagnostic journey.

The markers and the bioinformatics algorithm used are patent-protected.

guidelines of the European Association of Urology (“EAU”) and of the American Urological Association/Society of Urologic Oncology

(“AUA/SUO”) both recommend the use of blood-based biomarker tests, such as Proclarix, to aid in the early detection and evaluation

of prostate cancer.

Proclarix can be performed in any laboratory using standard equipment.

Proteomedix announced commercial availability

of Proclarix in Europe on February 26, 2020 and began marketing Proclarix to selected pilot laboratories offering Proclarix in Switzerland,

Germany, Italy and the United Kingdom.

Proclarix is currently not reimbursed in Europe, and therefore patients pay for Proclarix out of

The number of sold Proclarix tests current corresponds to the early market development stage and selected few laboratories offering

In 2023, we had revenues of $67,380 from sales of Proclarix, compared to $79,085 in 2022.

In the United States, the development

and commercialization of Proclarix is being pursued by Laboratory Corporation of America Holdings, more commonly called Labcorp, pursuant

to an exclusive license agreement entered into between Proteomedix and Labcorp in 2023.

was founded by a multi-disciplinary group of scientists and clinicians that include Prof.

Thomas Cerny, president of the

Swiss Cancer Research Foundation, Prof.

Ruedi Aebersold, a pioneer in proteomics technology development, and the late Prof.

Wilhelm Krek,

a leader in cancer research.

Proteomedix’s management consists of Dr.

Ralph Schiess (Chief Executive Officer), who developed the

biomarker technology, and Christian Bruehlmann (Chief Business Officer), with seasoned experience in finance, business development and

product management.

Terms of the PMX Transaction

Consideration

full payment for the Purchased Shares, Onconetix issued shares (the “Exchange Shares”) consisting of:

(i) 3,675,414 shares

of Common Stock equal to approximately 19.99% of the total issued and outstanding Common Stock prior to the acquisition and (ii) 2,696,729 shares

of Series B Preferred Stock convertible into 269,672,900 shares of Common Stock.

The parties agreed that the aggregate value

of the Exchange Shares at the Share Exchange Closing was equal to approximately Seventy-Five Million U.S.

Dollars ($75,000,000) (the “Exchange

Consideration”) less the value of the Proteomedix Shares for which the Proteomedix Stock Options (as defined below) are exercisable

immediately prior to the Share Exchange Closing, subject to adjustment for indemnification as described below.

Following the Share Exchange

Closing, 22,841,975 and 22,324,576 shares of Common Stock were issued and outstanding, respectively.

fair value of the 3,675,414 shares of Common Stock, was determined using the closing price of the Common Stock as of the Share Exchange

Closing Date, which was $0.2382.

The fair value of the 2,696,729 shares of Series B Preferred Stock was based on the underlying fair

value of the common shares issuable upon conversion, also based on the closing price of the Common Stock as of the Share Exchange Closing

The aggregate fair value of the common and preferred shares issued as consideration was equal to approximately $65.1 million.

Advisors acted as financial advisor to Proteomedix at Proteomedix’s expense.

As part of compensation for services rendered by Tungsten

Advisors, the parties agreed that $7,500,000 in Exchange Shares were issued to certain affiliates of Tungsten Advisors (the “Advisor

Parties”) out of the total Exchange Consideration issued by Onconetix.

a result of the PMX Transaction, Proteomedix became a direct, wholly owned subsidiary of Onconetix.

It is anticipated that, following

the Conversion (as defined below) and closing of the investment pursuant to the Subscription Agreement (as defined below), Sellers will

own approximately 87.2% of the outstanding equity interests of Onconetix, the PMX Investor will own approximately 7.5% of the outstanding

equity interests of Onconetix, and the stockholders of Onconetix immediately prior to the Share Exchange Closing will own approximately

5.3% of the outstanding equity interests of Onconetix.

option to purchase shares of Proteomedix (each, a “Proteomedix Stock Option”) outstanding immediately before the Share Exchange

Closing, whether vested or unvested, remains outstanding until the Conversion unless otherwise terminated in accordance with its terms.

At the Conversion, each outstanding Proteomedix Stock Option, whether vested or unvested, shall be assumed by Onconetix and converted

into the right to receive (a) an option to acquire shares of Common Stock (each, an “Assumed Option”) or (b) such

other derivative security as Onconetix and Proteomedix may agree, subject in either case to substantially the same terms and conditions

as were applicable to such Proteomedix Stock Option immediately before the Share Exchange Closing.

Each Assumed Option shall:

(i) represent

the right to acquire a number of shares of Common Stock equal to the product of (A) the number of Proteomedix Common Shares that

were subject to the corresponding Proteomedix Option immediately prior to the Share Exchange Closing, multiplied by (B) the Exchange

Ratio (as defined in the Share Exchange Agreement);

and (ii) have an exercise price (as rounded down to the nearest whole cent) equal

to the quotient of (A) the exercise price of the corresponding Proteomedix Option, divided by (B) the Exchange Ratio.

Indemnification .

the earlier of (i) Stockholder Approval or (ii) June 30, 2024 (the “Claim Deadline”), Onconetix may assert

Claims against Proteomedix and Sellers for any and all Losses incurred by Onconetix with respect to:

(i) any inaccuracy in or breach

of any of the representations or warranties made by Proteomedix contained in the Share Exchange Agreement or (ii) any breach or non-fulfillment of

any covenant, agreement or obligation to be performed by Proteomedix pursuant to the Share Exchange Agreement.

Until the Claim Deadline,

the Sellers’ Representative, acting on behalf of the Sellers, may assert Claims against Onconetix for any Loss incurred by the Sellers

with respect to:

(i) any inaccuracy in or breach of any of the representations or warranties of Onconetix contained in the Share

Exchange Agreement or (ii) any breach or non-fulfillment of any covenant, agreement or obligation to be performed by Onconetix

pursuant to the Share Exchange Agreement.

number of shares of Common Stock issued upon Conversion shall be increased or decreased by a number determined by dividing the Net Adjustment

by the ten-day volume-weighted average price (“VWAP”) of the Common Stock for the ten (10)-day period preceding

the third day prior to the Share Exchange Closing Date and rounding down to the nearest whole share;

provided, however, that (i) there

shall be no adjustment to the number of shares of Common Stock issued upon Conversion if the Net Adjustment is less than $1,000,000 and

(ii) the number of shares of Common Stock issued upon Conversion shall not be increased or decreased by more than 10% of the number

of shares of Common Stock that would be issuable absent such adjustment.

As used herein, “Net Adjustment” means the absolute

value of the difference between the aggregate adjustment in favor of each party with respect to Losses that is agreed by Onconetix and

the Sellers’ Representative or determined by a mutually acceptable dispute resolution firm.

and after the Share Exchange Closing and until the first anniversary of the Share Exchange Closing, Sellers, severally and not jointly,

are required to indemnify Onconetix and its affiliates and their respective representatives (collectively, the “Onconetix Indemnitees”)

against (i) any inaccuracy in or breach of any of the representations or warranties of such Seller contained in the Share Exchange

Agreement and (ii) breach or non-fulfillment of any covenant, agreement or obligation to be performed by such Seller pursuant

to the Share Exchange Agreement.

Any payment due from any Seller in respect of an indemnification claim by any Onconetix Indemnitee shall

solely be satisfied by recourse to the Exchange Shares and the shares of Common Stock issuable upon the Conversion, with each share of

Common Stock valued at the same price per share of Common Stock used to determine the Exchange Ratio.

Covenants of the Parties

party to the Share Exchange Agreement agreed to use its commercially reasonable efforts to effect the PMX Transaction.

obtained a duly executed Stockholder Support Agreement (as defined below) from each director and executive officer of Onconetix, and used

commercially reasonable efforts to obtain a duly executed Stockholder Support Agreement from

each holder of more than five percent (5%) of Onconetix’s voting stock.

Share Exchange Agreement contains certain covenants by each of the parties, to be observed during the period between the Share

Exchange Closing and Conversion, including covenants regarding:

(1) the provision of access to properties, books and personnel;

delivery of Onconetix’s financial statements;

(3) litigation support;

(4) Onconetix’s public filings;

(5) no insider

(6) further assurances;

(7) public announcements;

(8) confidentiality;

(9) indemnification of directors and officers and

tail insurance;

(10) intended tax treatment of the Share Exchange;

(11) Section 16 matters and (12) transfer taxes.

parties agreed to take all necessary actions to cause Onconetix’s board of directors immediately after the Stockholder Approval

(the “Post-Stockholder Approval Onconetix Board”) to consist of five directors, including:

(i) two persons who are designated

by Onconetix and reasonably acceptable to Proteomedix ;

and (ii) three persons who are

designated by Proteomedix and reasonably acceptable to Onconetix .

issuance of the Conversion Shares, amendment of Onconetix’s Amended and Restated Certificate of Incorporation to authorize sufficient

additional shares of Common Stock to permit the Conversion (to the extent required to consummate the PMX Transaction) and the appointment

of the post-Stockholder Approval Onconetix Board requires the approval of Onconetix’s stockholders.

Onconetix agreed to prepare

and file with the SEC a proxy statement (a “Proxy Statement”) for the purpose of soliciting proxies from the stockholders

of Onconetix for the matters to be acted on at the special meeting of the stockholders of Onconetix.

Onconetix also agreed to prepare

a registration statement on Form S-1 or Form S-4 in connection with the registration under the Securities Act of 1933, as amended (the

“Securities Act”), of the issuance of Onconetix Securities to be issued under the Share Exchange Agreement.

Sellers, Onconetix and Proteomedix

agreed to, at the election of Onconetix (which election it has determined not to exercise) or upon the request of CFIUS, submit to CFIUS

a joint declaration or notice with respect to the PMX Transaction as promptly as practicable, but in no event later than sixty (60) days

after the date of the Share Exchange Agreement.

The parties, in cooperation with each other, agreed to use reasonable best efforts to

take all such actions within their respective powers to obtain the approval of CFIUS (“CFIUS Approval”), and, without limiting

the foregoing, the parties agreed to, after reasonable negotiation efforts, agree to such requirements or conditions to mitigate any national

security concerns as may be requested or required by CFIUS in connection with, or as a condition of, CFIUS Approval, including entering

into a mitigation agreement, letter of assurance, or national security agreement, but provided:

(1) the parties shall have no obligation

to (A) propose, negotiate, commit to or effect, by consent decree, hold separate order, agreement or otherwise, the sale, transfer, license,

divestiture or other disposition of, any of the businesses, product lines or assets of Onconetix or any of its affiliates or of the Sellers,

(B) terminate existing, or create new, relationships, contractual rights or obligations of Onconetix or its affiliates, (C) effect any

other change or restructuring of Onconetix or its affiliates, or (D) otherwise take or commit to take any actions reasonably expected

to have a material adverse effect on the operation of the business of the Sellers or that interfere with Onconetix’s ability to

control Proteomedix or Onconetix’s ability to direct the management and policies of the business of Proteomedix in any material

and (2) Proteomedix and the Sellers agreed not take or agree to take any of the foregoing actions without the prior written consent

of Onconetix.

The parties agreed

to use commercially reasonable best efforts to (i) ensure that the application for Onconetix’s change of control (“Nasdaq

Change of Control Application”) is filed with The Nasdaq Stock Market LLC (“Nasdaq”) and (ii) to respond to any questions

from Nasdaq with respect to the Nasdaq Change of Control Application promptly following receipt of such questions, but in no event later

than ten (10) business days following receipt of such questions.

During the time between

the Share Exchange Closing and the Conversion, Onconetix also agreed, and agreed to cause its Subsidiaries, to conduct their

respective businesses in the ordinary course of business in all material respects and agreed to covenants regarding operation of

their respective businesses, including covenants related to (i) amendments to Onconetix’s organizational documents;

recapitalization of Onconetix’s equity interests;

(iii) issuance of additional securities;

(iv) incurrence of additional

indebtedness;

(v) material changes to tax elections;

(vi) amendments or termination of material contracts;

(vii) records and books;

(viii) establishment of any Subsidiary or entry into a new line of business;

(ix) maintenance of insurance policies;

(x) revaluation

of material assets or material changes in accounting methods, principles or policies except to the extent to comply with U.S.

(xi) waiver or settlement of any claim, action or proceeding, other than waivers not in excess of $500,000;

(xii) acquisition of

equity interests or assets, or any other form of business combination, outside of the ordinary course of business;

(xiii) capital

expenditures in excess of $500,000 individually or $1,000,000 in the aggregate;

(xiv) adoption of a plan of liquidation,

dissolution, merger, consolidation, restructuring, recapitalization or other reorganization;

(xv) voluntary incurrence of

any liability or obligation in excess of $500,000 individually or $1,000,000 in the aggregate other than pursuant to the terms of a

Contract in existence as of the date of the Share Exchange Agreement or entered into in the ordinary course of business, except in

connection with a Permitted Financing (as defined below);

(xvi) sale, lease, license or other disposition of any material

portion of Onconetix properties, assets or rights;

(xvii) entry into any agreement, understanding or arrangement with

respect to the voting of Common Stock, except in connection with a Permitted Financing;

(xviii) taking any action that

would reasonably be expected to significantly delay or impair the obtaining of any Consents of any Governmental Authority to be

obtained in connection with the Share Exchange Agreement;

or (xix) authorizing or agreeing to do any of the foregoing actions.

Financing” means one or more debt or equity financing transactions consummated by and funded into Onconetix during the time

between the Share Exchange Closing and the Conversion resulting in aggregate gross proceeds of no greater than $25 million.

Governing Law

The Share Exchange Agreement

is governed by the laws of the State of Delaware.

Terms of the Series B Preferred

Stockholder Approval, each share of Series B Preferred Stock shall automatically convert into 100 shares of Common Stock in accordance

with the terms of the Certificate of Designation, Preferences and Rights of Series B Preferred Stock (the “Series B Certificate

of Designation”) (the “Conversion”).

If Stockholder Approval is not obtained by January 1, 2025, Onconetix shall

be obligated to cash settle the Series B Preferred Stock, as described below.

The terms of the Series B Preferred Stock, as described

in the Series B Certificate of Designation, are as follows:

shares of Series B Preferred Stock carry no voting rights except:

(i) with respect to the election of the Proteomedix Director

(as described below) and (ii) that the affirmative vote of the holders of a majority of the outstanding shares of Series

B Preferred Stock (the “Majority Holders”), acting as a single class, shall be necessary to (A) alter or change

adversely the powers, preferences or rights given to the Series B Preferred Stock, (B) alter or amend the Series B Certificate

of Designation, or amend or repeal any provision of, or add any provision to, Onconetix’s Amended and Restated Certificate of Incorporation

or bylaws, if such action would adversely alter or change the preferences, rights, privileges or powers of, or restrictions provided for

the benefit of the Series B Preferred Stock, (C) issue further shares of Series B Preferred Stock or increase or decrease (other

than by conversion) the number of authorized shares of Series B Preferred Stock, or (D) authorize or create any class or series of

stock, or issue shares of any class or series of stock, that has powers, preferences or rights senior to the Series B Preferred Stock

The Majority Holders, voting exclusively and as a separate class, shall be entitled to elect one

(1) director of Onconetix.

Any director elected as provided in the preceding sentence may be removed without cause by, and only by,

the affirmative vote of the holders of the Series B Preferred Stock.

If the holders of Series B Preferred Stock fail to elect a director,

then any directorship not so filled shall remain vacant until such time as the holders of the Series B Preferred Stock elect a person

to fill such directorship;

and no such directorship may be filled by stockholders of Onconetix other than by the holders of Series B Preferred

At any meeting held for the purpose of electing a director, the presence in person or by proxy of the holders of a majority of

the outstanding shares of Series B Preferred Stock shall constitute a quorum for the purpose of electing such director.

On February 6,

2024, the Majority Holders appointed Thomas Meier, PhD, to the Board.

of Series B Preferred Stock are not redeemable by Onconetix.

Upon a liquidation, dissolution or winding-up of Onconetix, whether voluntary or involuntary

(a “Liquidation”), the holders of Series B Preferred Stock shall be entitled to receive out of the assets, whether capital

or surplus, of Onconetix the same amount that a holder of Common Stock would receive if such Holder’s Series B Preferred Stock were

fully converted to Common Stock at the Conversion Ratio (as defined below) plus an additional amount equal to any dividends declared but

unpaid to such shares, which amounts shall be paid pari passu with all holders of Common Stock.

holders of the Series B Preferred Stock shall be entitled to receive, dividends on shares of Series B Preferred Stock (on an as-if-converted-to-common-stock basis)

equal to and in the same form, and in the same manner, as dividends (other than dividends on shares of the Common Stock payable in the

form of Common Stock) actually paid on shares of the Common Stock when, as and if such dividends (other than dividends payable in the

form of Common Stock) are paid on shares of the Common Stock.

Stockholder Approval, each share of Series B Preferred Stock shall be converted into shares of Common Stock (the “Conversion Shares”)

at a ratio of 100 Conversion Shares for each share of Series B Preferred Stock (the “Conversion Ratio”).

All shares of Series

B Preferred Stock shall automatically and without any further action required be converted into Conversion Shares at the Conversion Ratio

upon the latest date on which (i) Onconetix has received the Stockholder Approval with respect to the issuance of all of the shares

of Common Stock issuable upon Conversion in excess of 20% of the issued and outstanding Common Stock on the Share Exchange Closing Date

and (ii) Onconetix has effected an increase in the number of shares of Common Stock authorized under its Amended and Restated Certificate

of Incorporation, to the extent required to consummate the PMX Transaction.

Cash Settlement .

at any time after the earlier of the date of the Stockholder Approval or January 1, 2025 (the earliest such date, the “Cash Settlement

Date”), Onconetix (x) has obtained the Stockholder Approval but fails to or has failed to deliver to a holder certificate or certificates

representing the Conversion Shares, or deliver documentation of book entry form of (or cause its transfer agent to electronically deliver

such evidence) Conversion Shares on or prior to the fifth business day after the date of the Stockholder Approval, or (y) has failed to

obtain the Stockholder Approval, Onconetix shall, in either case, at the request of the holder setting forth such holder’s request

to cash settle a number of shares of Series B Preferred Stock, pay to such holder an amount in cash equal to (i) the Fair Value (as defined

below) of the shares of Series B Preferred Stock set forth in such request multiplied by (ii) the Conversion Ratio in effect on the trading

day on which the request is delivered to Onconetix, with such payment to be made within two (2) business days from the date of the request

by the holder, whereupon, after payment in full thereon by Onconetix, Onconetix’s obligations to deliver such shares underlying

the request shall be extinguished.

“Fair Value” of shares shall be fixed with reference to the last reported closing stock

price on the principal trading market of the Common Stock on which the Common Stock is listed as of the trading day on which the request

is delivered to Onconetix.

Certain Adjustments .

If Onconetix, at any time while the Series B Preferred Stock is outstanding:

(A) pays a stock dividend or otherwise makes a distribution

or distributions payable in shares of Common Stock;

(B) subdivides outstanding shares of Common Stock into a larger number of shares;

or (C) combines (including by way of a reverse stock split) outstanding shares of Common Stock into a smaller number of shares, then the

Conversion Ratio shall be multiplied by a fraction of which the numerator shall be the number of shares of Common Stock outstanding immediately

after such event and of which the denominator shall be the number of shares of Common Stock outstanding immediately before such event

(excluding any treasury shares of the Corporation).

If, at any time while the Series B Preferred Stock is outstanding, either (A) Onconetix

effects any merger or consolidation of Onconetix with or into another person or any stock sale to, or other business combination with

or into another person (other than such a transaction in which Onconetix is the surviving or continuing entity and holds at least a majority

of the Common Stock after giving effect to the transaction and its Common Stock is not exchanged for or converted into other securities,

cash or property), (B) Onconetix effects any sale, lease, transfer or exclusive license of all or substantially all of its assets in one

transaction or a series of related transactions, (C) any tender offer or exchange offer (whether by Onconetix or another person) is completed

pursuant to which more than 50% of the Common Stock not held by Onconetix or such person is exchanged for or converted into other securities,

cash or property, or (D) Onconetix effects any reclassification of the Common Stock or any compulsory share exchange pursuant to which

the Common Stock is effectively converted into or exchanged for other securities, cash or property (in any such case, a “Fundamental

PMX Transaction”), then, in connection with any such transaction in (A) through (D), the holders of Series B Preferred Stock shall

receive in such transaction, the same kind and amount of securities, cash or property that a holder of Common Stock would receive if such

holder’s Series B Preferred Stock were fully converted to Common Stock, plus an additional amount equal to any dividends declared

but unpaid to such shares, which amounts shall be paid pari passu with all holders of Common Stock in the Fundamental PMX Transaction

(the “Alternate Consideration”).

If holders of Common Stock are given any choice as to the securities, cash or property to

be received in a transaction in (A) through (D), then the holders of Series B Preferred Stock shall be given the same choice as to the

Alternate Consideration it receives in such transaction.

Lock-Up Agreement

Simultaneously

with the execution of the Share Exchange Agreement, the Sellers and the Advisor Parties, as shareholders of Proteomedix, entered into

Lock-Up Agreements (each, a “Lock-Up Agreement”).

Pursuant to each Lock-Up Agreement, each signatory thereto will agree not

to, during the period commencing from the Share Exchange Closing Date and ending on the 6-month anniversary of the date of Stockholder

(i) lend, offer, pledge, hypothecate, encumber, donate, assign, sell, contract to sell, sell any option or contract to

purchase, purchase any option or contract to sell, grant any option, right or warrant to purchase, or otherwise transfer or dispose of,

directly or indirectly, the Exchange Shares or the Conversion Shares, (ii) enter into any swap or other arrangement that transfers

to another, in whole or in part, any of the economic consequences of ownership of the Exchange Shares or the Conversion Shares, or (iii) publicly

disclose the intention to do any of the foregoing, whether any such transaction described in clauses (i), (ii) or (iii) above is to be

settled by delivery of the Exchange Shares or the Conversion Shares or other securities, in cash or otherwise (subject to certain exceptions).

Non-Competition and Non-Solicitation Agreement

Simultaneously

with the execution of the Share Exchange Agreement, certain executive officers (each, a “Management Shareholder”) of Proteomedix

each entered into a non-competition and non-solicitation agreement (collectively, the “Non-Competition and Non-Solicitation Agreements”)

with Onconetix.

Under the Non-Competition and Non-Solicitation Agreements, each Management Shareholder agreed not to compete with Proteomedix,

and after the Share Exchange Closing, Onconetix, and their respective affiliates during the three-year period following the Share Exchange

Closing and, during such three-year restricted period, not to solicit employees or customers of such entities.

Each Non-Competition and

Non-Solicitation Agreement also contains customary confidentiality and non-disparagement provisions.

Stockholder Support Agreement

Simultaneously

with the execution of the Share Exchange Agreement, Onconetix, Proteomedix and certain directors of Onconetix who are stockholders of

Onconetix, entered into a Stockholder Support Agreement (the “Stockholder Support Agreement”), pursuant to which, among other

things, each such stockholder of Onconetix has agreed (a) to support the adoption of the Share Exchange Agreement and the approval of

the PMX Transaction, subject to certain customary conditions, and (b) not to transfer any of their subject shares (or enter into any arrangement

with respect thereto), subject to certain customary conditions.

Stockholder Subscription

Agreement and Debenture

In connection with the PMX

Transaction, on December 18, 2023, Onconetix entered into a Subscription Agreement (the “Subscription Agreement”) with the

PMX Investor for a private placement of $5.0 million of units (the “Units”), each Unit comprised of (i) one share of Common

Stock and (ii) one pre-funded warrant (collectively, the “Warrants”) to purchase 0.3 shares of Common Stock at an exercise

price of $0.001 per share, for an aggregate purchase price per Unit of $0.25 (the “Purchase Price”).

Additional shares are

issuable to the PMX Investor to the extent the PMX Investor continues to hold Common Stock included in the Units and if the VWAP during

the 270 days following the Share Exchange Closing is less than the Purchase Price, as set forth in the Subscription Agreement.

The offering contemplated

by the Subscription Agreement is expected to close following Stockholder Approval.

Within 30 days after closing of the offering, Onconetix

will file a resale registration statement with the SEC registering the resale of the Common Stock issuable pursuant to the Subscription

Agreement and the Warrants.

January 23, 2024, the Company issued a non-convertible debenture (the “Debenture”) to the PMX Investor in the principal sum

of $5.0 million, the payment of which shall offset the $5 million subscription amount for the Units pursuant to the Subscription Agreement.

Debenture has an interest rate of 4.0% per annum, and the principal and accrued interest are repayable in full upon the earlier of (i)

the closing under the Subscription Agreement and (ii) June 30, 2024.

Additionally, the $5.0 million subscription amount under the Subscription

Agreement shall be increased by the amount of interest payable under the Debenture.

As of April 5, 2024, a total of $5 million of principal

was outstanding under the Debenture.

On April 19, 2023, the

Company entered into an asset purchase agreement with Veru Inc., a Wisconsin corporation (“Veru”) (the “Veru APA”).

Pursuant to, and subject to the terms and conditions of, the Veru APA, the Company purchased substantially all of the assets related to

Veru’s ENTADFI business.

The transaction closed on April 19, 2023.

The Company purchased substantially

all of Veru’s assets, rights and property related to ENTADFI for a total possible consideration of $100.0 million (as described

The acquisition of ENTADFI capitalizes on the demonstrable success of the FDA-approved drug ENTADFI for treating benign prostatic

hyperplasia and counteracting negative sexual side effects seen in men on alternative BPH therapies.

to the terms of the Veru APA, the Company agreed to provide Veru with initial consideration totaling $20.0 million, consisting of (i)

$6.0 million paid upon the closing of the transaction, (ii) an additional $4.0 million in the form of a non-interest bearing note payable

due on September 30, 2023, and (iii) an additional $10.0 million in the form of two equal (i.e.

each for $5.0 million) non-interest bearing

notes payable, each due on April 19, 2024 and September 30, 2024.

The Company does not currently have cash to pay the notes due on April

19, 2024 and September 30, 2024 and is exploring options to restructure such notes with Veru.

On September 29, 2023, the Company

entered into an amendment (the “Veru Amendment”) of the Veru APA.

Pursuant to the Veru Amendment, the $4.0 million note payable

originally due on September 30, 2023 was deemed paid and fully satisfied upon (1) the payment to Veru of $1 million in immediately available

funds on September 29, 2023, and (2) the issuance to Veru by October 3, 2023 of 3,000 shares of Series A Preferred Stock of the Company.

The terms of the Series A

Preferred Stock are set forth in the Certificate of Designations, which was filed with the State of Delaware on September 29, 2023.

to the Certificate of Designations, each share of Series A Preferred Stock will convert one year from the date of issuance of the Series

A Preferred Stock into that number of shares of the Company’s common stock determined by dividing the Stated Value (as defined in

the Certificate of Designations) of $1,000 per share by the Conversion Price (as defined in the Certificate of Designations) of $0.5254

per share, subject to adjustment as provided in the Certificate of Designations, subject to certain stockholder approval limitations.

The Series A Preferred Stock is entitled to share ratably in any dividends paid on the Company’s common stock (on an as-if-converted-to-common-stock

basis), has no voting rights except as to certain significant matters specified in the Certificate of Designations, and has a liquidation

preference equal to the Stated Value of $1,000 per share plus any accrued but unpaid dividends thereon.

The Series A Preferred Stock is

redeemable in whole or in part at the Company’s option at any time.

The Certificate of Designations authorized the issuance of up

to 10,000 shares of Series A Preferred Stock.

The Series A Preferred Stock

issued to Seller is initially convertible, in the aggregate, into approximately 5,709,935 shares of the Company’s common stock,

subject to adjustment and certain stockholder approval limitations specified in the Certificate of Designations.

The Company is still

in the process of obtaining such shareholder approval.

If the Company does not obtain such stockholder approval, it will not be able to

issue Common Stock in excess of the stockholder approval limitations specified in the Certificate of Designations.

The Company also agreed

to include the shares of common stock issuable upon conversion of the Series A Preferred Stock in the next resale registration statement

filed with the SEC.

Additionally, the terms of

the Veru APA require the Company to pay Veru up to an additional $80.0 million based on the Company’s net sales from the ENTADFI business

after closing.

The Milestone Payments are payable as follows:

(i) $10.0 million is payable if the Company’s annual net sales

from the ENTADFI business equal or exceed $100.0 million, (ii) $20.0 million is payable if the Company’s annual net sales

from the ENTADFI business equal or exceed $200.0 million, and (3) $50.0 million is payable if annual net sales from the ENTADFI business

equal or exceed $500.0 million.

No more than one Milestone Payment shall be made for the achievement of each net sales milestone.

can be no assurance that the net sales milestones for payment of any of the Milestone Payments will be reached.

Furthermore, in connection

with the transaction, the Company assumed royalty and milestone obligations under an asset purchase agreement for tadalafil-finasteride

combination entered into by Veru and Camargo Pharmaceutical Services, LLC on December 11, 2017.

The Camargo Obligations assumed by the

Company include a 6% royalty on all sales of tadalafil-finasteride and sales milestone payments of up to $22.5 million as follows:

million is payable upon the first time the Company achieves net sales from ENTADFI of $100.0 million during a calendar year, (ii) $7.5

million is payable upon the first time the Company achieves net sales from ENTADFI of $200.0 million during a calendar year, and (3) $10.0

million is payable upon the first time the Company achieves net sales from ENTADFI of $300.0 million during a calendar year.

As noted above, the Company

has determined to temporarily pause its commercialization of ENTADFI, as it considers strategic alternatives.

The Company expects to appoint

a new Chief Executive Officer in the second quarter of 2024, after which the new CEO and the Board will reassess its ENTADFI program in

light of the foregoing and other relevant factors.

On June 13, 2023 (the “Execution

Date”), the Company entered into an asset purchase agreement with the WraSer Seller and Parent (the “WraSer APA”).

to, and subject to the terms and conditions of, the WraSer APA, on the WraSer Closing Date (as defined below) the Company will purchase

six FDA-approved pharmaceutical assets across several indications, including cardiology, otic infections, and pain management (the “WraSer

Under the terms of the WraSer

APA, the Company will purchase the WraSer Assets for (i) $3.5 million in cash at signing of the WraSer APA (the “Signing Cash”);

(ii) $4.5 million in cash on the later of (x) 90 days after the signing of the WraSer APA or (y) the date that all closing conditions

under the WraSer APA are met or otherwise waived (the “WraSer Closing Date”);

(iii) 1.0 million shares of the Company’s

common stock (the “Closing Shares”) issuable on the WraSer Closing Date, and (iv) $500,000 in cash one year from the WraSer

Closing Date.

The closing of the transaction is subject to certain customary closing conditions and the delivery to the Company of financial

statements of WraSer Seller and Parent for the fiscal years ended December 31, 2022 and 2021 audited by a qualified auditor reasonably

acceptable to the Company.

Within 90 days of the WraSer

Closing Date, the Company will use its best efforts to file with the SEC, (at its sole cost and expense,) a registration statement to

register on Form S-3 registering under the Securities Act, the resale of the Closing Shares and will use its best efforts to have the

registration statement declared effective as soon as practicable after filing.

In conjunction with the WraSer

APA, the Company and the WraSer Seller entered into a Management Services Agreement (the “MSA”) on the Execution Date.

to the terms of the MSA, the Company was to act as the manager of the WraSer Seller’s business during the period between the Execution

Date and WraSer Closing Date.

During this period, the Company was to make advances to WraSer, if needed to sustain operations.

The Company’s

involvement as manager of the WraSer Seller’s business ended when WraSer filed for relief under chapter 11 of the U.S.

Code in the Bankruptcy Court (see below).

If, on the WraSer Closing Date, the WraSer Seller’s cash balance is in excess of the target

amount specified in the MSA of $1.1 million (the “Cash Target”), the Company was to apply that excess to the $4.5 million

cash payment due upon closing.

Conversely, if there is a shortfall, the Company would have been required to remit the difference to the

WraSer Seller over time.

Specifically, as the Company would have collected accounts receivable generated after the WraSer Closing Date,

the Company would have been required to remit 50% of the collections to the WraSer Seller until the shortfall is paid in full.

terminates on the WraSer Closing Date.

The WraSer APA can be terminated

prior to closing as follows (i) upon agreement with all parties;

(ii) upon breach of contract of either party, uncured within 20 days

If the WraSer APA is terminated upon agreement with all parties or upon uncured breach of contract by the WraSer Seller, the

initial $3.5 million payment is retained by the WraSer Seller.

If it is determined that there is an uncured breach of contract by the

WraSer Seller, and the WraSer APA is terminated, the Company will have an unsecured claim against WraSer for the $3.5 million payment

made by the Company upon execution of the WraSer APA.

The closing of the transaction was subject to various closing conditions, including

submission of the FDA transfer documentation to transfer ownership of the acquired product regulatory approvals to the Company.

On September 26, 2023, WraSer

and its affiliates filed for relief under chapter 11 of the U.S.

Bankruptcy Code in the Bankruptcy Court.

On October 4, 2023, the parties

agreed to amend the WraSer APA, subject to court approval.

Shortly after its bankruptcy filing, WraSer filed a motion seeking approval

of the WraSer APA as amended.

The amendment, among other things, eliminates the $500,000 post-closing payment due June 13, 2024 and staggers

the $4.5 million cash payment that the Company would otherwise have to pay at closing to:

(i) $2.2 million to be paid at closing, (ii)

$2.3 million, to be paid in monthly installments of $150,000 commencing January 2024 (the “Post-Closing Payment”) and (iii)

789 shares of Series A Preferred Stock to be paid at closing.

The amendment also reduced the number of products we were acquiring by excluding

pain medications and including only (i) Ciprofloxacin 0.3% and Fluocinolone 0.025% Otic Solution, under the trademark OTOVEL and its Authorized

Generic Version approved under US FDA NDA No.

208251, (ii) Ciprofloxacin 0.2% Otic solution, under the trademark CETRAXAL, and (iii) Vorapaxar

Sulfate tablets under the trademark Zontivity approved under US FDA NDA N204886.

In October 2023, WraSer alerted

us that its sole manufacturer for the active pharmaceutical ingredient (“API”) for Zontivity, the key driver for the WraSer

acquisition, would no longer manufacture the API for Zontivity.

We believe that this development constituted a Material Adverse Effect

under the APA enabling us to terminate the APA and MSA.

On October 20, 2023, we filed a motion for relief from the automatic stay in the

Bankruptcy Court to exercise our termination rights under the WraSer APA, as amended.

On December 18, 2023, the Bankruptcy Court entered

an Agreed Order lifting the automatic stay to enable us to exercise our rights to terminate the APA and the MSA without prejudice to the

parties’ respective rights, remedies, claims, and defenses they had against one another under the APA and MSA.

On December 21, 2023,

we filed a Notice with the Bankruptcy Court terminating the APA and MSA.

WraSer has advised us that it does not believe that a Material

Adverse Event occurred.

Due to the WraSer bankruptcy filing and our status as an unsecured creditor of WraSer, it is also unlikely that

we will recover the $3.5 million Signing Cash or any costs and resources in connection with services provided by the Company under the

Business of the Company

Business Model

Proteomedix develops novel

diagnostic tests in a highly regulated field.

Proteomedix’s core competencies include the development of high-quality immunoassays

and management of regulatory affairs.

Our expertise in immunoassay development is the result of a highly specialized workforce that, together

with an external software development company, developed the proprietary software integrated in the company’s lead IVD product,

Our personnel also have extensive experience in implementing and maintaining a state-of-the-art quality management system to

comply with regulatory requirements, including performing clinical studies and managing key opinion leaders (“KOLs”).

experience and expertise in these fields was obtained by hiring experienced personnel as well as through key advisors.

Proteomedix is initially

focusing on seeking to license its intellectual property to third party laboratories.

Sales will be through a specialized distributor

and/or laboratory partner, but Proteomedix will still provide technical customer support to laboratories that offer the testing service

to physicians.

Proteomedix does not have production capabilities built up in-house, and instead outsources manufacturing to a CMO in Germany.

All of the key reagents used in Proteomedix’s IVD kits (i.e., antigens and antibodies) are proprietary and owned exclusively by

Proteomedix, which uses an independent supplier in Germany to produce these reagents and supply them to its CMO.

is an FDA-approved, once daily pill that combines finasteride and tadalafil for the treatment of BPH.

To the extent that we resume

the commercialization of ENTADFI, Onconetix will initially focus on commercializing ENTADFI

through a telemedicine channel.

In July 2023, the Company signed an agreement with UpScriptHealth to generate a robust, online telemedicine

platform to distribute ENTADFI .

Through this platform, UpScriptHealth will support patients

with BPH throughout prescription and coverage process, as well as provide eligible patients access to ENTADFI

mailed directly to their homes.

Additionally, to meet the demands of the supply chain, manufacturing is outsourced to contract manufacturing

organizations (“CMOs”) in the U.S.

The product will be distributed exclusively by Cardinal Health 105, LLC, an Ohio limited

liability company (“Cardinal Health”) as third-party logistics distribution agent for sales of ENTADFI and any other products the parties mutually agree to.

As noted above, the Company has determined to temporarily pause its

commercialization of ENTADFI, as it considers strategic alternatives.

The Company expects to appoint a new Chief Executive Officer in

the second quarter of 2024, after which the new CEO and the Board will reassess its ENTADFI program in light of the foregoing and other

relevant factors.

Proteomedix is seeking to

develop diagnostic, prognostic and predictive tools to enable more efficient cancer management at all stages of disease progression.

Proteomedix’s

tests use proprietary protein biomarkers to address the limitations in current cancer detection, prognosis, and therapy prediction.

addition, Decision Support Systems support the clinical decision-making by integrating different inputs in a risk score (see Figure 1).

Product Pipeline

Proclarix is used to indicate

the risk of clinically significant prostate cancer through a risk score derived from a clinical decision support system (Figure 2).

the reagent side it is comprised of two quantitative Enzyme-linked Immunosorbent Assays (“ELISA”) that measure the concentration

of thrombospondin 1 (“THBS1”) and cathepsin D (“CTSD”) in human serum.

The clinical decision support system is

a web-based software running a proprietary algorithm that integrates the values for THBS1 and CTSD, the patient’s age and total

and free PSA levels from third party providers (e.g., Roche Diagnostics, Siemens Healthineers) to calculate a risk score.

Assays and software

algorithm for risk score calculation.

Proclarix is used as an aid in prostate cancer diagnosis as a second-line

test after PSA and DRE testing.

It enables a personalized decision for each patient based on objective risk parameters (4 serum glycoproteins

+ age) to triage between biopsy or a monitoring approach.

Proclarix has been validated and approved for use in men with elevated total

PSA (2.0 to 10.0 ng/mL), a normal DRE not suspicious for cancer and an elevated prostate volume (≥35 mL) (Figure 3).

The Proclarix

decision support tool returns a risk score that can be used as an aid in discriminating between clinically significant (grade group 2

or higher [GG2+]) and insignificant prostate cancer or benign prostate disease.

The risk score of Proclarix gives the physician and patient

actionable information to confidently make decisions when considering the necessity of a prostate biopsy which is required for diagnosis

of prostate cancer.

Finding clinically significant prostate

cancer in the diagnostic “grey zone.”

Clinical Studies

Proteomedix’s biomarkers

have been tested in clinical studies including a total of more than 2,000 patient samples from multiple clinical sites, and results have

been published in peer-reviewed journals.

We believe these results demonstrate that Proclarix is a valuable test identifying clinically

significant prostate cancer thereby facilitating informed decision making for patients considering a prostate biopsy.

Validation Study .

study leading to the granting of regulatory approval in Europe included 955 samples collected at two clinical sites, a screening center

in Innsbruck, Austria, as well as a referral center in Hamburg, Germany.

The results of this study demonstrated that by using the Proclarix

test the burden of unneeded biopsies could have been lowered by approximately 43% — twice as much compared to clinical comparators

percent free PSA (“%fPSA”) or PSA density.

High sensitivity of 90% and a negative predictive value of 95% for clinically significant

prostate cancer indicated that the diagnosis of very few cancers would have been delayed.

PROPOSe Study.

PROPOSe study evaluated the accuracy of Proclarix in prostate biopsy decision making.

Ten clinical sites in Germany, Denmark and Austria

prospectively enrolled 457 men presenting for prostate biopsy.

Proclarix detected clinically significant cancer with high sensitivity

above 90% and reliably ruled out patients with no or indolent cancer with a negative predictive value greater than 90%.

When the biopsy

performed was guided by magnetic resonance imaging (“MRI”), both sensitivity (97%) and negative predictive value (96%) were

Importantly, Proclarix was significantly superior to the current clinical standard, %fPSA, in ruling out unneeded biopsies

14%) and the primary study endpoint was met (p-value < 0.005).

Naples Study.

study evaluated Proclarix and the Prostate Health Index (phi) test from Beckman Coulter, Inc.

for predicting clinically significant prostate

cancer in a total of 344 men.

Both Proclarix and the phi test accurately predicted clinically significant cancer.

When using predefined

cut-offs recommended by the manufacturers, Proclarix (cut-off 10) outperformed phi (cut-off 27) in terms of specificity and positive predictive

value (p < 0.002) at similar sensitivities.

Clinical evaluation of

Results of multiple clinical evaluations using Proclarix together with MRI for prostate cancer diagnosis showed that Proclarix

can be used in a broad range of patients without the need for prostate volume restriction.

The aim of one such evaluation was the assessment

of the diagnostic performance of Proclarix in combination with MRI.

Blood samples from 721 men undergoing MRI followed by biopsy at two

clinical centers were analyzed.

The combined Proclarix-MRI score’s specificity (68%) was significantly (p<0.001) better compared

to Proclarix (27%) or MRI (28%) alone for diagnosing clinically significant prostate cancer.

Importantly, Proclarix by itself was found

to be useful in men with indetermined imaging results by outperforming PSA density in terms of specificity (25% vs 13%, p=0.004) at 100%

In another evaluation of a study of 517 men with suspected prostate cancer, Proclarix performed well in accurately diagnosing

prostate cancer in the overall study population and in a subset of men with elevated PSA 2 to 10 ng/mL, prostate volume ≥35 mL, and

normal DRE (n=281).

In addition, a sub-analysis of was performed specifically analyzing 169 men with an indeterminate MRI result and Proclarix

was more accurate in selecting appropriate candidates for prostate biopsy when compared to PSA density and online risk calculators.

third evaluation describes which patients with suspected prostate cancer can benefit from Proclarix after MRI and concluded that Proclarix

outperformed PSA density in the selection of candidates for prostate biopsy, especially in men with PI-RADS 1-3.

In these studies, Proclarix

proved to be effective before, after, and together with MRI assessment to identify men at risk of clinically significant prostate cancer

and those who can safely avoid biopsy.

Proclarix in combination with MRI reliably predicted clinically significant prostate cancer and

ruled out men with no or indolent cancer.

Clinical Guidelines

Guidelines assist clinicians

in making informed treatment decisions, taking into account the available scientific data.

To reduce the number of negative biopsies in

asymptomatic men with a PSA level between 3–10 ng/mL and a normal DRE, the EAU guidelines recommend using an online risk-calculator

that is correctly calibrated to the population prevalence, MRI of the prostate or an additional biomarker test such as Proclarix.

EAU guidelines specifically state that Proclarix has been correlated with the detection of significant prostate cancer, notably in case

of equivocal MRI results.

Proclarix was also included

in the 2023 AUA/SUO clinical practice guideline.

The AUA/SUO guideline covers recommendations on the early detection of prostate cancer

and provides a framework to facilitate clinical decision-making in the implementation of prostate cancer screening, biopsy, and follow-up.

The AUA/SUO guideline concludes that the evaluation of prostate cancer risk should be focused on the detection of clinically significant

prostate cancer (GG2+).

The AUA/SUO guidelines advice that use of laboratory biomarkers such as Proclarix, prostate MRI, and biopsy techniques

may improve detection and safety when a prostate biopsy is deemed necessary following prostate cancer screening.

The inclusion of Proclarix

in the European and U.S.

guidelines is an important recognition of the clinical value of Proclarix.

It serves as a validation for the

clinical utility and importance of using Proclarix in the detection of prostate cancer and we believe it will lead to broader acceptance

of Proclarix and accelerate payor adoption.

Product Quality and Safety

Proteomedix’s quality

management system is ISO (International Organization for Standardization) 13485:2016 certified for the “Design and development,

production and distribution of in-vitro diagnostic reagents and stand-alone software for prostate cancer management”.

is annually audited by TÜV SÜD Product Service GmbH, an internationally recognized notified body headquartered in Germany.

certification is a prerequisite for obtaining CE-mark, the regulatory clearance requirement for market access, recognized by the European

Commission (“EC”) in the IVDR.

Under the IVDR, diagnostic products are categorized under a new system of one of four classifications

from class A (low risk) to class D (highest risk).

Proclarix, as class C device, was assessed by TÜV SÜD for conformity resulting

in IVDR certification.

The certification of Proclarix under the new IVDR demonstrates compliance to the highest quality standard currently

in force for tests used in screening, diagnosis, or staging of cancer.

Proteomedix is marketing Proclarix as one of the first IVDR compliant

cancer tests demonstrating the commitment to highest analytical and clinical performance.

Prosgard as a clinical support

system is designed to aggregate multimodal information in an effort to develop a patient centric diagnostic approach.

The vision for Prosgard

is to add more information to the existing Proclarix risk score in the future such as other biomarkers, clinical information, or MRI imaging

data to provide an even more powerful tool to guide the patient’s diagnostic journey.

Prognosis (Px)

A subset of Proteomedix’s

protein biomarkers also correlate with prostate cancer prognosis.

Radical prostatectomy provides excellent cancer control of clinically

localized prostate cancer.

However, approximately 30% of surgically treated men will experience cancer recurrence within 10 years of surgery.

Several clinical parameters and the combination thereof (e.g., the Cancer of the Prostate Risk Assessment (“CAPRA”) score)

have been shown to be reliable predictors of treatment failure.

Still, there is a compelling need to identify novel markers that are specifically

linked to the presence of biologically aggressive prostate cancer for improved prediction of outcome in populations with moderately elevated

A novel serum biomarker quintet that improves disease prognosis

in men with confirmed prostate cancer

A clinical evaluation of a

multivariable model comprising fibronectin 1, galectin-3-binding protein, lumican, matrix metalloprotease 9, thrombospondin-1 and PSA

together with clinical Grade Group (GG) and clinical stage (cT) was performed.

The prognostic utility of the proposed marker

combination was assessed in serum samples from 557 men with confirmed localized prostate cancer.

The analysis showed that the proposed

model had a better prediction for disease progression and thus prostate cancer aggressiveness compared to the “CAPRA” score.

This novel biomarker test has the potential to improve prostate cancer patient management by indicating who needs active treatment.

contrast to the existing biomarker tests from competitors that all need tissue specimens, the test is non-invasive and can be directly

measured in patients’ blood samples.

Prediction (Rx)

Proteomedix’s protein

biomarkers further have the potential to predict the response of patients treated with drugs that inhibit the PI3K signaling pathway.

Proteomedix analyzed the blood of patients participating in a Phase II trial (SAKK 08/08).

The patients were treated with Novartis AG’s

Everolimus, a drug inhibiting the PI3K pathway signaling by blocking mTOR.

A subset of 8 serum biomarkers could individually predict reaching

the primary endpoint (progression free survival at 12 weeks) with an accuracy of at least 75%.

Decision Support Systems

Recent initiatives are incorporating

as well as interpreting clinical information from various sources (e.g., biomarker information and other patient data) enabling physicians

to have more comprehensive biochemical insight into each patient’s disease in order to determine the optimal treatment plan for

Collating multiple data sources in clinical workflows allows precision-medicine resulting in cost-effective diagnostics and

Proclarix already consists of a decision support system integrating different values in a risk score.

In the future, additional

clinical information like the results of an MRI scan could be integrated in the report to provide a complete picture of the diagnostic situation

of the patient to enable effective patient management.

is an FDA-approved, once daily pill that combines finasteride and tadalafil for the treatment of BPH.

BPH, a condition in men

in which the prostate gland is enlarged but not cancerous, is a common problem that affects the quality of life in approximately

half of men over the age of 50 and 90% of men over the age of 85.

Men with BPH suffer from challenges with urination flow,

frequency, and urgency, and about 70% of men with BPH also experience sexual dysfunction.

In 2022, there was approximately 44

million total prescriptions and 20 million new prescriptions related to BPH symptoms.

is an oral, once daily treatment for BPH that combines finasteride, a 5α- reductase inhibitor, and tadalafil, a

phosphodiesterase 5 (“PDE5”) inhibitor, offering a more effective treatment option compared to other available

Clinical trials have shown that ENTADFI is more effective in treating BPH

symptoms, including urinary frequency, urgency, weak stream, and difficulty initiating or maintaining urination, compared to

finasteride monotherapy.

Additionally, ENTADFI has demonstrated a favorable safety

profile, with fewer adverse sexual side effects compared to finasteride.

reduces potential adverse sexual side effects, making it preferred choice for men seeking relief from BPH symptoms without

compromising their sexual health.

ENTADFI has received FDA approval for the indication

of initiating treatment of the signs and symptoms of BPH in men with enlarged prostate for up to 26 weeks.

Commercialization Strategy

Proclarix is currently not

reimbursed in Europe, and therefore patients pay for Proclarix out of pocket.

We intend to pursue reimbursement from public and private

payors in key European markets to secure broad adoption in the longer term.

The market introduction of Proclarix has followed a two-phased

first a market preparation phase in which we reach out to key opinion leaders in selected European countries to solicit their

support for Proclarix, followed by a market development phase where we begin commercializing Proclarix in those markets with focused marketing

and sales activities to urologists and general practitioners.

We intend to secure access to testing through partnerships with reference

diagnostic labs.

We have initiated outreach to commercial laboratories and hospital laboratories that are routinely serving study sites

and academic collaboration partners, and have established pilots with laboratories in Switzerland, Germany, Italy, and the United Kingdom.

In the United States, Proteomedix

entered into an exclusive partnership with Labcorp in 2023 pursuant to which Labcorp has the exclusive right to develop and commercialize

Proclarix, and other products developed by Labcorp using Proteomedix’s intellectual property covered by the license, in the United

States for identification, screening, staging, predisposition, diagnosis, prognosis, monitoring, prevention or treatment selection with

respect to prostate cancer.

In consideration for granting Labcorp an exclusive license, Proteomedix received an upfront license fee and

is entitled to royalty and milestone payments based upon sales of licensed products or services in the United States.

Labcorp is wholly

responsible for the cost of research, development and commercialization of licensed products or services in the United States but has

the right to offset a portion of those costs against future royalty and milestone payments otherwise due to Proteomedix.

As noted above, the Company has determined to temporarily pause its

commercialization of ENTADFI, as it considers strategic alternatives.

The Company expects to appoint a new Chief Executive Officer in

the second quarter of 2024, after which the new CEO and the Board will reassess its ENTADFI program in light of the foregoing and other

relevant factors.

To the extent that we resume

the commercialization of ENTADFI, in order to provide ENTADFI to patients suffering from BPH, we have established relationships with key

vendors to distribute, commercialize, and market ENTADFI.

On the distribution side, we have partnered with Cardinal Health to serve as

our third-party logistics provider.

Under our agreement, Cardinal Health with serve as our exclusive distributor of ENTADFI, and we intend

to leverage its title model services, allowing us to utilize its state wholesale pharmacy license portfolio to ship ENTADFI to states

where we do not currently hold a license.

Utilizing Cardinal Health’s title model program will maximize access for ENTADFI across

while we pursue licenses for Onconetix.

In the commercialization

plan for ENTADFI, we have partnered with UpScriptHealth to generate an online telemedicine platform where patients with BPH can interact

with a healthcare provider, receive support through the prescription process, as well as provide eligible patients access to ENTADFI mailed

directly to their homes.

UpScriptHealth is a leading provider of telehealth services, has over 20 years of experience generating effective,

web-based campaigns for life science companies with a wide range of services, including virtual prescribing, coverage and benefit support,

as well as long-term adherence support.

In recent years, telehealth has become increasingly popular for both patients and providers and

represents a significant opportunity for the commercialization of ENTADFI.

Through telemedicine, we will be able to provide BPH patients

with access to ENTADFI without another trip to a doctor’s office or pharmacy, which can be incredibly burdensome for patients and

provide them with a time-saving option for receiving medication.

The current commercialization

strategy for ENTADFI centers around our telemedicine platform, and we believe this may be more cost effective versus more traditional

sales representative approaches that target physicians.

We plan to generate targeted marketing and advertising materials to support our

web platform, which will drive traffic to the site and maximize ENTADFI sales.

Under the current sales model, we will be offering ENTADFI

for cash-paying patients and do not currently plan on seeking reimbursement from insurance or Medicare and Medicaid channels.

may change in the future, we believe there is a significant market opportunity for patients to use the web portal to access ENTADFI and

receive medication by cash pay.

Sales, Distribution, Marketing and Advertising

In clinical diagnostics high

throughput assay parameters like PSA typically are performed on closed, fully integrated systems that use proprietary reagents.

systems are provided by a few mid-sized to large diagnostic companies (e.g., Roche Diagnostics, Abbott Laboratories, Siemens Healthineers

AG, DiaSorin S.p.A.) with a worldwide distribution network.

Reagents are provided in a closed-system approach, access is through collaboration

agreements only.

Business development discussions with multiple diagnostic companies have already started.

Lower volume parameters are

run on smaller, open systems that are used in laboratories for tests with lower throughput to complement the test menu.

Access to these

open systems presents an option for direct commercialization in selected markets during market introduction.

First, the goal is to establish

commercial proof of concept and drive initial market adoption.

Market adoption of a new test

is driven by KOLs and clinical urology centers.

Publication of clinical studies proving the medical benefit of the test and KOLs advocating

it at scientific conferences will trigger the usage by other physicians.

Additionally, demand is created through urology centers specialized

in prostate cancer that cover a large geographical area.

Their influence on other urologists and general practitioners in the region will

lead to multiplier effects.

Diagnostic testing in clinical urology centers is provided either by an in-house hospital laboratory or a

commercial laboratory where Proclarix will be implemented.

General practitioners recruit

patients for screening and decide whether to refer a patient to a specialist.

They have an important gatekeeper role and Proclarix is

a helpful tool for this triage.

Marketing outreach of commercial laboratory networks (e.g., Unilabs, Switzerland;

Sonic Healthcare, Australia;

Labcorp, U.S.A.) provides an opportunity to directly address the large number of general practitioners and urologists in private practices

through their specialized sales force.

Market Opportunity

Proclarix, the first diagnostic

product of Proteomedix, is addressing unmet medical needs related to prostate cancer, which is the second most frequently diagnosed cancer

in men, with an estimated 1.4 million new cases and more than 395,000 deaths worldwide in 2020, according to World Cancer Research Fund

International.

The PSA test represents the

current standard of care in prostate cancer diagnosis.

It accurately identifies individuals with no sign of disease.

Approximately 10%

of all men have elevated PSA levels, commonly referred to as the diagnostic “grey zone”, of which only 20-40% present clinically

Proclarix is intended for use in diagnosing these patients where it is difficult to decide if a biopsy is necessary to verify

a potential clinically significant cancer diagnosis.

The high unmet need for improved patient stratification or diagnostic triage in this

segment is addressed only by a few tests.

Compared to those tests Proclarix has important competitive advantages:

(i) it shows comparable

or often superior clinical performance, (ii) it is blood-based and therefore minimally invasive and (iii) it is highly reproducible in

comparison to e.g., urine-based tests.

The use of Proclarix does not require prior prostate massage.

Samples are stable and can be shipped

at ambient temperature.

Proclarix has a high accuracy and negative predictive value (NPV) and is easy to automate on equipment readily

available as well as adaptable to current laboratory practice and thus clinical routine.

The worldwide market for in

vitro diagnostic (“IVD”) products was valued at $117.8 billion in 2022.

Europe and North America are the largest markets,

followed by Asia, mainly Japan and China, according to MarketsandMarkets.

About two-thirds of prostate cancer diagnoses occur in countries ranking

very high in the Human Development Index, where only 18% of the world’s male population resides, according to the American Cancer

This underscores a significant market demand for improved diagnostic tools, especially in regions with robust healthcare infrastructure

where early detection and treatment are paramount.

Our innovative test aims to meet this demand by offering enhanced accuracy, accessibility,

and efficiency, positioning it as a valuable asset in the fight against prostate cancer while also presenting lucrative commercial opportunities

for stakeholders.

Currently, standard prostate

cancer screening combines a digital rectal exam (“DRE”) with the measurement of PSA.

PSA is not a highly cancer specific marker,

meaning it picks up many benign conditions of raised PSA levels in the blood—such as clinically not significant enlargement of the

prostate or inflammation.

The consequences are prostate cancer overdiagnosis, leading to unnecessary prostate biopsies.

It is currently

estimated that more than 60% of men that undergo a biopsy have no clinically significant prostate cancer, but due to the biopsy become

exposed to potential side effects such as infections, bleeding and incontinence.

The use of MRI for the diagnosis of prostate cancer has been rapidly

adopted during the last decade.

There is clinical evidence that MRI allows clinicians to verify diagnosis and improve localization, risk

stratification and staging of clinically significant prostate cancer over other methods.

MRI-guided biopsy has a higher accuracy than

ultrasound-guided biopsy.

However, MRI-based diagnosis of prostate cancer is hampered by the relatively high costs of US$415 – US$900

and limited availability.

Still, up to one-third of MRIs are inconclusive.

Thus, there is a clear need for an improved non-invasive diagnostic

test with higher specificity for clinically significant prostate cancer to aid in selecting patients undergoing MRI, MRI-guided biopsy,

Proper classification in clinically significant cancer and non-significant type or non-cancer conditions such as benign prostate

hyperplasia is important to prevent overtreatment and its associated side-effects and costs.

Proteomedix is developing diagnostic tools

for disease prognosis and monitoring that are essential for reliable, patient-friendly, and cost-effective disease management.

Proteomedix’s

biomarkers have shown the potential to distinguish between those prostate cancer patients who are more likely to respond to certain drug-based

interventions.

With this information, better choices for drug therapies can be made to maximize the likelihood of efficacious treatment.

Proteomedix’s biomarkers could also aid in clinical drug development.

BPH is a condition that affects

men, primarily those over 50 years old, and is caused by swelling in the prostate gland due to hormonal changes and cell growth during

the aging process.

It is estimated that about 50% of men between the ages of 51 and 60 have BPH, and that number increases to about 70%

among men 60-69 and around 80% of men over 70 years of age, according to Yale Medicine.

This translates to upwards of 55 million men in

the United States at risk or experiencing symptoms of BPH each year.

Men with BPH may suffer from a range of symptoms, including increased

urinary frequency, urgency, and an inability to completely empty the bladder.

While there are surgical interventions to treat BPH, many

men choose prescription medications to treat their symptoms and, with certain medications, decrease the size of the prostate.

Two medications commonly

used to treat BPH are tamsulosin, brand name Flomax ® , and finasteride, sold under the brand name Proscar ® .

According to ClinCalc.com, tamsulosin was the 24 th most commonly prescribed medication in 2020 and has increased in rank consistently

This resulted in over 24.6 million prescriptions and an average per prescription cost of $54.40, resulting in over $1.3 billion

Finasteride, ranked the 90 th most commonly prescribed medication in the U.S.

in 2020, has also seen consistent increases

in utilization since 2013.

Over 8 million finasteride prescriptions in 2020 resulted in over $162 million in sales based on an average

price per prescription of $19.83.

ENTADFI, which can treat

BPH without negative sexual side effects seen in some men on finasteride alone, represents a novel therapeutic treatment for patients.

There is a significant market opportunity for an additional therapeutic option in BPH, shown both by the prevalence in older men and by

the high, and increasing, number of BPH prescriptions written each year.

ENTADFI Competitive Analysis

Treatments for men with BPH and lower urinary tract symptoms (“LUTS”)

fall into five drug classes each with a different mechanism of action in alleviating symptoms:

(i) alpha blockers that target alpha receptors

to relax prostatic smooth muscle, (ii) 5-alpha reductase inhibitors (“5ARIs”) that block the enzyme 5-alpha reductase to decrease

cell growth, (iii) PDE5 inhibitors that decrease urethral smooth muscle tone, (iv) anticholinergics that block the action of acetylcholine

to relax the smooth muscle of the bladder and (v) beta-3 agonists that increase bladder capacity by relaxing smooth muscle.

Figure 4 below

lists the current AUA- and EUA-recommended therapies for BPH and BPH with LUTS, their mechanisms of action, and potential side effects.

Several of these medications are commercially available as generics.

Current AUA and EAU recommended therapies for BPH and

BPH with LUTS.

Should we decide to

resume commercialization of ENTADFI, Potential competitors with respect to ENTADFI in North America, Europe and elsewhere include

major pharmaceutical companies, specialty pharmaceutical companies and biotechnology firms, universities and other research

institutions and government agencies.

Many of our competitors have substantially greater research and development and regulatory

capabilities and experience, and substantially greater management, manufacturing, distribution, marketing and financial resources,

than we have.

We may be unable to compete successfully against current and future competitors, and competitive pressures could have

a negative effect on our net revenues and profit margins.

Zydus Life Sciences recently

received FDA approval for a combined finasteride-tadalafil (5 mg/5 mg) capsule, pursuant to the FDA’s Competitive Generic Therapy

Program, which was designed to enhance patient access to affordable medications by encouraging the development and commercialization of

generic drugs in clinical areas with limited generic options for patients.

Pursuant to the program, Zydus has a 180 day period to be the

sole supplier of the generic version of the drug in the market and during this period, other generic manufacturers cannot enter the market

with their versions of the same drug, provided that Zydus commences marketing the drug by 75 days from approval.

As a result, there is

a risk that the Company will face additional challenges in resuming commercializing ENTADFI, if it chooses to do so.

Other parties have developed

and marketed drugs for BPH that have been accepted by the healthcare provider, patient and payor communities.

Many of these other products

have also reached the point where they are now generic drugs, which means that they are sold at a very low price, a price which ENTADFI

may not be able to meet which could limit the reach of ENTADFI into the healthcare provider, patient and payor communities, including

government payors.

ENTADFI Competitive Advantages

Adherence to the prescribed

treatment regimen is an ongoing issue in BPH therapy.

Adherence rates are low for BPH treatments, as BPH medicines are typically taken

chronically and are often taken for up to 6 to 12 months prior to significant symptom relief.

Adherence rates are particularly low in patients taking multiple BPH treatments concurrently, with reported adherence rates as low as

2 Delayed symptom relief, adversely impacting quality

of life, is thought to be a major factor resulting in poor patient adherence to prescribed treatment schedules.

Importantly, discontinuation of treatment or non-adherence to a prescribed treatment protocol are independent risk factors for BPH related

hospitalization or surgery.

4 A recent study suggested that

first-time 5ARI patients with low adherence to their treatment schedule are 27% more likely to need BPH-related surgery.

A more effective, rapid acting therapy with a simple treatment regimen could significantly improve patient compliance, reduce the need

for medical or surgical intervention and improve the patient’s quality of life.

1 Casabé A et al.

191:727-733 2014.;

10.1007/s40136-017-0152-6.

Epub 2017 May 20.

PMC5446555.).

estimated $4.3 billion USD is spent on AOM treatment each year in the U.S.

(Tong S, BMC Health Serv Res.

2018 May 2;18(1):318.

10.1186/s12913-018-3139-1.

PMC5932897.).

The current standard of care treatment for AOM

in children is reliant on antibiotics.

The resolution rate of AOM in children is 81% without antibiotic treatment vs.

93% with antibiotic

Antibiotic treatment of AOM in children has limitations, including recurrence within 30 days.

Pneumococcal pneumonia, caused by colonization

pneumoniae in the lungs, primarily impacts elderly adults and, according to the CDC, results in approximately 150,000 hospitalizations

in the United States alone each year.

In addition to the disease burden, pneumococcal pneumonia accounts for approximately $1.3 billion

in direct medical costs annually plus costs associated with lost productivity (O’Brien K, Pneumococcus, Pneumococcal Disease and

Prevention, The Vaccine Book (Second Edition), Academic Press, 2016, Pages 225-243, ISBN 9780128021743).

While there are currently available

pneumococcal vaccines, outlined below, these vaccines provide limited levels of protection against pneumonia, as they are administered

intramuscularly and do not elicit strong mucosal immunity (Berild JD, 2020.

Pathogens, 9(4), 259.

10.3390/pathogens9040259).

technology from St.

Jude is delivered intranasally, which is hypothesized to provide adequate levels of mucosal immunity to prevent non-invasive

pneumococcal disease, including pneumonia and AOM.

The CDC recommends broad pneumococcal vaccines

for children younger than 2 and for adults over 65 years of age (CDC).

The CDC also recommends vaccinations for children and adults aged

2 through 64 either previously unvaccinated or partially vaccinated.

Three vaccines are currently approved in the U.S.

and other countries:

(i) Prevnar13 or PCV13 (under 18), (ii) Prevnar20 or PCV20 (Pfizer) and (iii) Pneumovax or PPSV23 (Merck).

An additional vaccine, Synflorix,

is approved for use outside of the U.S.

for the prevention of pneumococcal disease and S.

pneumoniae induced AOM for the 10 serotypes

included in the vaccine.

Therefore, an effective serotype independent S.

pneumoniae AOM vaccine could significantly impact pediatric healthcare demand and may reduce hospitalizations for pneumococcal pneumonia

in older adults.

As a preventative treatment, the vaccine’s advantages include reduction of near-term pain;

reduction of recurrent

AOM that may result in the need for tympanostomy tube placement;

lessening of antibiotic usage, which would decrease the number of antibiotic

resistant organisms in the environment;

avoiding potential long-term hearing loss;

and prevention of hospitalizations and deaths caused

by pneumococcal pneumonia.

Previous live, attenuated strains of S.

were generated by deleting several highly immunogenic virulent genes and therefore may not be optimal vaccine candidates.

Some of these

deletions include antigens that induce antibody responses following pneumococcal carriage and otitis media in young children and therefore

may not be optimal vaccine candidates.

Our technology in-licensed from St.

on candidate genes essential for microbial adaptation to the host environment while maintaining virulence determinants.

Jude researchers

developed a S.

pneumoniae strain with a deletion in ftsY , a central component of the signal recognition pathway (SRP).

mutants have greatly reduced virulence, although virulence factors are still produced.

pneumoniae ftsY deletion strain may

potentially make an ideal live-attenuated vaccine, as it can transiently colonize the nasopharyngeal cavity without inducing immune responses

to virulence protein antigens but does not cause invasive disease.

Our candidate vaccine is a live-attenuated serotype-independent vaccine,

that early data supports further development to pursue a potential long-term preventive intranasal treatment.

BWV-201 will likely require

two doses to provide life-long protection.

BWV-201 has the ability to transiently colonize the nasopharyngeal cavity and significantly

decrease the incidence of AOM and sinusitis in animal models.

The vaccine candidate is derived from the noninvasive serotype 19F strain

BHN97, which normally causes sinusitis/purulent rhinitis and AOM.

As previously noted, the ftsY gene was deleted by St.

Jude researchers,

and is designated BHN97∆ftsY (Rosch, Jason W et al.

EMBO molecular medicine vol.

Doi:10.1002/emmm.201202150).

We are also exploring the potential for BWV-201

to present antigens from additional AOM-causing pathogens, such as non-typeable Haemophilus influenzae and Moraxella catarrhalis .

Based on preliminary data from St.

Jude, we are able to present additional antigens and following intranasal vaccination with the new

construct, vaccinated mice generate antibodies to both non-typeable Haemophilus influenzae and Moraxella catarrhalis , in

addition to generating antibodies from various strains of S.

Our vaccine production is a straightforward approach,

utilizing the entire bacterium with purification and concentration steps only in the downstream process thereby significantly reducing

the time and cost of production compared to polysaccharide or conjugate vaccines.

Preclinical data colonization and invasiveness and Otitis Media/Sinusitis

Our pre-clinical data has shown encouraging results

from the research and development of BWV-201 as a potential intranasally delivered vaccine candidate.

Multiple animal models have demonstrated

protection from AOM.

To demonstrate vaccine efficacy against AOM and

sinusitis, mice were immunized (prime and two boosts) with Prevnar 7 (PCV7), Prevnar 13 (PCV13), Pneumovax (PCV23), D39x and BHN197 caxP

and ftsY deletion mutants.

Deletion of ftsY, a central component of the signal recognition particle (SRP) pathway show heightened sensitivity

to environmental stress and have greatly diminished virulence.

Deletion of caxP, a calcium/magnesium transporter, renders host physiological

conditions in blood and mucosa toxic to the bacterium.

BHN97ftsY serotype 19F is also characterized in PCV7, PCV13, and PCV23 (Rosch,

Jason W et al.

EMBO molecular medicine vol.

Doi:10.1002/emmm.201202150).

In this head-to-head preclinical study, mice (n=25-31)

were either mock-vaccinated (PBS) or live-attenuated vaccinated (with deletions of either type 2 or 19F backgrounds).

PPV23 was used as

a negative control.

Two weeks following the second boost, the bioluminescent strain BNH97x (type 19F), a serotype included in Prevnar

7, Pneumovax and BHN97ftsY (referred to as homologous challenge) were introduced to the mice and imaged twice daily for development of

AOM and sinusitis.

Only BHN97∆ftsY (BWV-201), and to a lesser extent Prevnar 7, showed significant reduction in AOM and only BHN97∆ftsY

demonstrated significantly reduced sinusitis compared to mock infected animals.

The incidence of AOM was significantly ( p <0.05

compared to mock) lower in BHN97∆ftsY — vaccinated mice (Figure A-below).

Only BHN97∆ftsY vaccine significantly decreased

the incidence of sinusitis ( p < 0.05).

Measurement of luminescence at 24 and 72 h confirmed protection engendered by BHN97∆ftsY.

Vaccine protection against otitis

media and sinusitis.

Mice (n=25 – 31 per group, performed at least twice for each group) were mock-vaccinated with PBS (Mock) or

vaccinated with live-attenuated vaccines deleted for caxP or ftsY on either a type2 (D39∆caxP, D39∆ftsY) or type19F (BNH97∆caxP,

BNH97∆ftsY) background.

Mice were challenged with a bioluminescent S.

pneumoniae strain BNH97X (type19F) and imaged twice

daily for development of AOM or sinusitis.

The proportion of mice developing an infection of the ear or sinus by Xenogen imaging.

=p<0.05 by Chi-squared test compared to the mock vaccinated group.

PPV23 was used as a negative control (60% otitis and 80% sinusitis).

Errors bars represent standard error of the mean.

PCV7 is Prevnar 7, PPV23 is Pneumovax and BHN97∆ftsY is BWV-201.

To determine if BHN97∆ftsY, or BWV-201,

(serotype 19F) can induce heterotypic AOM protection (AOM caused by a S.

pneumoniae serotype not contained in the vaccine), mice

(n=20) were immunized as detailed above and challenged with BHN54 (serotype 7), which causes otitis media in about 50% of challenged animals.

The control vaccine Prevnar 13 contains serotype 7;

therefore, this study compares heterotypic (BHN97∆ftsY) versus homotypic (Prevnar

13) vaccine protection.

BHN97∆ftsY had a 10-fold lower incidence of AOM, (*p < 0.05) when compared to mock immunized animals,

demonstrating that the attenuated vaccine does induce heterotypic protection.

Bioluminescent signaling as well as, reduction in weight

loss also demonstrated secondary analysis supporting vaccine protection.

BHN97∆ftsY induced protection from AOM

was additionally confirmed in a chinchilla (n=20) animal model.

The animals were immunized (prime and two boosts) and then challenged

with BHN97 two weeks after the final boost.

Vaccinated animals had a decreased incidence of culture-positive ears and had a significantly

decreased number of recoverable bacteria from the middle ear (A).

Following vaccination, a reduction in the number of culture positive

ears in vaccinated group compared to the mock animals was observed (B) as well as significant reduction in recoverable CFUs from middle

ear 7 days post challenge (C) * = p < 0.05 by Mann — Whitney.

Vaccine protection in a chinchilla

model of otitis media.

The BHN97strain is capable of causing otitis media in chinchillas via intranasal administration as observed by

recoverable bacterial colony forming units (CFUs) from the middle ear (A) following challenge.

B, C Following vaccination with BHN97 ∆ftsY

(BWV-201), a reduction in the number of culture positive ears in the vaccinated group compared to the mock animals was observed (B) as

well as a significant reduction in recoverable CFUs from the middle ear at 7days post challenge (C).

* =p<0.05by Mann — Whitney.

Vaccine is BHN97 ∆ftsY (BWV-201).

A potential advantage of an attenuated S.

vaccine such as BHN97∆ftsY is that immune responses are directed to bacterial proteins rather than just polysaccharides and

should not be limited to serotype specific protection.

Purified polysaccharide (PPV) vaccines such as Pneumovax (produced by Merck &Co.)

and pneumococcal conjugate vaccines such as Prevnar 7/13/20 (produced by Wyeth/Pfizer) or Synflorix (produced by GlaxoSmithKline plc)

are generally considered serotype specific, inducing protection to disease caused only by pneumococcal strains contained in the vaccines.

Utilizing BWV-201 as a platform to protect against other pathogens

pneumoniae remains the leading

cause of acute otitis media, other otopathogens are known to cause the disease, including non-typeable Haemophilus influenzae and

Moraxella catarrhalis .

To holistically address acute otitis media, we plan to evaluate the possibility of adding antigens from

non-typeable Haemophilus influenzae and Moraxella catarrhalis to the surface of the S.

pneumoniae bacteria that make

Jason Rosch at St.

Jude Children’s Research Hospital has successfully anchored proteins from both additional

pathogens to BWV-201 and has performed ELISAs to ensure antibodies were generated against each pathogen.

Newly generated data, not yet published.

Rosch engineered the live

vaccine to express protective epitopes of non-typeable Haemophilus influenzae and Moraxella catarrhalis on the cell surface

Shown in the figure above, the novel vaccine construct raised antibodies against all three pathogens following intranasal

vaccination by ELISA.

Future development of this vaccine construct will include challenge

studies in mice to determine efficacy of this vaccine construct in preventing disease caused by each pathogen.

Mice will be vaccinated

with the new construct, and will subsequently be exposed to S.

pneumonaie , both heterologous and homologous strains, as well as

non-typeable Haemophilus influenzae and Moraxella catarrhalis.

Upon completion of this study and results showing decreased

incidence of AOM in mice, we plan to pursue development of this vaccine construct and transfer to a partner CMO for manufacturing optimization.

UNIVERSAL INFLUENZA & BWV-102:

The company’s influenza vaccine programs are focused on developing

transformational and novel influenza vaccines:

BWV-101 for an influenza vaccine to provide protection against H1, H3 and Flu B infections;

and BWV-102 for a H1 only vaccine.

This program is licensed from the University of Oxford in which all relevant studies were performed

to support our hypothesis.

Our goal is to develop a vaccine that protects against all influenza strains that commonly infect humans by

targeting specific parts of the influenza viruses, which are of limited variability across flu strains and induce a strong protective

immune response.

This proof of concept will be leveraged to develop BWV-101 by studying the cross-reactivity of different flu strains,

H1, H3 and influenza B.

The BWV-101 vaccine candidate may potentially provide a therapeutic benefit that negates the need for annual vaccination,

vaccine reformulation, and provide long-lasting broad protection against the flu to millions globally (Thompson et al.

Nature Communications.

Influenza is a viral infection of the respiratory

system, causing an infected person to suffer from certain symptoms, including fever, muscle aches, runny nose, cough, congestion, headaches,

The four types of influenza viruses include type A, B, C, and D.

The type A and B influenza viruses are referred to as human

influenza viruses that are primarily responsible for seasonal flu epidemics each year.

Type A flu viruses are further divided into two

subtypes, named based on differences in two viral surface proteins called hemagglutinin (H) and neuraminidase (N).

Influenza types C and

D present a lower priority for vaccination, as Type C viruses cause a mild respiratory illness in humans and has not been associated with

human epidemics, and Type D viruses primarily affect cattle and are not known to cause illness in humans ( https://www.cdc.gov/flu/about/viruses/types.htm ).

This graphic shows influenza

virus types including the two types of influenza viruses (A,B) that cause most human illness and that are responsible for the flu season

Influenza A viruses are further classified into subtypes, while influenza B viruses are further classified into two lineages:

B/Yamagata and B/Victoria.

There is a major unmet need for the development

of a novel universal flu vaccine as a prophylactic therapy.

Influenza is a major respiratory pathogen.

The WHO estimates there are an

estimated 1 billion cases of influenza infection with 3-5 million severe cases and 290,000-650,000 related respiratory human deaths worldwide

The estimate does not take into account deaths from other diseases such as cardiovascular disease, which can be influenza

The next influenza pandemic is believed by many experts to be a potentially devastating global health threat.

Influenza mortality

rates are highest for the very young and elderly.

The global influenza vaccine market was valued

at $3.96 billion in 2018, and is projected to reach $6.20 billion by 2026, representing a CAGR of 5.9% from 2019 to 2026.

Currently, the

standard of care and most effective protection against flu is through annual vaccination.

The WHO estimates that worldwide, approximately

$4 billion is spent on influenza vaccines annually.

However, the flu also a major cause of work absenteeism, leading to an estimated annual

productivity loss in the U.S.

of $87 billion.

Flu vaccination consists of a yearly injection of attenuated or inactivated (dead) influenza

viruses to induce humoral immunity in the form of the antibodies against the current circulating or anticipated seasonal influenza strains.

The induction of antibody-producing B-cells through vaccination allows the immune system to defend the body against the influenza virus

circulating during the winter months.

An annual seasonal flu vaccine is the best way

to help protect against flu.

Vaccination has been shown to have many benefits including reducing the risk of flu illnesses, hospitalizations

and even the risk of flu-related death in children.

The CDC recommends use of any licensed, age-appropriate influenza vaccine during the

2020-2021 influenza season, including inactivated influenza vaccine (IIV), recombinant influenza vaccine (RIV), or live-attenuated influenza

vaccine (LAIV).

No preference is expressed for any influenza vaccine over another.

Both trivalent and quadrivalent influenza vaccines

will be available.

The trivalent vaccines formulation will include A(H1N1) pdm09, A(H3N2) and B/Victoria.

The quadrivalent vaccine formulations

will include A(H1N1) pdm09, A(H3N2) and B/Victoria, plus B/Yamagata ( https://www.cdc.gov/flu/about/viruses/types.htm ).

The current influenza vaccines induce antibodies

that target regions of the virus that are highly variable and have serious shortcomings, as they:

be administered annually,

(ii) typically

provide protection to only 50% of the individuals who receive it;

to be updated annually and reformulated 6 months prior to influenza season, such that strains that are subsequently prevalent during

the applicable “flu season” are not protected against by the vaccine.

Our Proprietary Epitope Discovery

Using the technology that we have exclusively licensed from the University

of Oxford, we are developing a universal influenza vaccine.

Our exclusive license agreements include patented influenza epitopes of limited

variability, or ELV, identified through a proprietary computational research and discovery process, discovered by Dr.

Sunetra Gupta and

her team at the University of Oxford.

We have acquired intellectual property for cross-protective epitopes to be used for our vaccine

candidates that were developed and identified through a unique computational discovery process at Oxford University.

The data produced

through computational analysis at Oxford has shown that antigen evolution in influenza is limited to certain regions of the virus that

facilitate binding and entry to host cells and these regions of limited antigenic variability are naturally immunogenic and therefore

may be used to develop universal immunity to influenza viruses.

We have identified epitopes of limited variability in H1 influenza that

have circulated throughout history (since 1918) and make ideal vaccine targets and have completed similar analysis of H3 and Flu B strains

for similar epitopes which will be used to produce our lead vaccine candidate BWV-101 as a universal vaccine for influenza infection.

Due to the cross-reactive nature of the H1 epitopes in pre-pandemic H1 influenza A, we are also pursuing the development of a stand-alone

H1 vaccine (BWV-102).

These epitopes are able to be formulated into a vaccine candidate using our virus-like particle (VLP) platform technologies

and may be evaluated using other vaccine technologies through partnerships in order to accelerate development of potential vaccines or

to explore adjunct therapies (Thompson et al.

Nature Communications.

Current influenza vaccine targets.

Antigenic Drift (Thompson et al.

Nature Communications.

A single conformational epitope is typically 8

to 15 amino acids in length and in an extreme circumstance (where every change creates an escape mutant), a single epitope could theoretically

vary from 208 to 2015 different ways.

Therefore, a highly variable virus like influenza should be able to mutate in countless ways during

each subsequent season.

This would inevitability lead to an explosion of genetic diversity and numerous circulating strains.

However, it seems that there is a constraint limiting

how influenza evolves, leading to a single or limited number of strains dominating each season.

In 2007, Sunetra Gupta led a group of

researchers at the University of Oxford who published a proprietary mathematical model proposing that the single strain dominance, typically

seen worldwide annually, could be explained by hypothesizing that epitopes of ‘limited variability’ exist (Antigenic Drift

The model hypothesizes that while there is a significant amount of mutation of influenza strains, this variability occurs

in a specific portion of the virus, while certain epitopes are required to remain relatively constant and are more limited in their variability

in order for the virus to infect individuals, thus clarifying how influenza is not as variable as commonly thought.

Antigenic Drift Hypothesis Illustration

Identification of a site of limited

variability in the head domain of the H1 HA.

of ABS of lowest variability containing position 147 with position 147 shown in yellow and the rest of the site colored in red.

d Phylogenetic

trees of pre-pandemic and post-pandemic highlighted rectangle H1N1with tips colored according to the conformation of the epitope of limited

variability (hereafter called OREO).

Please note the re-introduction of H1N1influenza in 1977 involved a strain which previously circulated

The Antigenic Drift Hypothesis suggests the existence

of epitopes of limited variability mediate a population’s immunity to influenza strains.

As a particular influenza strain circulates

in the population, immunity to a specific pattern of epitopes is induced.

This leads the virus to change its antigenic configuration and

cycle through its limited repertoire of antigenic conformations.

However, population immunity also changes due to birth and death within

the population (i.e.

individuals in the population who had experienced and developed immunity to certain conformations die).

prior epitope conformations to reappear.

The loss of herd immunity to these epitope of limited variability causes the emergence of epidemics

( Thompson et al.

Nature Communications.

Oxford scientists have identified the naturally

antigenic regions that drive immunity to influenza by evaluating serum from these from various age groups of humans using assays and ELISAs

reveal periodic cross-reactivity to ELV.

Pseudotype microneutralisation data reveals a cyclical pattern of epitope recognition.

of children’s sera were used to detect antibodies and demonstrated that young children ages 6 to 12 had immunity to historical influenza

strains that circulated many years prior to when they were born and they could never have possibly been exposed to, one of which that

last circulated in 1934.

Mutagenesis of the identified regions of limited variability in various historical viruses removed the protective

Furthermore, vaccination of mice, as shown below, with these regions of the influenza virus produced an identical immune response

that was observed in the children.

For example, the mice vaccinated with either the region from the influenza virus circulating in 2006

or 1977 were protected against infection with an influenza with a virus that last circulated in 1934, replicating the immunity seen in

children ages 6 to 12.

(Thompson et al.

Nature Communications.

Sequential vaccination using

chimeric HA constructs.

Five groups of mice were sequentially vaccinated with 2009-like (blue), 2006-like (red),1995-like (orange), 1977-like

(green) and 1940-like (pink) epitope sequences substituted into H6, H5 and H11 Has.

Two further control groups were sequentially vaccinated

with H6, H5 and H11 constructs without any sequence substituted into the Has (vaccinated controls).

Further two groups were mock vaccinated

(unvaccinated controls).

c,d,f,g Pseudotype microneutralisation assays using 0.5μl of sera from the bleed at 21 weeks.

Error bars are mean ± s.e.m.n=6 for experimental groups and control groups.

The values provided are an average of two replicates.

This work demonstrated that vaccination with just

four variants of one region of limited variability in H1 influenza was able to elicit immunity to all historical H1 influenza strains.

As these regions periodically reappear and disappear over time, vaccination with all of the possible variants would be expected to provide

protection against future influenza strains as well.

The identified epitopes are restricted in their variability due to presence of a

receptor-binding site and small alpha helix structure between disulphide bonds.

The following research findings form the basis

for our influenza vaccine candidates:

of limited variability which are under strong immune selection exist within influenza.

epitopes drive the antigenic evolution of influenza.

epitopes cycle between a limited number of different conformations.

of limited variability would make ideal vaccine targets.

Universal Influenza Vaccine

Our approach to developing a novel, universal

flu vaccine for the prevention and protection against human influenza strains and potential pandemic strains by targeting specific limited

variability epitopes includes the following steps and processes.

We are exploring development of an influenza vaccine

utilizing both the S & P nanoparticles to determine the most effective and efficient presentation of our ELVs and the versatile S&P

nanoparticle vaccine platform from CHMC with the H1 influenza antigens.

Data in preclinical mice (Rotavirus-specific-antibody-free BALB/c

mice, n=5-7) challenge studies inserted M2e, a spike protein of influenza, into a P-particle loop;

showed mice that were vaccinated had

100% protection when injected with lethal doses of influenza (Tan et al.

JOURNAL OF VIROLOGY, Jan.

approach will allow us to gain valuable information as we further the development and manufacturing of the BWV-102 program and utilize

it for the development of BWV-101.

We are currently assessing the ELVs to determine the most effective and efficient route of antigen

presentation.

Additionally, we are currently optimizing antigens for H3 and Flu B to be included with the identified H1 antigens to finalize

our universal influenza vaccine formulation.

We are using established manufacturing

methods, including E.coli fermentation to produce our chimeric proteins, to reduce the cost and increase the efficiency and

scalability of our manufacturing process for the vaccine.

The antigens will be displayed by a proprietary VLP that can be produced

coli (Pharmaceutics 2019, 11, 472;

doi:10.3390/pharmaceutics11090472).

Our research and discovery model uses

bioinformatics and phylogenetic analysis to identify possible sites of epitopes of limited variability before confirming their

existence experimentally.

To date, we have identified naturally immunogenic

epitopes for H1, H3 and influenza B.

Bioinformatics studies and wet lab studies suggest that these epitopes, especially H1N1, and the

chimeric scaffold configuration of our vaccine induce immunity due to induction of broad cross-reactive antibodies in other strains such

as H10N3 (bird flu), and pandemic strains including H5NX, H7NX, and H9NX.

H9NX (Thompson et al.

Nature Communications.

we foresee the development of H1N1 vaccine as a priority due to its high cross-reactive priorities.

BWV-102 Stand-Alone H1 Vaccine

We are developing our H1 stand-alone influenza

prophylactic product, BWV-102, to address potential pandemic zoonotic H1 strains, specifically the G4 EA H1N1 identified by scientists

and reported in June 2020, as a potential next pandemic strain.

BWV-102 is being developed using the H1 ELVs identified by the team at

the University of Oxford.

While the product is designed to protect against infection from any H1 strain, there is potential for cross

protection from H5 and H10 strain infections as well.

Preclinical studies were conducted in Balb C mice (n=6) using a prime-boost-boost

protocol (Thompson et al.

Nature Communications.

The proposed Phase I clinical study will employ this prime — boost

however, it is possible that a single dose of the vaccine candidate will confer protection against current and historical H1

strains with a prime-boost dose or a single dose.

As reported in 2020, the G4 EA H1N1 strain is

the most prevalent influenza strain circulating among swine populations in China.

The strain was first identified in 2016 and has been

monitored by scientists in China through their swine surveillance program.

The strain has genes from a mix of pig, avian and human viruses,

including genes from the 2009 H1N1 flu pandemic virus.

Currently, the G4 EA H1N1 strain is not transmissible human to human, however,

scientists hypothesize that there is a high likelihood of strain reassortment occurring that could make human to human transmissibility

The current H1N1 influenza strain circulating may provide some protection against disease induced by G4 EA H1N1 infection.

The ability of the BWV-102 ELVs to induce an immune

response and protection against heterologous challenge with historical strains was assessed in Balb-C mice (n=6) ( Thompson et al.

Communications.

We are currently assessing the ELVs in combination with the S 60 particle, P 24

particle and a proprietary VLP, currently in development, to determine the most effective and efficient route of antigen presentation.

Manufacturing of the product is expected to occur in E.

coli (Pharmaceutics 2019, 11, 472;

doi:10.3390/pharmaceutics11090472) .

We anticipate results of the VLP presentation assessments in the first half of 2022.

BWV Norovirus (NoV) S&P Nanoparticle Versatile Vaccine Platform

Bioengineering the shell (S) and protruding

(P) domains of the norovirus capsid protein, polyvalent nanoparticles and polymers/oligomers provide a versatile vaccine platform with

wide applications

Our Approach to Stimulating the Immune System

for Infectious Disease Protection

Our S&P platform was co-invented by two researchers,

Xi Jason Jiang, Ph.D., and Ming Tan, Ph.D., of the Division of Infectious Disease at the Cincinnati Children’s Hospital Medical

The pre-clinical research conducted at CHMC provided encouraging data that supports further investigation and development of the

platform for our vaccine candidates.

The S&P platform combines two or more immunogenic components, a norovirus antigen plus at least

one additional antigen, together creating novel constructs.

The norovirus nanoparticle enhances immunogenicity of the inserted antigen.

The S & P particles themselves also act as antigens, and are large enough to trigger an immune response to a foreign substance.

combining the norovirus nanoparticle with one or more antigens from other infectious disease(s), the immune system is stimulated to create

antibodies to both the norovirus and the additional antigen(s).

Key Elements of our Platform

We are leveraging our disruptive norovirus nanoparticle

platform to develop novel, broad-spectrum vaccines for adult and child infectious disease prevention by taking advantage of:

and Scalable discovery platform engine.

We believe we are able to design and create novel vaccines that are stable and scalable for

broad spectrum prophylactics.

Through this platform’s adaptability, we may opportunistically expand our pipeline and potentially

collaborate with third parties for additional vaccines, as well as therapeutics.

● Cost-effective

and Rapid Production of Novel Vaccines.

We are potentially able to reduce the cost and time to manufacture a vaccine candidate by

utilizing an E.coli expression platform, compared to traditional vaccine production which uses other, longer production-time platforms,

such as Chinese Hamster Ovary (CHO) cells.

We have bioengineered these nanoparticles to be stable and effective, as determined through

animal immunogenicity studies, using E.coli expression which may provide cost savings and efficiency compared to other VLPs needing

a eukaryotic expression system.

(Pharmaceutics 2019, 11, 472;

doi:10.3390/pharmaceutics11090472).

● Multi-antigen

and Pathogen Capabilities.

One of the key features of our platform is its ability to carry multiple antigens at a time, thereby creating

a multi-targeted vaccine.

It also provides the opportunity to develop vaccines for protection against not only viral pathogens, but also

bacterial and potentially parasitic and fungal pathogens.

● Therapeutic

We believe our platform may offer opportunities to develop non-infectious disease therapeutic products, for example being

used as a carrier or vehicle to transport drugs to specific target locations.

Viral capsid proteins are responsible for many

basic functions necessary for viral life cycles, such as viral attachment and entry, and thus can elicit neutralizing antibodies against

viral infection after immunization to humans and animals.

Consequently, viral capsid proteins are promising vaccine targets against viral

Indeed, various capsid protein nanoparticles and complexes have been developed and used as nonreplicating subunit vaccines

to combat various infectious diseases.

Unlike traditional live-attenuated and inactivated

virus vaccines that need cultivation of infectious virions and are associated with certain safety concerns, the nonreplicating VLP vaccines

derived from bioengineered viral capsid proteins do not involve an infectious agent and, therefore, may be safer and have lower manufacturing

costs than traditional vaccines.

Thus, VLP vaccines represent a next generation of innovative vaccine strategy.

NoV (VP1) capsid structure consists of two major domains:

(i) a N-terminal shell (S) domain and (ii) a C-terminal protruding (P) domain.

The S domain builds the interior shell of the capsid and the P domain forms the dimeric protrusions of the capsid.

protrusions (P) of norovirus capsid interact with viral glycan receptors for attachment to host cells to initiate an infection.

S domain interacts homotypically and drives self-formation of an approximately 60 nm VLP.

P domain exhibits homotypic interactions, forming a 24 nm VLP with dimeric protrusions for stabilization of the viral capsid.

Additionally,

it can also form oligomers or polymers.

Lineage structures of norovirus

capsid protein or viral protein 1 (VP1) and various nanoparticles derived from full-length or truncated VP1.

The N-terminal shell (S)

(green) and the C-terminal protruding (P) (dark blue) domains with a short flexible hinge (light blue) in between (with amino acid numbers

based on GI.1 Norwalk virus VP1) are shown.

(A) Production of full-length norovirus VP1s via a eukaryotic expression system self-assembles

into virus-like particles (VLPs).

(B) Production of the S or P domain via the Escherichia coli expression system self-assembles

into S or P nanoparticles.

Due to the homotypic interaction attributed to

the norovirus capsid domains, researchers at CHMC, through bioengineering, designed and generated two subviral nanoparticles, the 24-valent

P 24 and the 60-valent S 60 nanoparticles, and P-derived polymers to serve as a multifunctional vaccine platform against

different pathogens and illnesses.

nanoparticles and polymers are easily produced, highly stable, and extremely immunogenic which we believe makes them compelling platforms

to serve to display foreign antigens, self-assembling into chimeric nanoparticles or polymers as vaccine candidates.

are several preclinical studies that showed P 24 /S 60 chimeric vaccine candidates that can display different foreign

antigens and epitopes, as set forth below in Tables 1 and 2.

Therefore, there may be additional candidates to further explore as human

ACS Nano 2018, 12, 10665−10682) .

VLPs and capsid-like nanoparticles may be excellent vaccine candidates against corresponding viral pathogens because they can retain

arrays of antigenic epitopes that faithfully mimic those of the native virions, and these repeated viral antigens and epitopes stimulate

strong immune responses in their animal and human hosts.

In addition, such highly immunogenic subviral nanoparticles may also serve as

versatile platforms that are able to display foreign antigens for improved immune responses to facilitate development of novel vaccines

against various pathogens and diseases.

fact that the P 24 VLP nanoparticles and polymers are composed of authentic norovirus antigens and retain norovirus-specific

molecular patterns make it an excellent vaccine candidate against the norovirus.

addition, the natures of self-formation, high stability, polyvalence, and high immunogenicity, as evidenced by animal studies conducted

in gnotobiotic pig models and mouse models, results included herein, of the nanoparticles and polymers make them strong vaccine candidate

platforms to display foreign antigens, resulting in chimeric nanoparticles as vaccine candidates against further pathogens and diseases.

Our multifunctional vaccine platform is a robust

discovery engine and has broad application using both S 60 and P 24 nanoparticles to target multiple pathogens and

The P 24 nanoparticle has also been

used to display multiple viral epitopes for enhanced immunogenicity for novel subunit vaccine development, see Table 1 below.

These include

the M2e epitope of the matrix 2 (M2) protein and the HA2 protein B cell epitope of influenza viruses, the B cell epitope of VP3 of enterovirus

71 (EV71), the 4E10 and 10E8 epitopes of human immunodeficiency virus type 1 (HIV-1), among others.

Summary of norovirus nanoparticles and polymers as vaccine

candidates and platforms to display foreign antigens and epitopes.

Nanoparticle/ Polymer

Antigen/Epitope to be Displayed (Pathogen)

Chimeric Products as

Vaccine Candidate

Immunity against

Pathogens or Diseases

VP8* (rotavirus)

P domain (norovirus)

VP8* (rotavirus)

Rotavirus and norovirus

M2e (influenza virus)

Influenza virus

HA2 B cell epitope

(influenza virus)

Trivalent HA2-PP

(P 24 -HA2:90-105)

Influenza A virus and influenza B virus

VP3 B cell epitope (EV71)

PP-71-6 (P 24 -71-6)

4E10/10E8 epitopes (HIV-1)

4E10-PP/10E8-PP

Amyloid-beta, Aβ

PP-3copy-Aβ1-6

Alzheimer’s disease

P domains (noroviruses)

NoV P GI -NoV P GII

Different noroviruses

P domain (HEV)

Norovirus and HEV

P domain (astrovirus) P domain (HEV)

Ast P-HEV P-NoV P

Norovirus, astrovirus,

P domain (astrovirus) P domain (HEV)

VP8* (rotavirus)

Ast P-HEV P-VP8*

Rotavirus, astrovirus,

EV71, enterovirus 71;

HIV-1, human immunodeficiency virus type

HEV, hepatitis E virus;

Ast, astrovirus, NoV, norovirus, P, protruding domain;

P+, the P domain with an end-linked cysteine-containing

peptide that can self-assemble into oligomers;

PP, P particle;

GI, norovirus genogroup I;

GII, norovirus genogroup II.

Please see the

main text for details.

The S 60 Nanoparticle as a Multifunctional vaccine platform

Recent technology has generated S nanoparticles

coli system with stabilized expression and self-assembly.

The S nanoparticles feature exposed C-terminal flexible hinge

sites that offer ideal fusion sites for displaying foreign antigens.

Researchers at CHMC have developed a technology

to produce uniform 60-valent NoV S 60 nanoparticles with high efficiency using a simple bacterial expression system.

achieved by taking advantage of the homotypic interactions of the NoVVP1 S domain that naturally builds the interior shells of NoV capsids,

as well as several modifications to stabilize the S domain proteins and enhance the inter-S domain interactions, respectively.

Specifically,

we introduced an R69A mutation to destruct the exposed protease cleavage sites on the surface of the native shell that otherwise leads

to easy degradation of the S proteins.

In addition, we introduced triple (V57C/Q58C/S136’C) cysteine mutations to establish inter-S

domain disulfide bonds between two pairs of sterically close residues that belong to two neighboring S domains.

This led to significantly

enhanced stability and yields of the self-assembled S 60 nanoparticles produced by the simple E.

bullets are supported by published data by Ming Tan, the co-inventor of the S&P platform, and his research team at CHMC.

important feature of our technology was to rationally introduce intermolecular disulfide bonds to stabilize the S 60 nanoparticles.

This approach could also be used to stabilize other viral protein particles or complexes.

60 freely exposed C-termini are a key feature facilitating the S 60 nanoparticle to be a useful vaccine platform.

Foreign antigens

or epitopes can simply be fused to the end of the S domain via flexible linker through recombinant DNA technology.

60-valent NoV VLPs or S particles produced in a bacterial expression system have not been produced before.

● Importantly,

our S 60 nanoparticles maintained the native conformation with authentic antigenicity;

thus, our NoV S 60 nanoparticle

technology represents a significant bioengineering advancement as uniform 60-valent NoV VLP or S particle via an expression system

have never been produced before (Xia et al.

ACS Nano 2018, 12, 10665−10682).

complexity and size of vaccine particles are important factors in quality control of vaccine products, as variations in complexity and

size will result in variations in immunization outcomes of the vaccines.

Broad application to fuse several antigens to the S 60

nanoparticle based on multiple studies shown below conducted by CHMC (Xia et al.

ACS Nano 2018, 12, 10665−10682)

CHMC has been able to fuse several antigens to

the S 60 nanoparticle to the same exposed S domain C-terminus via the same linker.

These included (1) the rotavirus (RV) surface

spike protein VP8*;

(2) the HA1 antigen or receptor-binding domain (RBD) (223 amino acids) of the hemagglutinin (HA) of anH7N9 influenza

(2) the TSR antigen (67 amino acids) of the circumsporozoite surface protein (CSP) of the malaria parasite Plasmodium falciparum;

(3) the protruding domain antigen (187 amino acids) of a hepatitis E virus;

(4) a longer version of the RV VP8*antigen (231 amino acids);

and (5) the VP8*antigen (159 amino acids) of the murine RV (mRV) EDIM strain (Table 1).

Particle formations of these fusion proteins have

been shown by gel-filtration and/or EM (Table1).

In addition, they have shown that the S 60 nanoparticle-displayed HA1 and mRV

VP8*antigens elicited significantly higher HA1- and mRV VP8*-specific antibody titers, respectively, than those elicited by the free HA1

or mRV VP8*antigens (Table 2).

List of Antigens That Have Been Displayed by the S 60

Nanoparticles

epitope/antigen

bacteria culture)

S 60 – antigen

particle formation

significant immune enhancement in mice f

RV VP8* antigen

HA1 antigen a

TSR/CSP antigen b

full RV VP8* antigen c

murine RV VP8* antigen d

HEV protruding domain antigen e

antigen containing the receptor binding site is the head portion of the hemagglutinin (HA) of H7N9 influenza A virus.

antigen is the C-terminal portion of the major surface protein of acircumsporozoite (CSP) that plays a key role in host cell invasion

of the malaria parasite Plasmodium falciparum.

RV VP8*antigen is the full-length VP8*domain of the spike protein of a human P[8] rotavirus.

RV VP8*antigen is the core portion of the VP8*protein constituting the head of the spike protein of a murine rotavirus EDIM strain.

protruding domain antigen is part of the protruding domain of a hepatitis E virus capsid.

enhancements of the S 60 nanoparticle-displayed antigens were measured in mice using free monomeric antigens as control for

“ND” = not determined.

S 60 nanoparticles may serve as a polyvalent vaccine platform

ACS Nano 2018, 12, 10665−10682)

believe the self-assembled, polyvalent S 60 nanoparticle with 60 flexibly exposed S domain C-termini is an ideal vaccine platform

for antigen presentation and immunogenicity enhancement.

has been supported by studies showing that when Hisx6 tag was fused to the hinge of the S domain via a linker, fusion proteins self-formed

into the S 60 nanoparticles.

has also been demonstrated by constructing a chimeric, and reconfirmed by cyroEM density map, S 60 nanoparticle displaying

60 RV (rotavirus) VP8* proteins, the major rotavirus neutralizing antigen.

The S 60 -VP8*particles can be easily produced with

high stability.

The chimeric nanoparticle induced higher immunoglobulin, or IgG, response in mice (n=6) toward the displayed VP8*antigen

than soluble VP8* antigen.

Mouse sera experiments were completed analyzing vaccinated versus the control group to show neutralizing activity

against RV infection.

The statistical differences between the groups are (*P < 0.05, **P < 0.01, ***P < 0.001) as shown below

(Figure 2) (Xia et al.

ACS Nano 2018, 12, 10665−10682).

RV surface spike protein, VP8* was tested for feasibility of the S 60 nanoparticle by the analysis using EM micrograph examination

and ESI-MS analysis.

S 60 -VP8*particles exhibited stronger blockade in mice (n=6) sera after vaccination (P=0.0003) (Xia et

ACS Nano 2018, 12, 10665−10682).

polyvalent B- and T-cell epitopes of the antigens on the polyvalent VLP platform led to induction of stronger humoral and cellular immune

responses, respectively, in animals and humans compared with those elicited by the monovalent epitopes of the free antigen.

polyvalent VLP platform is likely to increase the immunogenicity of the displayed antigens.

Mouse sera experiments were completed analyzing

vaccinated versus the control group to show neutralizing activity against RV infection.

The statistical differences between the groups

are (*P < 0.05, **P < 0.01, ***P < 0.001) as shown below.

ACS Nano 2018, 12, 10665−10682).

S 60 -VP8*particles

enhanced immunogenicity toward the displayed RV VP8*antigens.

The same dose/dosage of the S 60 -VP8*particles, free VP8*antigens,

and S 60 nanoparticles without VP8*was given to mice (N=6), respectively, followed by measurements of theVP8*-specific IgG responses

(A), 50% blocking titers (BT50) against RV VP8*-glycan ligand interaction (B), and neutralization activity against RV infection/replication

in culture cells (C) of the resulting mouse antisera.

(A) VP8*-specific IgG responses/titers elicited by theS60-VP8*particles, free VP8*antigens,

and the S60nanoparticles, respectively.

(B) BT50against RV VP8*−ligand interactions by the mouse sera after vaccination with the

same three immunogens, respectively.

with the same three immunogens, respectively.

In all these experiments mouse sera after immunization with diluent (PBS) are used as negative

The P 24 Nanoparticle as a versatile

platform (Tan et al.

Nanomedicine, 2012.

The crystal structure of norovirus VLPs indicates

that P domain is involved in strong dimeric interactions forming dimeric protrusions on the viral surface.

The oligomeric interactions

of the P domains are also observed at the five-fold axes to further stabilize the capsid structure.

When the P domain protein was expressed

coli system, it self-assembled into P dimers, as well as 24 valent P nanoparticles, P 24 .

P dimers and P 24

nanoparticles can exchange dynamically, depending on concentration of the P domain protein, indication that the assembled P 24

particles at this stage were unstable and easy to disassemble back into P dimers.

To facilitate P 24 nanoparticle formation,

inter-P domain disulfide bonds were introduced through fusion of a cysteine-containing peptide to the end of the P domain.

P 24 nanoparticle assembly, the cysteine patches were brought to the center of the P 24 nanoparticles, resulting in

sterically close contact and thus forming inter-P domain disulfide bonds that significantly stabilized the P 24 nanoparticles,

which could no longer disassemble back into the P dimers.

nanoparticles can be produced using an E.

coli expression system faster and a lower cost than VLPs.

VLP and P 24 nanoparticles without adjuvant produce innate, humoral, and cellular immunity.

platform can be used to display foreign antigens, epitopes and viral pathogens and non-infectious disease.

have demonstrated immune response against flu, rotavirus, and norovirus using bi- or trivalent vaccine candidates developed using this

approach, noting the potential for the development of a universal flu vaccine.

Pre-clinical studies in influenza and rotavirus are provided

below supporting our vaccine candidate programs.

See — Our Infectious Disease Vaccine Candidates .

BWV-301 Norovirus-Rotavirus Vaccine Program

We are developing BWV-301 to prevent acute gastroenteritis,

or AGE, caused by norovirus and rotavirus, utilizing the P 24 nanoparticle of our vaccine platform.

The vaccine is based on

one or two doses of the norovirus P 24 nanoparticle presenting 24 rotavirus VP8* antigens.

Most cases of gastroenteritis are

caused by viruses.

The CDC reports that viral gastroenteritis infections cause 200,000 deaths in children worldwide each year.

symptoms of viral gastroenteritis causes nausea, vomiting, diarrhea, anorexia, weight loss, and dehydration.

Gastroenteritis

Gastroenteritis, often called stomach flu, is

inflammation of the gastrointestinal tract — the stomach and intestine.

Symptoms may include diarrhea, vomiting and abdominal pain.

Fever, lack of energy and dehydration may also occur.

While gastroenteritis is usually caused by viruses, bacteria, parasites, and fungus

can also cause gastroenteritis.

Eating improperly prepared food, drinking contaminated water or close contact with a person who is infected

can spread the disease.

Norovirus and rotavirus are two viruses that cause gastroenteritis in adults and children.

In 2015, there were two billion cases of gastroenteritis,

resulting in 1.3 million deaths globally.

Children and those in the developing world are affected the most.

In 2011, there were about

1.7 billion cases, resulting in about 700,000 deaths of children under the age of five.

In the developing world, children less than two

years of age frequently get six or more infections a year.

It is less common in adults, partly due to the development of immunity.

adults, norovirus is the most common cause of severe disease.

Rotavirus, however, is the common cause of AGE in children.

Norovirus causes significant debilitating AGE,

with a reported 700 million infections and 20% of all diarrheal cases reported annually worldwide, according to the CDC.

About 200 million

cases are seen among children under 5 years old, leading to an estimated 50,000 child deaths every year.

Norovirus is the cause of approximately

20% of all AGE cases worldwide each year.

It is estimated that 68.9 cases of norovirus infection occur in every 1000 people.

America, norovirus induced AGE tends to be seasonal, occurring in cooler, rainy months and particularly impacts groups in close proximity,

such as in schools, dormitories, medical facilities, and cruise ships.

Norovirus costs $60.3 billion worldwide each year

Globally, norovirus resulted in a total of approximately $4.2 billion in direct health system costs and approximately $60.3 billion

in societal costs per year.

Disease among children younger than 5 years cost society $39.8 billion, compared to $20.4 billion for all

other age groups combined.

Costs per norovirus illness varied by both region and age and was highest among adults ages 55 years and older.

Productivity losses represented 84-99% of total costs varying by region.

While low and middle income countries and high income countries

had similar disease incidence (10,148 vs.

9,935 illness per 100,000 persons), high income countries generated 62% of global health system

costs (Bartsch et al.

PloS One 2016;

11:e0151219).

In North America, the median yearly cost of outbreaks

was $7.6 million in direct medical costs, and $165.3 million in productivity losses.

An average of approximately 113,000 hospitalizations,

8.2-122.9 million missed school/work days, $0.2-$2.3 billion in direct medical costs, and $1.4-$20.7 billion in productivity losses was

due to sporadic illness.

The total economic impact of norovirus infection was $10.6 billion based on the current incidence estimate 68.9

cases per 1000 population, or approximately $0.15 million per person infected.

The total economic burden is greatest in young

children but the highest cost per illness is among older age groups in some regions.

These large costs overwhelmingly are from productivity

losses resulting from acute illness.

Low, middle, and high income countries all have a considerable economic burden, suggesting that norovirus

gastroenteritis is a truly global economic problem.

There is not a norovirus vaccine on the market presently.

however, a number of rotavirus vaccines currently marketed around the world.

RotaTeq, owned by Merck, a live, oral pentavalent vaccine

and Rotarix, owned by GSK, a monovalent, human, live-attenuated vaccine are recommended by the WHO for global use in children and approved

for use in the U.S., Canada and Europe.

Other monovalent vaccines are available but only approved for use in one country, either China,

Vietnam or India.

P 24 VLPs produced in E.

and norovirus VP1 VLPs produced in a baculovirus expression system were both demonstrated to elicit innate, humoral and cellular immunity

in a mouse model, indicating that both constructs have potential as norovirus virus candidates.

In addition, when delivered intranasally

both constructs were able to induce partial cross-variant protection against diarrhea in a gnotobiotic pig model.

Ramesh et al.

European Urology.

68(3):418-425 2015.

Rotavirus is the most common cause of diarrheal

disease among infants and young children, causing an estimated 111 million episodes of diarrhea annually, 2 million hospitalizations and

352,000-592,000 deaths annually, according to the CDC.

After the introduction of live-attenuated oral vaccines the incidence of rotaviral

hospitalizations and deaths have significantly declined.

However, there is still a need for efficacious, cost-effective rotavirus vaccines.

The rotavirus vaccine is recommended by the CDC

and ACIP as a prevention for children.

However, managing the symptoms is the only way to help adults and children infected with either

of the viruses.

Due to the potential of death, most treatments are focused on dehydration prevention and management.

Treatment involves

getting enough fluids.

For mild or moderate cases, this can typically be achieved by drinking oral rehydration solution (a combination

of water, salts and sugar).

In those who are breastfed, continued breastfeeding is recommended.

For more severe cases, intravenous fluids

may be needed and care provided in the hospital.

Fluids may also be given by a nasogastric tube.

Zinc supplementation is recommended in

Antibiotics are generally not needed.

However, antibiotics are recommended for young children with a fever and bloody diarrhea.

To determine the potential of the P 24

VLP to serve as a rotavirus vaccine candidate, the 159 amino acid VP8* protein was inserted into a P 24 domain surface loop.

The fusion proteins self-assembled into P 24 VLPs, and the 24 rotavirus VP8* antigens were demonstrated by cryo-EM to be displayed

on the outermost surface of the chimeric P 24 VLP.

Mice (n-5-7) immunized intranasally with the P 24 -VP8* or intramuscularly

with Freund’s adjuvant elicited significantly higher rotavirus neutralizing antibodies than the free VP8* immunized under the same

conditions (IN or IM).

(P >0.05), (Tan et al.

2 Cindolo L, et al.

European Urology 68(3):418-425 2015.

3 Casabé A et al.

191:727-733 2014.

P 24 -VP8* VLPs were further characterized

as a potential rotavirus vaccine in mouse and gnotobiotic pig challenge studies.

A construct consisting of P 24 and the VP8*

antigen from the murine rotavirus EDIM strain was constructed and tested using a murine rotavirus challenge model.

Mice (n=5-7) were immunized

with P 24 -mouseVP8*, mouseVP8* alone or P 24 -human VP8* 3 times intranasally without adjuvant.

Rotavirus shedding

was significantly lower in animals immunized with P 24 -mouseVP8* than mock vaccinated or animals that received mouseVP8* only

or P 24 -humanVP8* * (P >0.05) (Tan et al.

4 Cindolo L, et al.

BMC Urol 2015;

Zhang H, et al.

204(2):325–331 2020.

Additionally, an immunogenicity study was conducted

in gnotobiotic pigs (n=25).

A construct of P 24 and the VP8* antigen corresponding to human rotavirus Wa strain was tested in

a gnotobiotic pig challenge model.

Animals were immunized intramuscularly (IM) three times with either P 24 -WuVP8* with luminium

hydroxide adjuvant or luminium hydroxide alone and were challenged with human Wa rotavirus 7 days post dose three.

Animals immunized with

P 24 -WuVP8* showed a significant reduction in the mean duration of diarrhea, virus shedding and significantly lower fecal cumulative

consistency scores compared to adjuvant only control group (*, p < 0.05;

**, p < 0.01).

(Ramesh et al.

doi:10.3390/vaccines7040177).

.P24-VP8* vaccine protected against

VirHRV diarrhea and reduced overall virus shed among vaccinated pigs.

Fecal consistency (A) and virus shedding (B) were monitored daily

from post challenge day (PCD) 1 to PCD 7 after the challenge with VirHRV.

Fecal consistency scores≥2 were considered to be diarrheic

(dashed line indicates the threshold of diarrhea).

Statistical significance between vaccinated and control groups, determined by multiple

t tests, are indicated by asterisks (*,p<0.05;

Additionally, serum samples were collected from

the pigs at the times of P 24 -VP8* vaccine administration (PID 0, PID 10, PID21 and PID 21) and VirHRV challenge (PID 27) and

upon euthanasia (PCD 7).

The P 24 -VP8* vaccine was highly immunogenic in Gn pigs.

It induced strong VP8*-specific serum IgG

and Wa-specific virus-neutralizing antibody responses from post-inoculation day 21 to PCD 7.

Comparisons between groups at the same time

points were carried out using Student’s t-test and significant differences are identified by *** (n = 10 – 15;

Tukey-Kramer HSD was used for the comparison of different time points within the same group, where different capital letters (A, B, C,D)

indicate a significant difference, p < 0.01, and shared letters indicate no significant difference.

These findings support further

investigation of the noro-rotavirus dual nanoparticle vaccine.

(Ramesh et al.

doi:10.3390/vaccines7040177)

Geometric mean VP8*-specific

IgG (A) and IgA (B) and Wa-HRV neutralizing (C) antibody titers in serum collected from Gn pigs at PID 0, 10, 21, 28, and PCD 7.

were vaccinated with P24-VP8* vaccine or Al(OH)3 adjuvant only.

Each serum specimen was tested at an initial dilution of 1:4.

samples were assigned an arbitrary value of 2 for calculation and graphical illustration purposes.

Comparisons between groups at the same

time points were carried out using Student’s t-test and significant differences are identified by *** (n = 10 – 15;

Tukey-Kramer HSD was used for the comparison of different time points within the same group, where different capital letters (A,

B, C, D) indicate a significant difference, p < 0.01, and shared letters indicate no significant difference.

An effective norovirus culture-based neutralization

assay is not available, due to the lack of an efficient cell culture system to produce human norovirus.

Therefore, a surrogate neutralization

assay has been developed in the field, measuring the ability of antisera to block norovirus VLP binding to host receptors.

to generating rotavirus neutralizing antibody, Tan et al (J.

2011) demonstrated that anti- P 24 -VP8* mouse

sera blocked norovirus VLP binding, indicating that the insertion of the VP8* fragment did not inhibit induction of norovirus VLP binding

antibodies and suggesting the P 24 -VP8 construct could potentially serve as a single vaccine against both rotavirus and norovirus

disease (P >0.05).

We hold the exclusive global license for the novel

norovirus-rotavirus combination vaccine (except in China and Hong Kong) from Cincinnati Children’s Hospital Medical Center, or CHMC,

CHMC researchers engineered the norovirus major structural protein VP1 such that the N-terminal shell (S) and C-terminal protruding (P)

domains of VPI could be expressed as separate S 60 and P 24 VLPs.

Unlike norovirus VLPs composed of the intact VP1

protein or the unmodified S 60 fragment, our S 60 and P 24 VLPs can be expressed in E.

The researchers

demonstrated that S 60 VLPs could be used to present foreign antigens on the surface of the S 60 VLP.

has also demonstrated that foreign antigens could also be expressed on the surface of the P 24 VLP.

The proposed norovirus-rotavirus

vaccine is based on the P 24 VLP technology.

Our vaccine production is based on an E.coli expression platform.

Following IND submission, if accepted, we intend

to initiate our Phase I clinical trial in healthy adults ages 18 to 54.

If approved, we believe our vaccine is well positioned to receive

a recommendation from the CDC, ACIP, and similar international advisory groups for inclusion in vaccine programs.

Norovirus-malaria vaccine program

Additionally, we are currently investigating a

malaria vaccine, BWV-302, utilizing our norovirus platform.

The vaccine is designed to offer protection from both norovirus and malaria,

infectious diseases that occur frequently together in geographic regions.

The vaccine utilizes a protein identified on the surface of

the plasmodium parasite being presented on the surface of the norovirus nanoparticle.

Malaria can be a deadly disease caused by

protozoan parasites from the Plasmodium family, primarily spread by mosquitos (CDC, https://wwwnc.cdc.gov/travel/diseases/malaria) .

Malaria may also, at times, be transmitted through blood transfusion, organ transplantation and from mother to fetus.

(CDC, https://wwwnc.cdc.gov/travel/yellowbook/2020/travel-related-infectious-diseases/malaria ).

While transmission through blood transfusion is rare in the U.S., there are no approved blood tests currently available to screen

blood donation for malaria.

There were approximately 219 million cases of malaria reported in 2019 globally, resulting in

approximately 409,000 deaths, of which approximately 67% were children.

(WHO, https://www.who.int/news-room/fact-sheets/detail/malaria ).

Symptoms of malaria normally manifest themselves within 7 to 10 days of exposure, and can at times, be mistaken for other illnesses,

including influenza.

Severe malaria is life-threatening and can cause multi-organ failure in adults and severe anemia, metabolic

acidosis and cerebral malaria in children.

The World Health Organization estimates that almost half of the global population is at

risk of contracting malaria.

Infants, children under 5 years of age, pregnant women and immune compromised individuals are highest

risk of developing the disease.

Additionally, non-immune migrants, mobile populations and travelers are at risk of developing severe

Neurological issues in children may continue to persist after cerebral malaria, including ataxia, palsy, speech impairment,

deafness and blindness.

More than 100 species of Plasmodium have been

Four of the species have been recognized as naturally infecting humans, while one that infects macaques and has been identified

as a cause of zoonotic malaria.

In rare cases, additional species may infect humans.

The primary four parasites that cause human infection

falciparum, P.

ovale and ( https://www.cdc.gov/malaria/about/biology/index.html ).

naturally occurring in macaques in Southeast Asia and has recently been reported as the cause zoonotic malaria, especially in Malaysia.

falciparum is found world-wide, can cause severe malaria and is the predominate human malaria causing species around the world.

There is currently one vaccine for malaria, RTS,S/AS01

(MVI-GSK) targeting the falciparum CS protein, which received a positive opinion from the European Medicines Agency (EMA) for use outside

of the European Union in infants 6 weeks of age and older.

( https://www.ema.europa.eu/en/news/first-malaria-vaccine-receives-positive-scientific-opinion-ema )

According to the EMA, the World Health Organization and the relevant regulatory agencies for countries outside of the European Union can

authorize its use.

The vaccine is currently being administered to infants and children in parts of Africa within high transmission regions.

The vaccine’s efficacy appears to wane after five years (Laurens MB.

RTS,S/AS01 vaccine (Mosquirix™):

Vaccin Immunother.

ENTADFI is a combination of

finasteride, a 5ARI, and tadalafil, a PDE5 inhibitor, that is indicated for use in the treatment of BPH is men with an enlarged prostate

for up to 26 weeks of treatment.

Tadalafil has been shown to be effective in reducing the erectile dysfunction symptoms of BPH, although

the exact mechanism by which the drug reduces the symptoms of LUTS is unknown.

Finasteride acts to shrink the prostate by preventing the conversion of testosterone to dihydrotestosterone.

This fixed combination of two different, clinically effective, BPH medications delivers rapid and sustained relief from the symptoms of

The combination of tadalafil and finasteride has demonstrated significant clinical efficacy within four weeks of treatment with significant

improvement in sexual functioning.

8 A single capsule formulation

of these two drugs removes the barriers to treatment adherence associated with delayed or poor symptom relief and a complex treatment

regimen involving separate individual medications.

Proclarix Competition Analysis

The molecular diagnostics

field is intensely competitive and characterized by rapid technological changes, frequent new product introductions, changing customer

preferences, emerging competition, evolving industry standards, reimbursement uncertainty and price competition.

Moreover, recent consolidation

in the industry permits larger clinical laboratory service providers to increase cost efficiencies and service levels, resulting in more

intense competition.

The market for assessing men

at risk for prostate cancer is large, with many competitors some of which possess substantially greater financial, selling, logistical

and laboratory resources, more experience in dealing with third-party payors, and greater market penetration, purchasing power and marketing

budgets, as well as more experience in providing diagnostic services.

Some companies and institutions are developing liquid biopsy (blood

and urine)-based tests and diagnostic tests based on the detection of proteins, mRNA, nucleic acids, or the presence of fragments of mutated

genes that are associated with prostate cancer.

These competitors could have technological, financial, reputational, and market access

advantages over us.

There are a number of tests

already on the market or in clinical testing or commercial development that are also intended to triage diagnostics in men with moderately

elevated PSA levels.

Of these tests the majority also target solely PSA as a biomarker.

Certain isoforms of PSA are differentiated, or

transcript levels (mRNA) are determined in addition to protein levels.

Of these tests the best established is %fPSA, which is also available

from all suppliers of the PSA test, including market leaders Abbott Laboratories, Roche Diagnostics, Siemens Healthineers AG and Beckman

Coulter, Inc.

However, the sensitivity and specificity improvements are very modest.

The 4Kscore from OPKO Health,

OPK) and the phi score from Beckman Coulter, Inc.

measure additional forms of PSA and related proteins but they do not include

additional biomarkers either.

The 4Kscore test is a blood based 4-plex test which combines the results of the blood test with clinical

information in an algorithm that calculates a patient’s percent risk for aggressive prostate cancer prior to an initial or repeat

biopsy (no previous diagnosis of prostate cancer).

The 4Kscore test received marketing approval from the FDA in December 2021.

score combines the results of three blood tests to provide information about what elevated PSA levels might mean and the probability of

finding prostate cancer on biopsy.

The IsoPSA test of Cleveland Diagnostics, Inc.

analyzes structural changes of PSA to detect underlying

cancer biology.

Over the last decade, gene-based

testing in urine targeting additional biomarkers became available.

The PCA3 test from Gen-Probe Inc.

(now a part of Hologic, Inc.) was

the first genetic assay to be introduced to the market.

The SelectMDx test from MdxHealth SA measures a combination of two genes and integrates

them together with PSA value, prostate volume, patient age and digital rectal exam to a risk score.

The assay targets mRNA transcripts

in the patient’s urine.

mRNA is normally not sufficiently shed into urine to allow for direct analysis.

Therefore, this test method

requires prostate massage prior to sample collection and the urine samples will be collected in a specialized practice.

The ExoDx IntelliScore

from Exosome Diagnostics, Inc., a subsidiary of Bio-Techne Corporation, measures PCA3 as well as other gene transcripts in exosomes harvested

The method does not require prostate massage, however, because mRNA is relatively unstable, the samples require cold storage

in shipment and relatively rapid testing turn-around.

The Stockholm3 test is part

of an academic initiative, OncoWatch, led by the Karolinska Institute, Sweden and funded by the European Institute of Innovation and Technology

Health program.

Established in 2020, A3P Biomedical AB (publ) is commercializing the Stockholm3 test.

It is a blood-based test that predicts

the risk for aggressive prostate cancer at biopsy by analyzing five protein markers, more than 100 genetic markers and clinical data.

Except for PCA3, Prostate

Health Index and 4Kscore, all of the above-mentioned tests are only available as a testing service through specialized reference laboratories,

they are not offered as commercial products.

Testing is performed centrally as a laboratory developed test (“LDT”) by a single

diagnostic laboratory.

Uptake of LDTs in the United States has been limited, and in Europe they are mostly not known to urologists.

CIALIS [Package Insert].

Indianapolis, IN:

Eli Lilly and Co;

7 ENTADFI [Package Insert].

Cincinnati, OH:

Blue Water Biotech,

8 Casabé A et al.

J Urol 191:727-733 2014.

9 Lee LK et al.

Patient Prefer Adherence 10:1205-1215 2026;

Glina S et al.

12(1):129-138 2015;

Doi:10.1080/21645515.2019.1669415).

The recommended course of action for preventing malaria

is prevention of mosquito bites, and for those most vulnerable, a preventative treatment with sulfadoxine-pyrimethamine, especially in

high transmission areas (WHO).

In certain regions, the WHO has recommended the addition of amodiaquine to children under 5 years of age

monthly during the high transmission season, along with sulfadoxine-pyrimethamine.

Many regions employ mosquito control measures to reduce

mosquito populations, however, 73 countries have reported mosquito resistance to at least 1 of the 4 most commonly used insecticides,

while 23 countries have reported mosquito resistance to all of the commonly used insecticides.

Once malaria is diagnosed, the two most common

treatments are Chloroquine phosphate and Artemisinin-based combination (ACT) therapies.

Chloroquine is the preferred treatment, however,

some malaria parasites have become resistant to chloroquine and it may not be an effective treatment.

ACT is a combination of two or more

drugs that work against the malaria parasite in different ways.

This is usually the preferred treatment for chloroquine-resistant malaria.

However, as recently reported in Nature Medicine, there is growing concern about Artemisinin — derivative resistant P.falciparum

in the Greater Mekong subregion (Cambodia, Thailand, Vietnam, Myanmar and Laos) ( https://www.nature.com/articles/s41591-020-1005-2.pdf ).

Previous occurrences of resistant strains also first appeared in the Greater Mekong subregion and then spread to other parts of the world.

( https://www.nature.com/articles/s41591-020-1005-2.pdf ).

We hold the exclusive global license for the novel

norovirus-malaria combination vaccine from Cincinnati Children’s Hospital Medical Center, or CHMC, CHMC researchers engineered the

norovirus major structural protein VP1 such that the N-terminal shell (S) and C-terminal protruding (P) domains of VPI could be expressed

as separate S 60 and P 24 VLPs.

Unlike norovirus VLPs composed of the intact VP1 protein or the unmodified S 60

fragment, our S 60 and P 24 VLPs can be expressed in E.

The researchers, Xi Jason Jiang, Ph.D., and Ming

Tan, Ph.D., demonstrated that S 60 VLPs could be used to present foreign antigens on the surface of the S 60 VLP.

Further, it has also demonstrated that foreign antigens could also be expressed on the surface of the P 24 VLP.

Norovirus (NoV) S&P Nanoparticle Versatile Vaccine Platform ).

The proposed norovirus-malaria vaccine, P-CS)TSR is based on

the P 24 VLP technology.

Our vaccine production is based on an E.coli expression platform.

The circumsporozoite (CS) protein is the major

surface component of P.

falciparum sporozoites and is essential for host cell invasion.

Our vaccine, developed by Jiang and Ming

from CHMC, combines a small domain of the CS protein with the norovirus P 24 particle creating a chimeric nanoparticle capable

of eliciting an immune response.

A mouse immunization study was conducted using the P 24 particle presenting the small domain

of the CS protein.

Mice (n=16) were immunized three times with the chimeric nanoparticle using aluminum hydroxide as an adjuvant, 3D7-His,

3D7-GST and PBS.

Sera was collected and evaluated.

High antibody titers, as determined by ELISA,

were observed after the second immunization and higher titers were observed after the third immunization.

The antibodies were also shown

to recognize the plasmodium falciparum 3D7 strain using immunofluorescence assays.

These data demonstrate the potential of our vaccine

candidate against malaria.

We expect to conduct an animal challenge study to further analyze the protective nature of BWV-302 and support

an IND application.

Mouse malaria antibody titer post-immunization

Antibody titer after 2 nd immunization

Antibody titer after 3 rd immunization

IFA of plasmodium sporozoites (3D7)

stained with anti-P 24 particle presenting the small domain of the CS protein mouse sera

We anticipate conducting an animal challenge study

for BWV-302 in the second half of 2023.

Upon completion, the technology will be transferred to a partner contract manufacturing organization

(CMO) for process optimization, GMP production and toxicology studies, as well as other studies required by the FDA for IND submission,

currently anticipated for the second half of 2022.

Following IND submission immediately upon completion of the toxicology study, if successful,

we intend to initiate our Phase I clinical trial in healthy adults ages 18 to 54 upon acceptance by the FDA.

Exploration of a Novel Monkeypox Vaccine Using BWV VLP Platform

In addition to norovirus, rotavirus, and malaria,

we are exploring the potential to utilize the norovirus S&P platform to create a novel monkeypox vaccine.

Research into the viability

of this vaccine candidate is ongoing and includes insertion of selected monkeypox antigens into the S&P particles and sequence optimization,

establishing the optimal expression system to enhance future manufacturing of the vaccine product, as well as immunogenicity and efficacy

studies at various stages of development.

To date, antigens of interest have been identified and the vaccine construct has been generated

in small amounts using our VLP platform licensed from CHMC.

Immunogenicity studies in mice are ongoing and results will inform our decision

to move forward with a challenge study, which will evaluate the in vivo efficacy of this vaccine in the mouse model.

Given this vaccine

is in early stages of development and optimization, study designs and development paths are flexible.

Upon completion of immunogenicity

and efficacy studies with promising results, this technology may be transferred to a partner CMO for process optimization, GMP production

and toxicology studies, as well as other studies required by the FDA for IND submission.

Monkeypox is a viral zoonosis, or a virus transmitted

from humans to animals, and is a member of the same genus as the smallpox virus, Orthopoxvirus .

While clinical symptoms of monkeypox

are less severe than those of smallpox, several recent outbreaks and the eradication of smallpox in 1980 have brought global attention

to the prevention of monkeypox spread.

Monkeypox primarily occurs in central and west Africa, often in proximity to tropical rainforests,

but has been increasing in urban areas, particularly with a recent outbreak in 2022 that spread to 110 countries and caused approximately

85,000 cases as of January 2023.

There are currently two approved vaccines for the

prevention of monkeypox infection in the United States:

JYNNEOS and ACAM2000.

Both vaccines were originally approved to prevent smallpox

infection but have been approved for use in monkeypox.

JYNNEOS is a 2-dose vaccine, with doses given 4 weeks apart and is a live-attenuated,

non-replicating vaccine while ACAM2000 is a live, replication-competent vaccinia virus given via bifurcated needle in a single dose.

are designed to elicit an immune response to prevent monkeypox and smallpox infection without causing disease.

While vaccines have shown

efficacious in preventing disease, there remains a need for additional vaccination options, particularly those that are not comprised

of live virus.

Chlamydia Vaccine

Chlamydia Background

Chlamydia is a sexually transmitted infection caused

by the bacterium Chlamydia trachomatis and can impact both men and women.

According to the Centers for Disease Control and Prevention,

there were about 1.6 million new cases of chlamydia reported in 2020 in the United States and globally, the World Health Organization

estimates about 129 million new cases each year.

Additionally, given high estimations of asymptomatic cases and low availability of diagnostic

testing in low- and middle-income countries, these annual estimates may be an underrepresentation.

Currently, there is no vaccine available to prevent

chlamydia infection, and the main treatment is through antibiotic regimens with the possibility of reinfection after antibiotics have

treated the disease.

If left undetected or untreated, Chlamydia represents a major cause of pelvic inflammatory disease and infertility

It is estimated that about 10 – 15% of women that experience untreaded chlamydia develop pelvic inflammatory disease and

face chronic pain or fertility problems later in life.

Additionally, should women contract chlamydia during pregnancy or give birth with

an active infection, newborns may develop eye infections or pneumonia resulting from the disease.

BWV-401 Approach

BWV-401 is an orally delivered, live-attenuated

chlamydia vaccine derived from a murine strain, Chlamydia muridarum, developed in the laboratory of Guangming Zhong, M.D., Ph.D.

at the University of Texas Health at San Antonio.

By administering this vaccine orally, BWV-401 may elicit transmucosal immunity and provide

protection against chlamydia in the genital tract post-vaccination without altering the gut microbiota or the development of gut mucosal

resident memory T cell responses to non-chlamydial infection.

In the initial publication establishing this approach

as a viable vaccine development pathway, mice were intragastrically inoculated with C.

muridarum to mimic oral immunization.

each inoculation, both vaginal and rectal swabs were periodically taken to monitor viable C.

muridarum colonization or organs/tissues

were harvested to titrate viable organisms.

Through this study, researchers identified the following key findings supporting further development

of this vaccine candidate.

muridarum induces transmucosal protection against genital tract infection.

muridarum colonization in the gastrointestinal

tract correlated with reduced C.

muridarum infection in the genital tract of the same mice.

First, the extent to which C.

muridarum organisms

spread from the genital tract into the GI tract inversely correlated with their course of shedding in the genital tract.

coinoculation of C.

muridarum organisms into the GI tracts of mice infected vaginally with plasmid-deficient C.

muridarum significantly

shortened the course of vaginal infection.

Finally, the reduced spreading of plasmid-free C.

muridarum into the GI tract also minimized

immunity against reinfection in the genital tract (Fig.

Effect of intragastric inoculation as an oral vaccination

on genital tract susceptibility to C.

muridarum challenge infection.

C57BL/6J mice intragastrically inoculated with buffer only (control

group, n 8) (a and a1) or 2x10E5 IFU of wild-type C.

muridarum (clone CM-mCherry, immunization group, n 8) (b and b1) were challenged

intravaginally on day 56 with 2x10E5 IFU of wild-type C.

muridarum clone G13.32.1.

(A) Mice were monitored for live organism shedding

by the collection of both vaginal (a and b) and rectal (a1 and b1) swab specimens over the time course displayed along the x axis.

results are expressed as the log10 number of IFU per swab specimen along the y axis.

Black bars, titers of G13.32.1;

red bars, titers

of CM-mCherry;

dark red bars, titers of both G13.32.1 and CM-mCherry.

Note that on days 3, 7, and 14 after intravaginal challenge (designated

in parentheses as 3=, 7=, and 14=, respectively) after intragastric immunization, immunized mice displayed a >1,000-fold decrease in

the number of IFU by evaluation of vaginal swab specimens at each time point (*, P< 0.05, Wilcoxon rank-sum test).

The overall shedding

course was also significantly reduced (*, P<0.05, Wilcoxon rank-sum test, AUC, for panel b versus panel a).

(B) All mice were sacrificed

on day 128 after intragastric immunization (or day 63= after challenge) for evaluation of the upper genital tract pathology both macroscopically

(a and b) and microscopically (d and e).

(a and b) Representative macroscopic images of one entire genital tract from the control (a)

and immunization (b) groups are shown.

White arrows, oviducts positive for hydrosalpinges.

Magnified images of oviduct/ovary regions are

shown on the right of the overall genital tract images, with the white numbers indicating the hydrosalpinx scores.

and the severity of hydrosalpinx were quantitated.

The group immunized in the GI tract developed a significantly lower incidence ($, P<0.05,

Fisher’s exact test) and a reduced score (*, P<0.05, Wilcoxon rank-sum test) compared with those for the control mice.

e) Microscopically, severely dilated oviducts (marked with a white line with arrows at both ends) were easily identified from control

mice, as shown in the representative image (d), while the immunized mice mostly displayed normal oviduct cross sections ©.

e1) The inflammatory cells were identified using a 100x objective lens, as shown in the representative images from the control (d1) and

immunized (e1) mice.

The areas observed with a 100x objective lens are marked with white squares in the 10x images.

(f) The severity of

the inflammatory infiltration was semiquantitated using the criteria described in the Materials and Methods section.

Note that the immunized

mice developed scores significantly decreased (*, P<0.05, Wilcoxon rank-sum test) compared with those for the control mice.

● Transmucosal

protection is rapidly induced, durable, and independent of sustained C.

muridarum colonization in the gastrointestinal tract.

the time required for GI tract C.

muridarum induction of transmucosal protection and the duration of protection were determined (Fig.

One week after intragastric inoculation with CM-mCherry, mice gained significant resistance to intravaginal challenge infection with

G13.32.1, with G13.32.1 shedding being reduced by >100-fold on day 3 and the course of infection being shortened by ~1 week, leading

to a significant reduction in both the overall infection course and the upper genital tract pathology.

The protection was enhanced over

1) and lasted 20 weeks.

Whether the transmucosal protection was dependent on ongoing CM-mCherry colonization in the GI tract

was further determined (Fig.

Mice with or without CM-mCherry in the GI tract for 28 days were either left untreated or treated with

doxycycline daily for 2 weeks.

After resting for another 2 weeks, the mice were vaginally challenged with G13.32.1.

Mice colonized with

CM-mCherry in the GI tract for 56 days became highly resistant to intravaginal challenge infection and hydrosalpinx induction, as described

Importantly, after the immunized mice received daily doxycycline treatment between days 28 and 42, which completely cured the

GI tract CM-mCherry infection, the mice still maintained a robust resistance to intravaginal challenge infection and hydrosalpinx development.

Thus, within 4 weeks, intragastrically inoculated C.

muridarum induced a robust memory response that was protective.

Mock-immunized mice

similarly treated with doxycycline developed severe hydrosalpinx after the same intravaginal challenge, suggesting that the doxycycline

treatment protocol did not affect chlamydial pathogenicity in the upper genital tract.

It is worth noting that although the immunized

mice were resistant to challenge infection with C.

muridarum in the genital tract, the GI tract remained susceptible to colonization

muridarum organisms.

Intragastric immunization elicits rapid and durable protective

immunity to genital tract challenge.

C57BL/6J mice with (n 5) or without (n 5) prior intragastric immunization with 2x10E5 IFU of CM-mCherry

for 1 week (1W) (a) or 20 weeks (20W) (b) were challenged vaginally with clone G13.32.1.

The mice were monitored for C.

muridarum shedding

by evaluation of both vaginal and rectal (not shown) swab specimens on days 3 and 7 postinfection (3= and 7=, respectively) and weekly

The results are expressed as the log10 number of IFU per swab specimen.

Mice were significantly resistant to a genital tract

challenge only 1 week after immunization in the GI tract (*, P<0.05, Wilcoxon rank-sum test, AUC), and the resistance increased and

lasted for up to 20 weeks (**, P< 0.01, Wilcoxon rank-sum test, AUC).

All mice were sacrificed on day 56 after the challenge infection,

and the upper genital tract was evaluated for the incidence (in percent) of hydrosalpinx and the severity score (mean + standard

Immunization via the GI tract resulted in significant protection against hydrosalpinx induced by the vaginal infection (#,

P<0.05, Fisher’s exact test;

*, P<0.05, Wilcoxon rank-sum test;

**, P<0.01, Wilcoxon rank-sum test).

The durable transmucosal protection induced by intragastric

immunization is not dependent on long-term gastrointestinal infection.

Groups of C57BL/6J mice immunized intragastrically with 2x10E5

IFU of CM-mCherry (n 5 for panel a and n 7 for panel b) or not immunized (n 6) © were treated on day 28 with doxycycline (20 ug/kg

of body weight intragastrically once daily) for 2 weeks (days 28 to 42) (b and c) or were not treated with doxycycline (a).

The doxycycline-treated

mice were then rested for 2 weeks (days 43 to 56).

On day 56 after immunization in the GI tract, all mice were intravaginally challenged

with 2x10E5 IFU of clone G13.32.1.

(A) Mice were monitored for the shedding of chlamydiae by evaluation of both vaginal (a to c) and rectal

(a1 to c1) swab specimens over the course of infection (the days after challenge infection are designated 3= to 56= in parentheses).

are expressed as the log10 number of IFU per swab specimen.

Mice in the immunization plus doxycycline treatment group displayed no IFU

in the rectal swab specimens prior to the intravaginal challenge (days 31 to 56) (b) but maintained transmucosal protection against chlamydial

infection in the genital tract (*, P<0.05, Wilcoxon rank-sum test, for panel b1 versus panel c1), equivalent to the findings for immunized

mice not treated with doxycycline (*, P<0.05, Wilcoxon rank-sum test, for panel a1 versus panel c1).

These two groups maintained similar

levels of protection (*, P<0.05, Wilcoxon rank-sum test, for panel b1 versus panel a1).

(b and c) The genital tract G13.32.1 organisms

spread to the GI tracts.

(a and a1) Black bars, G13.32.1 alone;

dark red bars;

both CM-mCherry and G13.32.1.

(B) On day 114 after intragastric

immunization, all mice were sacrificed to evaluate the upper genital tract pathology macroscopically.

Representative images of the entire

genital tracts from the groups receiving immunization without doxycycline treatment (a2), immunization plus doxycycline treatment (b2),

or doxycycline treatment without immunization (c2) are shown.

White arrows, oviducts positive for hydrosalpinges.

Magnified images of

oviduct/ovary regions are shown on the right of the overall genital tract images, with the white numbers indicating the hydrosalpinx scores.

Both the incidence of hydrosalpinx and the hydrosalpinx severity score (mean standard deviation) are listed above the corresponding images.

Regardless of doxycycline treatment, immunized mice were significantly protected from the development of hydrosalpinx (*, P<0.05, Wilcoxon

rank-sum test, for the immunization alone group in panel a2 versus panel c2 and for the immunization plus doxycycline treatment group

in panel b2 versus panel c2).

● Gastrointestinal

tract Chlamydia muridarum is nonpathogenic.

Having demonstrated the strong transmucosal protective immunity induced by GI tract C.

muridarum, researchers next evaluated whether C.

muridarum colonization in the GI tract is pathogenic.

Since long-lasting C.

colonization is restricted to the cecum, colon, and rectum, researchers carefully examined the mouse colons.

There was no significant

difference in the gross appearance or length of the cecum, colon, and rectum between mice with C.

muridarum colonization and mice without

muridarum colonization for 7, 28, or 56 days, suggesting that C.

muridarum did not cause colitis.

muridarum inclusions were microscopically

localized in the colon mucosal epithelial cells.

Despite the presence of clusters of C.

muridarum-infected epithelial cells, the epithelial

tissue architecture remained intact when the adjacent sections were examined following hematoxylin-eosin (H&E) staining.

there was a general lack of significant inflammatory infiltration, although scattered inflammatory cells were always detectable.

to control colonic tissue, no significant difference was found between infected and noninfected mice (data not shown).

We believe that this data, presented by Zhong

et al., is sufficient to pursue development of this vaccine candidate.

Given the high numbers of Chlamydia cases both in the United States

and around the globe each year, as well as the lack of an available Chlamydia vaccine, we believe this vaccine will serve a high unmet

We hold a global, exclusive right to develop a novel Chlamydia vaccine from this technology at the University of Texas Health at

BWV-401 Development

As the approach to utilize an attenuated murine

strain of Chlamydia is novel, we plan to establish the infectivity of C.

muridarum in a non-human primate model.

This will provide

robust data supporting potential efficacy of this vaccine candidate in humans, once we reach clinical trials.

In collaboration with Dr.

Zhong and the University of Texas Health at San Antonio, we will develop a protocol to test both wild-type C.

muridarum and our

attenuated strain in non-human primates and complete necessary endpoints for this study.

Proper endpoints will allow us to determine the

ability of murine strain C.

muridarum to infect non-human primates and the efficacy of the attenuated strain, which will represent

our vaccine candidate, following challenge of the non-human primates with human Chlamydia strain, Chlamydia trachomatis.

Following completion of the non-human primate

study, we plan to transfer this technology to a partner CMO for process optimization, GMP production and toxicology studies, as well as

other studies required by the FDA for IND submission.

Government Regulation and Product Approval

The FDA and other regulatory authorities at federal,

state and local levels, as well as in foreign countries, extensively regulate, among other things, the research, development, testing,

manufacture, quality control, import, export, safety, effectiveness, labeling, packaging, storage, distribution, record keeping, approval,

advertising, promotion, marketing, post-approval monitoring and post-approval reporting of drugs and biologics such as those we are developing.

Small molecule drugs are subject to regulation

under the Food, Drug, and Cosmetic Act, or FDCA, and biological products are additionally subject to regulation under the Public Health

Service Act, or PHSA, and both are subject to additional federal, state, local and foreign statutes and regulations.

We, along with third-party

contractors, will be required to navigate the various preclinical, clinical and commercial approval requirements of the governing regulatory

agencies of the countries in which we wish to conduct studies or seek approval or licensure of our product candidates.

Cindolo L et al.

BMC Urol 96(15):

In recent years, MRI-based

diagnosis followed by targeted biopsy is becoming the standard of choice in specialized centers.

As MRI instrumentation is costly and

its availability is still limited, there is a need for diagnostics supporting the decision to perform MRI that Proclarix can fulfill.

MRI is not regarded as competitive to the Proclarix positioning, but complementary.

Competitive Advantages of Proclarix

We believe Proclarix has

important competitive advantages:

invasive, high reproducibility, no prostate massage required, suitably stable for shipment, the most common sample type in clinical

laboratories and therefore fitting in current lab workflow

Immunoassay-based

with existing laboratory instrumentation in local laboratory

to clinical routine, fast time to result

result generation

results independent of operator

Genetics-guided

Cancer-related,

highly plausible biomarkers

Proclarix can be applied in

any diagnostic laboratory, using readily available immunoassay technology platforms.

Furthermore, Proclarix fits very well into the current

laboratory workflow, which is important for laboratories that are driven by efficiency and cost.

The stakeholders benefit in various ways from

more certainty whether a biopsy is really needed through a minimally invasive procedure with a fast time to result.

This results in reduced

anxiety about prostate cancer diagnosis and less complications and side effects from biopsies.

Focus on relevant patients with clinically significant cancer and increased

patient satisfaction by significantly reducing unneeded prostate biopsies and its accompanying complications.

No need for additional training

or new logistic processes:

Standard blood-drawing equipment can be used, and the blood sample sent to the current laboratory.

revenue with no additional investment for new equipment because Proclarix is readily applicable in most laboratories.

Payer (insurance company):

Increase profits by saving costs for avoided biopsies (accompanied by risk of complications, discomfort) and resulting overtreatment.

Government Regulation

The FDA and other regulatory

authorities at federal, state and local levels, as well as in foreign countries, extensively regulate, among other things, the research,

development, testing, manufacture, quality control, import, export, safety, effectiveness, labeling, packaging, storage, distribution,

record keeping, approval, advertising, promotion, marketing, post-approval monitoring and post-approval reporting of drugs and diagnostics.

Small molecule drugs, like

ENTADFI, are subject to regulation in the United States under the Food, Drug, and Cosmetic Act (“FDCA”) and are subject to

additional federal, state, local and foreign statutes and regulations.

We, along with third-party contractors, are required to navigate

the various requirements of the governing regulatory agencies of the countries in which we wish to market products.

United States

Biopharmaceuticals Regulation

The process required by the FDA before drug and

biologic product candidates may be marketed in the United States generally involves the following:

Pharmaceuticals Regulation

The process required by the

FDA before drugs may be marketed in the United States generally involves the following:

of extensive preclinical laboratory tests and animal studies performed in accordance with applicable regulations, including the FDA’s

2 unchanged sentences

by an independent institutional review board or ethics committee at each clinical site before the trial is commenced;

● performance

of adequate and well-controlled human clinical trials in accordance with FDA’s Good Clinical Practice, or GCP, regulations to establish

the safety and efficacy of a drug candidate and safety, purity and potency of a proposed biologic product candidate for its intended

● preparation

of and submission to the FDA of a new drug application, or NDA, or biologics license application, or BLA, as applicable, after completion

of all pivotal clinical trials;

● satisfactory

of adequate and well-controlled human clinical trials in accordance with FDA’s Good Clinical Practice, or GCP, regulations

to establish the safety and efficacy of a drug candidate for its intended purpose;

of and submission to the FDA of a new drug application (“NDA”) after completion of all pivotal clinical trials;

completion of an FDA Advisory Committee review, if applicable;

determination by the FDA within 60 days of its receipt of an NDA or BLA to file the application for review;

● satisfactory

completion of an FDA pre-approval inspection of the manufacturing facility or facilities at which the proposed product is produced to

assess compliance with current Good Manufacturing Practice requirements, or cGMPs, and of selected clinical investigation sites to assess

compliance with GCPs;

review and approval of an NDA, or licensure of a BLA, to permit commercial marketing of the product for particular indications for use

in the United States.

Preclinical and Clinical Development

Prior to beginning the first clinical trial with

a product candidate, we must submit an IND to the FDA.

An IND is a request for authorization from the FDA to administer an investigational

new drug product to humans.

The central focus of an IND submission is on the general investigational plan and the protocol or protocols

for preclinical studies and clinical trials.

The IND also includes results of animal and in vitro studies assessing the toxicology, pharmacokinetics,

pharmacology and pharmacodynamics characteristics of the product, chemistry, manufacturing and controls information, and any available

human data or literature to support the use of the investigational product.

An IND must become effective before human clinical trials

The IND automatically becomes effective 30 days after receipt by the FDA, unless the FDA, within the 30-day period, raises

safety concerns or questions about the proposed clinical trial.

In such a case, the IND may be placed on clinical hold and the IND sponsor

and the FDA must resolve any outstanding concerns or questions before the clinical trial can begin.

Submission of an IND therefore may

or may not result in FDA authorization to begin a clinical trial.

Clinical trials involve the administration of

the investigational product to human subjects under the supervision of qualified investigators in accordance with GCPs, which include

the requirement that all research subjects provide their informed consent for their participation in any clinical study.

Clinical trials

are conducted under protocols detailing, among other things, the objectives of the study, the parameters to be used in monitoring safety

and the effectiveness criteria to be evaluated.

A separate submission to the existing IND must be made for each successive clinical trial

conducted during product development and for any subsequent protocol amendments.

Furthermore, an independent institutional review board

for each site proposing to conduct the clinical trial must review and approve the plan for any clinical trial and its informed consent

form before the clinical trial begins at that site, and must monitor the study until completed.

Regulatory authorities, the institutional

review board or the sponsor may suspend a clinical trial at any time on various grounds, including a finding that the subjects are being

exposed to an unacceptable health risk or that the trial is unlikely to meet its stated objectives.

Some studies also include oversight

by an independent group of qualified experts organized by the clinical study sponsor, known as a data safety monitoring board, which provides

authorization for whether or not a study may move forward at designated check points based on access to certain data from the study and

may halt the clinical trial if it determines that there is an unacceptable safety risk for subjects or other grounds, such as no demonstration

For purposes of biopharmaceutical development,

human clinical trials are typically conducted in three sequential phases that may overlap or be combined;

The investigational product is initially introduced into patients with the target disease or condition.

These studies are designed

to test the safety, dosage tolerance, absorption, metabolism and distribution of the investigational product in humans, the side effects

associated with increasing doses, and, if possible, to gain early evidence on effectiveness.

The investigational product is administered to a limited patient population to evaluate the preliminary efficacy, optimal dosages

and dosing schedule and to identify possible adverse side effects and safety risks.

The investigational product is administered to an expanded patient population to further evaluate dosage, to provide statistically

significant evidence of clinical efficacy and to further test for safety, generally at multiple geographically dispersed clinical trial

These clinical trials are intended to establish the overall risk/benefit ratio of the investigational product and to provide an

adequate basis for product approval.

In some cases, the FDA may require, or companies

may voluntarily pursue, additional clinical trials after a product is approved to gain more information about the product.

These so-called

Phase 4 studies may be made a condition to approval of the application.

Concurrent with clinical trials, companies may complete additional

animal studies and develop additional information about the characteristics of the product candidate and must finalize a process for manufacturing

the product in commercial quantities in accordance with cGMP requirements.

The manufacturing process must be capable of consistently producing

quality batches of the product candidate and, among other things, must develop methods for testing the identity, strength, quality and

purity of the final product, or for biologics, the safety, purity and potency.

Additionally, appropriate packaging must be selected and

tested and stability studies must be conducted to demonstrate that the product candidate does not undergo unacceptable deterioration over

its shelf life.

During all phases of clinical development, regulatory

agencies require extensive monitoring and auditing of all clinical activities, clinical data, and clinical study investigators.

or the sponsor or its data safety monitoring board may suspend a clinical study at any time on various grounds, including a finding that

the research patients or patients are being exposed to an unacceptable health risk.

Similarly, an institutional review board can suspend

or terminate approval of a clinical study at its institution if the clinical study is not being conducted in accordance with the institutional

review board’s requirements or if the biological product candidate has been associated with unexpected serious harm to patients.

There are also requirements governing the reporting of ongoing clinical trials and completed clinical trial results to public registries.

Sponsors of clinical trials of FDA-regulated products are required to register and disclose certain clinical trial information, which

is publicly available at www.clinicaltrials.gov .

NDA/BLA Submission and Review

Assuming successful completion of all required

testing in accordance with all applicable regulatory requirements, the results of product development, nonclinical studies and clinical

trials are submitted to the FDA as part of an NDA or BLA, as applicable, requesting approval to market the product for one or more indications.

The application must include all relevant data available from pertinent preclinical studies and clinical trials, including negative or

ambiguous results as well as positive findings, together with detailed information relating to the product’s chemistry, manufacturing,

controls, and proposed labeling, among other things.

The submission of an application requires payment of a substantial application user

fee to the FDA, unless a waiver or exemption applies.

The FDA has sixty days from the applicant’s submission to either issue a refusal

to file letter or accept the application for filing, indicating that it is sufficiently complete to permit substantive review.

Once an NDA or BLA has been accepted for filing,

the FDA’s goal is to review standard applications within 10 months after it accepts the application for filing, or, if the application

qualifies for priority review, six months after the FDA accepts the application for filing.

In both standard and priority reviews, the

review process is often significantly extended by FDA requests for additional information or clarification.

The FDA reviews an NDA to

determine whether a drug is safe and effective for its intended use and a BLA to determine whether a biologic is safe, pure and potent.

FDA also reviews whether the facility in which the product is manufactured, processed, packed or held meets standards designed to assure

and preserve the product’s identity, safety, strength, quality, potency and purity.

The FDA may convene an advisory committee to

provide clinical insight on application review questions.

Before approving an NDA or BLA, the FDA will typically inspect the facility

or facilities where the product is manufactured.

The FDA will not approve an application unless it determines that the manufacturing processes

and facilities are in compliance with cGMP requirements and adequate to assure consistent production of the product within required specifications.

Additionally, before approving an application, the FDA will typically inspect one or more clinical sites to assure compliance with GCPs.

If the FDA determines that the application, manufacturing process or manufacturing facilities are not acceptable, it will outline the

deficiencies in the submission and often will request additional testing or information.

Notwithstanding the submission of any requested

additional information, the FDA ultimately may decide that the application does not satisfy the regulatory criteria for approval.

After the FDA evaluates an application and conducts

inspections of manufacturing facilities where the investigational product and/or its drug substance will be manufactured, the FDA may

issue an approval letter or a Complete Response letter.

An approval letter authorizes commercial marketing of the product with specific

prescribing information for specific indications.

A Complete Response letter will describe all of the deficiencies that the FDA has identified

in the application, except that where the FDA determines that the data supporting the application are inadequate to support approval,

the FDA may issue the Complete Response letter without first conducting required inspections, testing submitted product lots and/or reviewing

proposed labeling.

In issuing the Complete Response letter, the FDA may recommend actions that the applicant might take to place the application

in condition for approval, including requests for additional information or clarification, which may include the potential requirement

for additional clinical studies.

The FDA may delay or refuse approval of an application if applicable regulatory criteria are not satisfied,

require additional testing or information and/or require post-marketing testing and surveillance to monitor safety or efficacy of a product.

If regulatory approval of a product is granted,

such approval will be granted for particular indications and may entail limitations on the indicated uses for which such product may be

For example, the FDA may approve the application with a risk evaluation and mitigation strategy, or REMS, to ensure the benefits

of the product outweigh its risks.

A REMS is a safety strategy to manage a known or potential serious risk associated with a product and

to enable patients to have continued access to such medicines by managing their safe use, and could include medication guides, physician

communication plans, or elements to assure safe use, such as restricted distribution methods, patient registries and other risk minimization

The FDA also may condition approval on, among other things, changes to proposed labeling or the development of adequate controls

and specifications.

Once approved, the FDA may withdraw the product approval if compliance with pre- and post-marketing requirements is

not maintained or if problems occur after the product reaches the marketplace.

The FDA may require one or more Phase 4 post-market studies

and surveillance to further assess and monitor the product’s safety and effectiveness after commercialization, and may limit further

marketing of the product based on the results of these post-marketing studies.

Expedited Development and Review Programs

The FDA offers a number of expedited development

and review programs for qualifying product candidates.

The fast track program is intended to expedite or facilitate the process for reviewing

new products that meet certain criteria.

Specifically, new products are eligible for fast track designation if they are intended to treat

a serious or life-threatening disease or condition and demonstrate the potential to address unmet medical needs for the disease or condition.

Fast track designation applies to the combination of the product and the specific indication for which it is being studied.

of a fast track product has opportunities for frequent interactions with the review team during product development and, once an NDA or

BLA is submitted, the product may be eligible for priority review.

A fast track product may also be eligible for rolling review, where

the FDA may consider for review sections of the NDA or BLA on a rolling basis before the complete application is submitted, if the sponsor

provides a schedule for the submission of the sections of the application, the FDA agrees to accept sections of the application and determines

that the schedule is acceptable, and the sponsor pays any required user fees upon submission of the first section of the application.

A product intended to treat a serious or life-threatening

disease or condition may also be eligible for breakthrough therapy designation to expedite its development and review.

A product can receive

breakthrough therapy designation if preliminary clinical evidence indicates that the product, alone or in combination with one or more

other drugs or biologics, may demonstrate substantial improvement over existing therapies on one or more clinically significant endpoints,

such as substantial treatment effects observed early in clinical development.

The designation includes all of the fast track program features,

as well as more intensive FDA interaction and guidance beginning as early as Phase 1 and an organizational commitment to expedite the

development and review of the product, including involvement of senior managers.

Any marketing application for a drug or biologic

submitted to the FDA for approval, including a product with a fast track designation and/or breakthrough therapy designation, may be eligible

for other types of FDA programs intended to expedite the FDA review and approval process, such as priority review and accelerated approval.

A product is eligible for priority review if it has the potential to provide a significant improvement in the treatment, diagnosis or

prevention of a serious disease or condition.

Priority review designation means the FDA’s goal is to take action on the marketing

application within six months of the 60-day filing date.

Additionally, products studied for their safety

and effectiveness in treating serious or life-threatening diseases or conditions may receive accelerated approval upon a determination

that the product has an effect on a surrogate endpoint that is reasonably likely to predict clinical benefit, or on a clinical endpoint

that can be measured earlier than irreversible morbidity or mortality, that is reasonably likely to predict an effect on irreversible

morbidity or mortality or other clinical benefit, taking into account the severity, rarity, or prevalence of the condition and the availability

or lack of alternative treatments.

As a condition of accelerated approval, the FDA will generally require the sponsor to perform adequate

and well-controlled post-marketing clinical studies to verify and describe the anticipated effect on irreversible morbidity or mortality

or other clinical benefit.

In addition, the FDA currently requires as a condition for accelerated approval pre-approval of promotional

materials, which could adversely impact the timing of the commercial launch of the product.

Fast track designation, breakthrough therapy designation

and priority review do not change the standards for approval but may expedite the development or approval process.

Even if a product qualifies

for one or more of these programs, the FDA may later decide that the product no longer meets the conditions for qualification or decide

that the time period for FDA review or approval will not be shortened.

Orphan Drug Designation

Under the Orphan Drug Act, the FDA may grant orphan

designation to a drug or biologic intended to treat a rare disease or condition, which is a disease or condition that affects fewer than

200,000 individuals in the United States, or more than 200,000 individuals in the United States for which there is no reasonable expectation

that the cost of developing and making available in the United States a drug or biologic for this type of disease or condition will be

recovered from sales in the United States for that drug or biologic.

Orphan drug designation must be requested before submitting an NDA

After the FDA grants orphan drug designation, the generic identity of the therapeutic agent and its potential orphan use are disclosed

publicly by the FDA.

The orphan drug designation does not convey any advantage in, or shorten the duration of, the regulatory review or

approval process.

If a product that has orphan drug designation

subsequently receives the first FDA approval for the disease for which it has such designation, the product is entitled to orphan drug

exclusive approval (or exclusivity), which means that the FDA may not approve any other applications, including a full NDA or BLA, to

market the same drug or biologic for the same indication for seven years, except in limited circumstances, such as a showing of clinical

superiority to the product with orphan drug exclusivity or if the FDA finds that the holder of the orphan drug exclusivity has not shown

that it can assure the availability of sufficient quantities of the orphan drug to meet the needs of patients with the disease or condition

for which the drug was designated.

Orphan drug exclusivity does not prevent the FDA from approving a different drug or biologic for the

same disease or condition, or the same drug or biologic for a different disease or condition.

Among the other benefits of orphan drug

designation are tax credits for certain research and a waiver of the NDA or BLA application fee.

A designated orphan drug may not receive orphan

drug exclusivity if it is approved for a use that is broader than the indication for which it received orphan designation.

exclusive marketing rights in the United States may be lost if the FDA later determines that the request for designation was materially

determination by the FDA within 60 days of its receipt of an NDA to file the application for review;

completion of an FDA pre-approval inspection of the manufacturing facility or facilities at which the proposed product is produced

to assess compliance with current Good Manufacturing Practice requirements, or cGMPs, and of selected clinical investigation sites

to assess compliance with GCPs;

review and approval of an NDA to permit commercial marketing of the product for particular indications for use in the United States.

Post-Approval Requirements

Any products manufactured or distributed by us

pursuant to FDA approvals are subject to pervasive and continuing regulation by the FDA, including, among other things, requirements relating

to record-keeping, reporting of adverse experiences, periodic reporting, product sampling and distribution, and advertising and promotion

of the product.

After approval, most changes to the approved product, such as adding new indications or other labeling claims, are subject

to prior FDA review and approval.

There also are continuing user fee requirements, under which the FDA assesses an annual program fee

for each product identified in an approved NDA or BLA.

Biopharmaceutical manufacturers and their subcontractors are required to register

their establishments with the FDA and certain state agencies, and are subject to periodic unannounced inspections by the FDA and certain

state agencies for compliance with cGMPs, which impose certain procedural and documentation requirements upon us and our third-party manufacturers.

Changes to the manufacturing process are strictly regulated, and, depending on the significance of the change, may require prior FDA approval

before being implemented.

FDA regulations also require investigation and correction of any deviations from cGMPs and impose reporting

requirements upon us and any third-party manufacturers that we may decide to use.

Accordingly, manufacturers must continue to expend time,

money and effort in the area of production and quality control to maintain compliance with cGMPs and other aspects of regulatory compliance.

The FDA may withdraw approval if compliance with

regulatory requirements and standards is not maintained or if problems occur after the product reaches the market.

Later discovery of

previously unknown problems with a product, including adverse events of unanticipated severity or frequency, or with manufacturing processes,

or failure to comply with regulatory requirements, may result in revisions to the approved labeling to add new safety information;

of post-market studies or clinical studies to assess new safety risks;

or imposition of distribution restrictions or other restrictions

under a REMS program.

Any products manufactured

or distributed by us pursuant to FDA approvals, like ENTADFI, are subject to pervasive and continuing regulation by the FDA, including,

among other things, requirements relating to record-keeping, reporting of adverse experiences, periodic reporting, product sampling and

distribution, and advertising and promotion of the product.

After approval, most changes to the approved product, such as adding new indications

or other labeling claims, are subject to prior FDA review and approval.

There also are continuing user fee requirements, under which the

FDA assesses an annual program fee for each product identified in an approved NDA.

Pharmaceutical manufacturers and their subcontractors

are required to register their establishments with the FDA and certain state agencies and are subject to periodic unannounced inspections

by the FDA and certain state agencies for compliance with cGMPs, which impose certain procedural and documentation requirements upon us

and our third-party manufacturers.

Changes to the manufacturing process are strictly regulated, and, depending on the significance of

the change, may require prior FDA approval before being implemented.

Manufacturers must continue to expend time, money and effort in the

area of production and quality control to maintain compliance with cGMPs and other aspects of regulatory compliance.

The FDA may withdraw approval

if compliance with regulatory requirements and standards is not maintained or if problems occur after the product reaches the market.

Later discovery of previously unknown problems with a product, including adverse events of unanticipated severity or frequency, or with

manufacturing processes, or failure to comply with regulatory requirements, may result in revisions to the approved labeling to add new

safety information;

imposition of post-market studies or clinical studies to assess new safety risks;

or imposition of distribution restrictions

or other restrictions under a Risk Evaluation and Mitigation Strategy program.

Other potential consequences include, among other things:

● restrictions

on the marketing or manufacturing of a product, complete withdrawal of the product from the market or product recalls;

fines, warning or untitled letters or holds on post-approval clinical studies;

refusal of the FDA to approve pending applications or supplements to approved applications, or suspension or revocation of existing product approvals;

product seizure or detention, or refusal of the FDA to permit the import or export of products;

consent decrees, corporate integrity agreements, debarment or exclusion from federal healthcare programs;

mandated modification of promotional materials and labeling and the issuance of corrective information;

the issuance of safety alerts, Dear Healthcare Provider letters, press releases and other communications containing warnings or other safety information about the product;

injunctions or the imposition of civil or criminal penalties.

The FDA closely regulates the marketing, labelling,

advertising and promotion of biopharmaceutical products.

A company can make only those claims relating to safety and efficacy, purity

and potency that are approved by the FDA and in accordance with the provisions of the approved label.

However, companies may share truthful

and not misleading information that is otherwise consistent with a product’s FDA approved labelling.

The FDA and other agencies

actively enforce the laws and regulations prohibiting the promotion of off-label uses.

Failure to comply with these requirements can result

in, among other things, adverse publicity, warning letters, corrective advertising and potential civil and criminal penalties.

may prescribe legally available products for uses that are not described in the product’s labelling and that differ from those tested

by us and approved by the FDA.

Such off-label uses are common across medical specialties.

Physicians may believe that such off-label uses

are the best treatment for many patients in varied circumstances.

The FDA does not regulate the behavior of physicians in their choice

of treatments.

The FDA does, however, restrict manufacturer’s communications on the subject of off-label use of their products.

Market Exclusivity

A biological product can obtain pediatric market

exclusivity in the U.S., which, if granted, adds six months to existing exclusivity periods, including some regulatory exclusivity periods

tied to patent terms.

This six-month exclusivity, which runs from the end of other exclusivity protection or patent term, may be granted

based on the voluntary completion of a pediatric study in accordance with an FDA-issued “Written Request” for such a study.

The Biologics Price Competition and Innovation

Act of 2009, or BPCIA, created an abbreviated approval pathway for biological products shown to be biosimilar to, or interchangeable with,

an FDA-licensed reference biological product.

This amendment to the PHSA attempts to minimize duplicative testing.

Biosimilarity, which requires that there be no

clinically meaningful differences between the biological product and the reference product in terms of safety, purity, and potency, can

be shown through analytical studies, animal studies, and a clinical trial or trials.

Interchangeability requires that a product is biosimilar

to the reference product and the product must demonstrate that it can be expected to produce the same clinical results as the reference

product and, for products administered multiple times, the biologic and the reference biologic may be interchanged after one has been

previously administered without increasing safety risks or risks of diminished efficacy relative to exclusive use of the reference biologic.

However, complexities associated with the larger, and often more complex, structure of biological products, as well as the process by

which such products are manufactured, pose significant hurdles to implementation that are still being worked out by the FDA.

The FDA will not accept an application for a biosimilar

or interchangeable product based on the reference biological product until four years after the date of first licensure of the reference

product, and the FDA will not approve an application for a biosimilar or interchangeable product based on the reference biological product

until 12 years after the date of first licensure of the reference product.

“First licensure” typically means the initial date

the particular product at issue was licensed in the U.S.

Date of first licensure does not include the date of licensure of (and a new

period of exclusivity is not available for) a biological product if the licensure is for a supplement for the biological product or for

a subsequent application by the same sponsor or manufacturer of the biological product (or licensor, predecessor in interest, or other

related entity) for a change (not including a modification to the structure of the biological product) that results in a new indication,

route of administration, dosing schedule, dosage form, delivery system, delivery device or strength, or for a modification to the structure

of the biological product that does not result in a change in safety, purity, or potency.

The BPCIA is complex and continues to be interpreted

and implemented by the FDA.

In addition, government proposals have sought to reduce the 12-year reference product exclusivity period.

Other aspects of the BPCIA, some of which may impact the BPCIA exclusivity provisions, have also been the subject of recent litigation.

As a result, the ultimate implementation and impact of the BPCIA is subject to significant uncertainty.

Pediatric Study Plan and Pediatric Exclusivity

Under the Pediatric Research Equity Act, as amended,

or the PREA, certain NDAs and certain NDA supplements must contain data that can be used to assess the safety and efficacy of the product

candidate for the claimed indications in all relevant pediatric subpopulations and to support dosing and administration for each pediatric

subpopulation for which the product is safe and effective.

The FDA may grant deferrals for submission of pediatric data or full or partial

The PREA requires that a sponsor who is planning to submit a marketing application for a product candidate that includes a new

active ingredient, new indication, new dosage form, new dosing regimen or new route of administration submit an initial Pediatric Study

Plan, or the PSP, within 60 days of an end-of-phase 2 meeting or, if there is no such meeting, as early as practicable before the initiation

of the phase 3 or phase 2/3 study.

The initial PSP must include an outline of the pediatric study or studies that the sponsor plans to

conduct, including study objectives and design, age groups, relevant endpoints and statistical approach, or a justification for not including

such detailed information, and any request for a deferral of pediatric assessments or a full or partial waiver of the requirement to provide

data from pediatric studies along with supporting information.

The FDA and the sponsor must reach an agreement on the PSP.

A sponsor can

submit amendments to an agreed-upon initial PSP at any time if changes to the pediatric plan need to be considered based on data collected

from preclinical studies, early phase clinical trials and/or other clinical development programs.

Unless otherwise required by regulation,

the PREA does not apply to a drug for an indication for which orphan designation has been granted, except that the PREA will apply to

an original NDA for a new active ingredient that is orphan-designated if the drug is a molecularly targeted cancer product intended for

the treatment of an adult cancer and is directed at a molecular target that the FDA determines to be substantially relevant to the growth

or progression of a pediatric cancer.

A drug can also obtain pediatric market exclusivity

in the United States.

Pediatric exclusivity, if granted, adds six months to existing exclusivity periods and patent terms.

This six-month

exclusivity, which runs from the end of other exclusivity protection or patent term, may be granted based on the voluntary completion

of a pediatric study in accordance with an FDA-issued “Written Request” for such a study.

Patent Term Restoration and Extension

Depending upon the timing, duration and specifics

of the FDA approval of our product candidates, some of our U.S.

patents may be eligible for limited patent term extension.

The provisions

of the Drug Price Competition and Patent Term Restoration Act, informally known as the Hatch-Waxman Act, permit a patent restoration term

of up to five years as compensation for patent term lost during product development and the FDA regulatory review process.

However, patent

term restoration cannot extend the remaining term of a patent beyond a total of 14 years from the product’s approval date.

term restoration period is generally one-half the time between the effective date of an IND and the submission date of a BLA plus the

time between the submission date of a BLA and the approval of that application.

Only one patent applicable to an approved product is eligible

for the extension and the application for the extension must be submitted prior to the expiration of the patent.

The USPTO, in consultation

with the FDA, reviews and approves the application for any patent term extension or restoration.

In the future, we may apply for restoration

of patent term for one of our currently owned or licensed patents to add patent life beyond its current expiration date, depending on

the expected length of the clinical trials and other factors involved in the filing of the relevant BLA.

Many other countries also provide for patent term

extensions or similar extensions of patent protection for biologic products.

For example, in Japan, it may be possible to extend the patent

term for up to five years and in Europe, it may be possible to obtain a supplementary patent certificate that would effectively extend

patent protection for up to five years.

Federal and State Fraud and Abuse, Data Privacy and Security, and

Transparency Laws and Regulations

In addition to FDA restrictions on marketing of

pharmaceutical products, federal and state healthcare laws and regulations restrict business practices in the biopharmaceutical industry.

These laws may impact, among other things, our current and future business operations, including our clinical research activities, and

proposed sales, marketing and education programs and constrain the business or financial arrangements and relationships with healthcare

providers and other parties through which we market, sell and distribute our products for which we obtain marketing approval.

include anti-kickback and false claims laws and regulations, data privacy and security, and transparency laws and regulations, including,

without limitation, those laws described below.

federal Anti-Kickback Statute prohibits

any person or entity from, among other things, knowingly and willfully offering, paying, soliciting or receiving remuneration to induce

or in return for purchasing, leasing, ordering or arranging for or recommending the purchase, lease or order of any item or service reimbursable

under Medicare, Medicaid or other federal healthcare programs.

The term “remuneration” has been broadly interpreted to include

anything of value.

federal Anti-Kickback Statute has been interpreted to apply to arrangements between pharmaceutical manufacturers

on the one hand and prescribers, purchasers and formulary managers on the other.

Although there are a number of statutory exceptions and

regulatory safe harbors protecting some common activities from prosecution, the exceptions and safe harbors are drawn narrowly.

that involve remuneration that may be alleged to be intended to induce prescribing, purchases or recommendations may be subject to scrutiny

if they do not qualify for an exception or safe harbor.

Several courts have interpreted the statute’s intent requirement to mean

that if any one purpose of an arrangement involving remuneration is to induce referrals of federal healthcare covered business, the statute

has been violated.

A person or entity does not need to have actual

knowledge of this statute or specific intent to violate it in order to have committed a violation.

In addition, the government may assert

that a claim including items or services resulting from a violation of the U.S.

federal Anti-Kickback Statute constitutes a false or fraudulent

claim for purposes of the federal civil False Claims Act or the civil monetary penalties laws.

Federal civil and criminal false claims laws and

civil monetary penalties laws, including the federal civil False Claims Act, which can be enforced by individuals through civil whistleblower

and qui tam actions, prohibit any person or entity from, among other things, knowingly presenting, or causing to be presented, a false

claim for payment to the federal government or knowingly making, using or causing to be made or used a false record or statement material

to a false or fraudulent claim to the federal government.

A claim includes “any request or demand” for money or property presented

Several pharmaceutical and other healthcare companies have been prosecuted under these laws for allegedly providing

free product to customers with the expectation that the customers would bill federal programs for the product.

Other companies have been

prosecuted for causing false claims to be submitted because of the companies’ marketing of products for unapproved, and thus non-reimbursable,

The federal Health Insurance Portability and Accountability

Act of 1996, or HIPAA, created additional federal criminal statutes that prohibit, among other things, knowingly and willfully executing

a scheme to defraud any healthcare benefit program, including private third-party payors and knowingly and willfully falsifying, concealing

or covering up a material fact or making any materially false, fictitious or fraudulent statement in connection with the delivery of or

payment for healthcare benefits, items or services.

Also, many states have similar fraud and abuse statutes or regulations that apply

to items and services reimbursed under Medicaid and other state programs, or, in several states, apply regardless of the payor.

In addition, we may be subject to data privacy

and security regulation by both the federal government and the states in which we conduct our business.

HIPAA, as amended by the Health

Information Technology for Economic and Clinical Health Act, or HITECH, and their respective implementing regulations, impose specified

requirements on certain types of individuals and entities relating to the privacy, security and transmission of individually identifiable

health information.

Among other things, HITECH makes HIPAA’s security standards directly applicable to “business associates,”

defined as independent contractors or agents of covered entities, which include certain healthcare providers, healthcare clearinghouses

and health plans, that create, receive, maintain or transmit individually identifiable health information in connection with providing

a service for or on behalf of a covered entity.

HITECH also increased the civil and criminal penalties that may be imposed against covered

entities, business associates and possibly other persons, and gave state attorneys general new authority to file civil actions for damages

or injunctions in federal courts to enforce HIPAA and seek attorney’s fees and costs associated with pursuing federal civil actions.

In addition, state laws govern the privacy and security of health information in certain circumstances, many of which are not pre-empted

by HIPAA, differ from each other in significant ways and may not have the same effect, thus complicating compliance efforts.

The federal Physician Payments Sunshine Act requires

certain manufacturers of drugs, devices, biologics and medical supplies for which payment is available under Medicare, Medicaid or the

Children’s Health Insurance Program, with specific exceptions, to report annually to the Centers for Medicare & Medicaid Services,

or CMS, information related to payments or other transfers of value made to physicians and teaching hospitals, and applicable manufacturers

and applicable group purchasing organizations to report annually to CMS ownership and investment interests held by physicians and their

immediate family members.

We may also be subject to state laws that require

pharmaceutical companies to comply with the pharmaceutical industry’s voluntary compliance guidelines and the relevant compliance

guidance promulgated by the federal government, state laws that require drug manufacturers to report information related to payments and

other transfers of value to physicians and other healthcare providers, marketing expenditures or drug pricing, and state and local laws

that require the registration of pharmaceutical sales representatives.

Because of the breadth of these laws and the narrowness

of available statutory exceptions and regulatory safe harbors, it is possible that some of our business activities could be subject to

challenge under one or more of such laws.

If our operations are found to be in violation of any of the federal and state laws described

above or any other governmental regulations that apply to us, we may be subject to significant criminal, civil and administrative penalties

including damages, fines, imprisonment, disgorgement, additional reporting requirements and oversight if we become subject to a corporate

integrity agreement or similar agreement to resolve allegations of non-compliance with these laws, contractual damages, reputational harm,

diminished profits and future earnings, disgorgement, exclusion from participation in government healthcare programs and the curtailment

or restructuring of our operations, any of which could adversely affect our ability to operate our business and our results of operations.

To the extent that any of our products are sold in a foreign country, we may be subject to similar foreign laws and regulations, which

may include, for instance, applicable post-marketing requirements, including safety surveillance, anti-fraud and abuse laws, implementation

of corporate compliance programs, reporting of payments or transfers of value to healthcare professionals, and additional data privacy

and security requirements.

Healthcare Reform

warning or untitled letters or holds on post-approval clinical studies;

of the FDA to approve pending applications or supplements to approved applications, or suspension or revocation of existing product

seizure or detention, or refusal of the FDA to permit the import or export of products;

decrees, corporate integrity agreements, debarment or exclusion from federal healthcare programs;

modification of promotional materials and labeling and the issuance of corrective information;

issuance of safety alerts, Dear Healthcare Provider letters, press releases and other communications containing warnings or other

safety information about the product;

or the imposition of civil or criminal penalties.

The FDA closely regulates the marketing, labelling, advertising, and

promotion of pharmaceutical products.

A company can make only those claims relating to safety and efficacy, that are approved by the FDA

and in accordance with the provisions of the approved label.

However, companies may share truthful and not misleading information that

is otherwise consistent with a product’s FDA approved labelling.

The FDA and other agencies actively enforce the laws and regulations

prohibiting the promotion of off-label uses.

Failure to comply with these requirements can result in, among other things, adverse publicity,

warning letters, corrective advertising, and potential civil and criminal penalties.

Physicians may prescribe legally available products

for uses that are not described in the product’s labelling and that differ from those tested by us and approved by the FDA.

off-label uses are common across medical specialties.

Physicians may believe that such off-label uses are the best treatment for many

patients in varied circumstances.

The FDA does not regulate the behavior of physicians in their choice of treatments.

The FDA does, however,

restrict manufacturer’s communications on the subject of off-label use of their products.

Federal and State Fraud and Abuse, Data Privacy

and Security, and Transparency Laws and Regulations

In addition to FDA restrictions

on marketing of pharmaceutical products, federal and state healthcare laws and regulations restrict business practices in the biopharmaceutical

These laws may impact, among other things, our current and future business operations and proposed sales, marketing and education

programs and constrain the business or financial arrangements and relationships with healthcare providers and other parties through which

we market, sell and distribute our products.

These laws include anti-kickback and false claims laws and regulations, data privacy and

security, and transparency laws and regulations, including, without limitation, those laws described below.

federal Anti-Kickback Statute prohibits any person or entity

from, among other things, knowingly and willfully offering, paying, soliciting, or receiving remuneration to induce or in return for purchasing,

leasing, ordering or arranging for or recommending the purchase, lease or order of any item or service reimbursable under Medicare, Medicaid

or other federal healthcare programs.

The term “remuneration” has been broadly interpreted to include anything of value.

federal Anti-Kickback Statute has been interpreted to apply to arrangements between pharmaceutical manufacturers on the one hand

and prescribers, purchasers, and formulary managers on the other.

Although there are a number of statutory exceptions and regulatory safe

harbors protecting some common activities from prosecution, the exceptions and safe harbors are drawn narrowly.

Practices that involve

remuneration that may be alleged to be intended to induce prescribing, purchases or recommendations may be subject to scrutiny if they

do not qualify for an exception or safe harbor.

Several courts have interpreted the statute’s intent requirement to mean that if

any one purpose of an arrangement involving remuneration is to induce referrals of federal healthcare covered business, the statute has

been violated.

A person or entity does not

need to have actual knowledge of this statute or specific intent to violate it in order to have committed a violation.

Violation of the

federal Anti-Kickback Statue carries criminal penalties and fines as well as administrative sanctions under the Civil Money Penalties

In addition, the government may assert that a claim including items or services resulting from a violation of the U.S.

federal Anti-Kickback

Statute constitutes a false or fraudulent claim for purposes of the federal civil False Claims Act.

Federal civil and criminal

false claims laws and civil monetary penalties laws, including the federal civil False Claims Act, which can be enforced by individuals

through civil whistleblower and qui tam actions, prohibit any person or entity from, among other things, knowingly presenting, or causing

to be presented, a false claim for payment to the federal government or knowingly making, using or causing to be made or used a false

record or statement material to a false or fraudulent claim to the federal government.

A claim includes “any request or demand”

for money or property presented to the U.S.

Several pharmaceutical and other healthcare companies have been prosecuted under

these laws for allegedly providing free product to customers with the expectation that the customers would bill federal programs for the

Other companies have been prosecuted for causing false claims to be submitted because of the companies’ marketing of products

for unapproved, and thus non-reimbursable, uses.

The federal Health Insurance

Portability and Accountability Act of 1996 (“HIPAA”) created additional federal criminal statutes that prohibit, among other

things, knowingly and willfully executing a scheme to defraud any healthcare benefit program, including private third-party payors and

knowingly and willfully falsifying, concealing or covering up a material fact or making any materially false, fictitious or fraudulent

statement in connection with the delivery of or payment for healthcare benefits, items or services.

These provisions are intended to punish

some of the same conduct in the submission of claims to private payors as the federal False Claims Act covers in connection with governmental

health programs.

Also, many states have similar fraud and abuse statutes or regulations that apply to items and services reimbursed under

Medicaid and other state programs, or, in several states, that apply regardless of the payor.

In addition, regulations promulgated pursuant to HIPAA, as amended

by the Health Information Technology for Economic and Clinical Health Act (“HITECH”) established privacy and security standards

that limit the use and disclosure of individually identifiable health information (known as “ protected health information ”

or “PHI”) and require the implementation of administrative, physical and technological safeguards to protect the privacy of

PHI and ensure the confidentiality, integrity and availability of electronic PHI.

HIPAA applies to “covered entities,” including

healthcare providers who submit certain standard transactions electronically, health plans, and healthcare clearinghouses, as well as

to their “business associates,” which are defined as independent contractors or agents of covered entities that create, receive,

maintain or transmit PHI in the performance of an administrative function or service for or on behalf of a covered entity.

increased the civil and criminal penalties that may be imposed against covered entities, business associates and possibly other persons,

and gave state attorneys general new authority to file civil actions for damages or injunctions in federal courts to enforce HIPAA and

seek attorney’s fees and costs associated with pursuing federal civil actions.

In addition, state laws govern the privacy and security

of health information in certain circumstances, many of which are not pre-empted by HIPAA, differ from each other in significant ways

and may not have the same effect, thus complicating compliance efforts.

The federal Physician Payments

Sunshine Act requires certain manufacturers of drugs, devices, biologics and medical supplies for which payment is available under Medicare,

Medicaid or the Children’s Health Insurance Program, with specific exceptions, to report annually to the Centers for Medicare &

Medicaid Services, or CMS, information related to payments or other transfers of value made to physicians and teaching hospitals, and

applicable manufacturers and applicable group purchasing organizations to report annually to CMS ownership and investment interests held

by Covered Recipients, as defined at 42 CFR Subpart I.

We may also be subject to

state laws that require pharmaceutical companies to comply with the pharmaceutical industry’s voluntary compliance guidelines and

the relevant compliance guidance promulgated by the federal government, state laws that require drug manufacturers to report information

related to payments and other transfers of value to physicians and other healthcare providers, marketing expenditures or drug pricing,

and state and local laws that require the registration of pharmaceutical sales representatives.

Because of the breadth of

these laws and the narrowness of available statutory exceptions and regulatory safe harbors, it is possible that some of our business

activities could be subject to challenge under one or more of such laws.

If our operations are found to be in violation of any of the

federal and state laws described above or any other governmental regulations that apply to us, we may be subject to significant criminal,

civil and administrative penalties including damages, fines, imprisonment, disgorgement, additional reporting requirements and oversight

if we become subject to a corporate integrity agreement or similar agreement to resolve allegations of non-compliance with these laws,

contractual damages, reputational harm, diminished profits and future earnings, disgorgement, exclusion from participation in government

healthcare programs and the curtailment or restructuring of our operations, any of which could adversely affect our ability to operate

our business and our results of operations.

Coverage and Reimbursement

The future commercial success of our product candidates,

if approved, will depend in part on the extent to which third-party payors, such as governmental payor programs at the federal and state

levels, including Medicare and Medicaid, private health insurers and other third-party payors, provide coverage of and establish adequate

reimbursement levels for our product candidates.

The future commercial success

of our product candidates will depend in part on the extent to which third-party payors, such as governmental payor programs at the federal

and state levels, including Medicare and Medicaid, private health insurers and other third-party payors, provide coverage of and establish

adequate reimbursement levels for our product.

Third-party payors generally decide which products they will pay for and establish reimbursement

6 unchanged sentences

Therefore, coverage and reimbursement can differ significantly from payor to payor.

In the United States, the European Union, or EU,

and other potentially significant markets for our product candidates, government authorities and third-party payors are increasingly attempting

to limit or regulate the price of products, particularly for new and innovative products, which often has resulted in average selling

prices lower than they would otherwise be.

Further, the increased emphasis on managed healthcare in the United States and on country and

regional pricing and reimbursement controls in the EU will put additional pressure on product pricing, reimbursement and usage.

pressures can arise from rules and practices of managed care groups, judicial decisions and laws and regulations related to Medicare,

Medicaid and healthcare reform, pharmaceutical coverage and reimbursement policies and pricing in general.

Third-party payors are increasingly imposing additional

requirements and restrictions on coverage and limiting reimbursement levels for products.

For example, federal and state governments reimburse

products at varying rates generally below average wholesale price.

These restrictions and limitations influence the purchase of products.

Third-party payors may limit coverage to specific products on an approved list, or formulary, which might not include all of the FDA-approved

products for a particular indication.

Similarly, because certain of our product candidates are physician-administered, separate reimbursement

for the product itself may or may not be available.

Instead, the administering physician may only be reimbursed for providing the treatment

or procedure in which our product is used.

Third-party payors are increasingly challenging the price and examining the medical necessity

and cost-effectiveness of products, in addition to their safety and efficacy.

We may need to conduct expensive pharmacoeconomic studies

in order to demonstrate the medical necessity and cost-effectiveness of our product candidates, in addition to the costs required to obtain

the FDA approvals.

Our product candidates may not be considered medically necessary or cost-effective.

A payor’s decision to provide

coverage for a product does not imply that an adequate reimbursement rate will be approved.

Adequate third-party payor reimbursement may

not be available to enable us to realize an appropriate return on our investment in product development.

Legislative proposals to reform

healthcare or reduce costs under government insurance programs may result in lower reimbursement for our product candidates, if approved,

or exclusion of our product candidates from coverage and reimbursement.

The cost containment measures that third-party payors and providers

are instituting and any healthcare reform could significantly reduce our revenue from the sale of any approved product candidates.

The United States and some foreign jurisdictions

are considering enacting or have enacted a number of additional legislative and regulatory proposals to change the healthcare system in

ways that could affect our ability to sell our product candidates profitably, if approved.

Among policy makers and payors in the United

States and elsewhere, there is significant interest in promoting changes in healthcare systems with the stated goals of containing healthcare

costs, improving quality and expanding access.

In the United States, the pharmaceutical industry has been a particular focus of these

efforts, which include major legislative initiatives to reduce the cost of care through changes in the healthcare system, including limits

on the pricing, coverage, and reimbursement of pharmaceutical and biopharmaceutical products, especially under government-funded healthcare

programs, and increased governmental control of drug pricing.

There have been several U.S.

government initiatives

over the past few years to fund and incentivize certain comparative effectiveness research, including creation of the Patient-Centered

Outcomes Research Institute under the ACA.

It is also possible that comparative effectiveness research demonstrating benefits in a competitor’s

product could adversely affect the sales of our product candidates.

The ACA became law in March 2010 and substantially

changed the way healthcare is financed by third-party payors, and significantly impacts the U.S.

pharmaceutical industry.

measures that may have an impact on our business, the ACA established an annual, nondeductible fee on any entity that manufactures or

imports specified branded prescription drugs and biologic agents;

a new Medicare Part D coverage gap discount program;

and a new formula

that increased the rebates a manufacturer must pay under the Medicaid Drug Rebate Program.

Additionally, the ACA extended manufacturers’

Medicaid rebate liability, expands eligibility criteria for Medicaid programs, and expanded entities eligible for discounts under the

Public Health Service Act.

At this time, we are unsure of the full impact that the ACA will have on our business.

Since its enactment, there have been judicial

and Congressional challenges to certain aspects of the ACA, as well as recent efforts by the Trump administration to repeal or replace

certain aspects of the ACA, and we expect such challenges and amendments to continue.

Since January 2017, President Trump has signed two

Executive Orders and other directives designed to delay the implementation of certain ACA provisions or otherwise circumvent requirements

for health insurance mandated by the ACA.

Concurrently, Congress has considered legislation that would repeal or repeal and replace all

or part of the ACA.

While Congress has not passed comprehensive repeal legislation, two bills affecting the implementation of certain

taxes under the ACA have been signed into law.

The Tax Cuts and Jobs Act of 2017, or Tax Act, includes a provision that repealed, effective

January 1, 2019, the tax-based shared responsibility payment imposed by the ACA on certain individuals who fail to maintain qualifying

health coverage for all or part of a year that is commonly referred to as the “individual mandate.” On January 22, 2018, President

Trump signed a continuing resolution on appropriations for fiscal year 2018 that delayed the implementation of certain ACA-mandated fees,

including the so-called “Cadillac” tax on certain high cost employer-sponsored insurance plans, the annual fee imposed on

certain health insurance providers based on market share, and the medical device excise tax on nonexempt medical devices.

The Bipartisan

Budget Act of 2018, or the BBA, among other things, amended the ACA, effective January 1, 2019, to increase from 50% to 70% the point-of-sale

discount that is owed by pharmaceutical manufacturers who participate in Medicare Part D and to close the coverage gap in most Medicare

drug plans, commonly referred to as the “donut hole.” In July 2018, CMS published a final rule permitting further collections

and payments to and from certain ACA qualified health plans and health insurance issuers under the ACA adjustment program in response

to the outcome of federal district court litigation regarding the method CMS uses to determine this risk adjustment.

In December 2018,

District Court Judge in the Northern District of Texas, or Texas District Court Judge, ruled that the individual mandate is a critical

and inseverable feature of the ACA, and therefore, because it was repealed as part of the Tax Act, the remaining provisions of the ACA

are invalid as well.

While the Texas District Court Judge, as well as the Trump administration and CMS, have stated that the ruling will

have no immediate effect, it is unclear how this decision, subsequent appeals, and other efforts to repeal and replace the ACA will impact

In addition, other legislative changes have been

proposed and adopted since the ACA was enacted.

In August 2011, the President signed into law the Budget Control Act of 2011, as amended,

which, among other things, included aggregate reductions to Medicare payments to providers of 2% per fiscal year, which began in 2013

and, following passage of subsequent legislation, including the BBA, will continue through 2027 unless additional Congressional action

In January 2013, the American Taxpayer Relief Act of 2012 was enacted which, among other things, reduced Medicare payments to

several types of providers and increased the statute of limitations period for the government to recover overpayments to providers from

three to five years.

Further, there has been increasing legislative

and enforcement interest in the United States with respect to drug pricing practices.

Specifically, there have been several recent U.S.

Congressional inquiries and proposed and enacted federal and state legislation designed to, among other things, bring more transparency

to drug pricing, review the relationship between pricing and manufacturer patient programs, and reform government program reimbursement

methodologies for drugs.

At the federal level, the Trump administration’s budget proposal for fiscal year 2019 contains further

drug price control measures that could be enacted during the 2019 budget process or in other future legislation.

Additionally, the Trump

administration released a “Blueprint” to lower drug prices and reduce out of pocket costs of drugs that contains additional

proposals to increase manufacturer competition, increase the negotiating power of certain federal healthcare programs, incentivize manufacturers

to lower the list price of their products and reduce the out of pocket costs of drug products paid by consumers.

In August 2022, Congress

passed the Inflation Reduction Act of 2022, which included a provision allowing Medicare to negotiate drug prices directly with pharmaceutical

manufacturers.

This provision may impact pricing strategies and determinations in the future.

Department of Health and Human

Services, or HHS, has already started the process of soliciting feedback on some of these measures and is implementing others under its

existing authority.

For example, in September 2018, CMS announced that it will allow Medicare Advantage plans the option to use step therapy

for Part B drugs beginning January 1, 2019.

On January 31, 2019, the HHS Office of Inspector General proposed modifications to U.S.

Anti-Kickback Statute safe harbors which, among other things, may affect rebates paid by manufacturers to Medicare Part D plans, the purpose

of which is to further reduce the cost of drug products to consumers.

In addition, CMS issued a final rule, effective on July 9, 2019,

that requires direct-to-consumer television advertisements of prescription drugs and biological products, for which payment is available

through or under Medicare or Medicaid, to include in the advertisement the Wholesale Acquisition Cost, or list price, of that drug or

biological product if it is equal to or greater than $35 for a monthly supply or usual course of treatment.

Prescription drugs and biological

products that are in violation of these requirements will be included on a public list.

Congress and the Trump administration have each

indicated that it will continue to seek new legislative and/or administrative measures to control drug costs.

At the state level, legislatures

have increasingly passed legislation and implemented regulations designed to control pharmaceutical and biological product pricing, including

price or patient reimbursement constraints, discounts, restrictions on certain product access and marketing cost disclosure and transparency

measures, and, in some cases, designed to encourage importation from other countries and bulk purchasing.

In addition, regional healthcare

authorities and individual hospitals are increasingly using bidding procedures to determine which drugs and suppliers will be included

in their healthcare programs.

Furthermore, there has been increased interest by third party payors and governmental authorities in reference

pricing systems and publication of discounts and list prices.

These measures could reduce future demand for our products or put pressure

on our pricing.

Additionally, in May 2018, the Trickett Wendler,

Frank Mongiello, Jordan McLinn, and Matthew Bellina Right to Try Act of 2017, or the Right to Try Act, was signed into law.

The law, among

other things, provides a federal framework for certain patients to access certain investigational new drug products that have completed

a Phase 1 clinical trial and that are undergoing investigation for FDA approval.

Under certain circumstances, eligible patients can seek

treatment without enrolling in clinical trials and without obtaining FDA permission under the FDA expanded access program.

obligation for a drug manufacturer to make its drug products available to eligible patients as a result of the Right to Try Act.

In the United States, government authorities and third-party payors

are increasingly attempting to limit or regulate the price of products, particularly for new and innovative products, which often has

resulted in average selling prices lower than they would otherwise be.

Further, the increased emphasis on managed healthcare in the United

States will put additional pressure on product pricing, reimbursement and usage.

These pressures can arise from rules and practices of

managed care groups, judicial decisions and laws and regulations related to Medicare, Medicaid and healthcare reform, pharmaceutical coverage

and reimbursement policies and pricing in general.

Third-party payors are increasingly

imposing additional requirements and restrictions on coverage and limiting reimbursement levels for products.

For example, federal and

state governments reimburse products at varying rates generally below average wholesale price.

These restrictions and limitations influence

the purchase of products.

Third-party payors may limit coverage to specific products on an approved list, or formulary, which might not

include all of the FDA-approved products for a particular indication.

Third-party payors are increasingly challenging the price and examining

the medical necessity and cost-effectiveness of products, in addition to their safety and efficacy.

We may need to conduct expensive pharmacoeconomic

studies in order to demonstrate the medical necessity and cost-effectiveness of our product.

Our product may not be considered medically

necessary or cost-effective.

A payor’s decision to provide coverage for a product does not imply that an adequate reimbursement

rate will be approved.

Legislative proposals to reform healthcare or reduce costs under government insurance programs may result in lower

reimbursement for our product or exclusion of our product candidates from coverage and reimbursement.

The cost containment measures that

third-party payors and providers are instituting and any healthcare reform could significantly reduce our revenue from the sale of our

approved product.

Foreign Regulation

In order to market any product outside of the

United States, we would need to comply with numerous and varying regulatory requirements of other countries regarding safety and efficacy

and governing, among other things, clinical trials, marketing authorization, commercial sales and distribution of our product candidates.

For example, in the EU, we must obtain authorization of a clinical trial application, or CTA, in each member state in which we intend

to conduct a clinical trial.

Whether or not we obtain FDA approval for a drug, we would need to obtain the necessary approvals by the

comparable regulatory authorities of foreign countries before we can commence clinical trials or marketing of the drug in those countries.

The approval process varies from country to country and can involve additional product testing and additional administrative review periods.

The time required to obtain approval in other countries might differ from and be longer than that required to obtain FDA approval.

approval in one country does not ensure regulatory approval in another, but a failure or delay in obtaining regulatory approval in one

country may negatively impact the regulatory process in others.

Further, some countries outside of the United

States, including the EU member states, Switzerland and the United Kingdom, have also adopted data protection laws and regulations, which

impose significant compliance obligations.

In the EU, the collection and use of personal health data is governed by the provisions of

the General Data Protection Regulation, or GDPR.

The GDPR became effective on May 25, 2018, repealing its predecessor directive and increasing

responsibility and liability of pharmaceutical companies in relation to the processing of personal data of EU subjects.

The GDPR, together

with the national legislation of the EU member states governing the processing of personal data, impose strict obligations and restrictions

on the ability to process personal data, including health data from clinical trials and adverse event reporting.

In particular, these

obligations and restrictions concern potentially burdensome documentation requirements, granting certain rights to individuals to control

how we collect, use, disclose, retain and process information about them, the information provided to the individuals, the transfer of

personal data out of the EU, security breach notifications, and security and confidentiality of the personal data.

The processing of sensitive

personal data, such as physical health condition, may impose heightened compliance burdens under the GDPR and is a topic of active interest

among foreign regulators.

In addition, the GDPR provides for more robust regulatory enforcement and fines of up to €20 million or

4% of the annual global revenue of the noncompliant company, whichever is greater.

Data protection authorities from the different EU member

states may interpret the GDPR and national laws differently and impose additional requirements, which add to the complexity of processing

personal data in the EU.

In order to market any product

outside of the United States, we would need to comply with numerous and varying regulatory requirements of other countries regarding safety

and efficacy and governing, among other things, clinical trials, marketing authorization, commercial sales and distribution of our product

For example, in the EU, we must obtain authorization of a clinical trial application, or CTA, in each member state in which

we intend to conduct a clinical trial.

Whether or not we obtain FDA approval for a drug, we would need to obtain the necessary approvals

by the comparable regulatory authorities of foreign countries before we can commence clinical trials or marketing of the drug in those

The approval process varies from country to country and can involve additional product testing and additional administrative

review periods.

The time required to obtain approval in other countries might differ from and be longer than that required to obtain FDA

Regulatory approval in one country does not ensure regulatory approval in another, but a failure or delay in obtaining regulatory

approval in one country may negatively impact the regulatory process in others.

Further, some countries outside

of the United States, including the EU member states, Switzerland and the United Kingdom, have also adopted data protection laws and regulations,

which impose significant compliance obligations.

In the EU, the collection and use of personal health data is governed by the provisions

of the General Data Protection Regulation, or GDPR.

The GDPR became effective on May 25, 2018, repealing its predecessor directive and

increasing responsibility and liability of pharmaceutical companies in relation to the processing of personal data of EU subjects.

GDPR, together with the national legislation of the EU member states governing the processing of personal data, impose strict obligations

and restrictions on the ability to process personal data, including health data from clinical trials and adverse event reporting.

In particular,

these obligations and restrictions concern potentially burdensome documentation requirements, granting certain rights to individuals to

control how we collect, use, disclose, retain and process information about them, the information provided to the individuals, the transfer

of personal data out of the EU, security breach notifications, and security and confidentiality of the personal data.

The processing of

sensitive personal data, such as physical health condition, may impose heightened compliance burdens under the GDPR and is a topic of

active interest among foreign regulators.

In addition, the GDPR provides for more robust regulatory enforcement and fines of up to €20

million or 4% of the annual global revenue of the noncompliant company, whichever is greater.

Data protection authorities from the different

EU member states may interpret the GDPR and national laws differently and impose additional requirements, which add to the complexity

of processing personal data in the EU.

Guidance on implementation and compliance practices are often updated or otherwise revised.

1 unchanged sentence

European Union Coverage Reimbursement and Pricing

In the European Union, pricing and reimbursement

schemes vary widely from country to country.

Some countries provide that drug products may be marketed only after a reimbursement price

has been agreed.

Some countries may require the completion of additional studies that compare the cost-effectiveness of a particular drug

candidate to currently available therapies, or so called health technology assessments, in order to obtain reimbursement or pricing approval.

For example, the European Union provides options for its member states to restrict the range of drug products for which their national

health insurance systems provide reimbursement and to control the prices of medicinal products for human use.

European Union member states

may approve a specific price for a drug product or may instead adopt a system of direct or indirect controls on the profitability of the

In the European Union, pricing

and reimbursement schemes vary widely from country to country.

Some countries provide that drug products may be marketed only after a

reimbursement price has been agreed.

Some countries may require the completion of additional studies that compare the cost-effectiveness

of a particular drug candidate to currently available therapies, or so-called health technology assessments, in order to obtain reimbursement

or pricing approval.

For example, the European Union provides options for its member states to restrict the range of drug products for

which their national health insurance systems provide reimbursement and to control the prices of medicinal products for human use.

Union member states may approve a specific price for a drug product or may instead adopt a system of direct or indirect controls on the

profitability of the company.

EU Drug regulation

In order to market any product outside of the

United States, we would need to comply with numerous and varying regulatory requirements of other countries and jurisdictions regarding

quality, safety and efficacy and governing, among other things, clinical trials, marketing authorization, commercial sales and distribution

of our products.

Whether or not we obtain FDA approval for a product, we would need to obtain the necessary approvals by the comparable

foreign regulatory authorities before we can commence clinical trials or marketing of the product in foreign countries and jurisdictions

such as in China and Japan.

Although many of the issues discussed above with respect to the United States apply similarly in the context

of the EU, the approval process varies between countries and jurisdictions and can involve additional product testing and additional administrative

review periods.

The time required to obtain approval in other countries and jurisdictions might differ from and be longer than that required

to obtain FDA approval.

Regulatory approval in one country or jurisdiction does not ensure regulatory approval in another, but a failure

or delay in obtaining regulatory approval in one country or jurisdiction may negatively impact the regulatory process in others.

to comply with applicable foreign regulatory requirements, may be subject to, among other things, fines, suspension or withdrawal of regulatory

approvals, product recalls, seizure of products, operating restrictions and criminal prosecution.

In order to market any product

outside of the United States, we would need to comply with numerous and varying regulatory requirements of other countries and jurisdictions

regarding quality, safety and efficacy and governing, among other things, clinical trials, marketing authorization, commercial sales and

distribution of our products.

Whether or not we obtain FDA approval for a product, we would need to obtain the necessary approvals by

the comparable foreign regulatory authorities before we can commence clinical trials or marketing of the product in foreign countries

and jurisdictions such as in China and Japan.

Although many of the issues discussed above with respect to the United States apply similarly

in the context of the EU, the approval process varies between countries and jurisdictions and can involve additional product testing and

additional administrative review periods.

The time required to obtain approval in other countries and jurisdictions might differ from

and be longer than that required to obtain FDA approval.

Regulatory approval in one country or jurisdiction does not ensure regulatory

approval in another, but a failure or delay in obtaining regulatory approval in one country or jurisdiction may negatively impact the

regulatory process in others.

Failure to comply with applicable foreign regulatory requirements may be subject to, among other things,

fines, suspension or withdrawal of regulatory approvals, product recalls, seizure of products, operating restrictions and criminal prosecution.

Non-clinical studies and clinical trials

Similarly to the United States, the various phases

of non-clinical and clinical research in the EU are subject to significant regulatory controls.

Non-clinical studies are performed to demonstrate

the health or environmental safety of new chemical or biological substances.

Non-clinical studies must be conducted in compliance with

the principles of good laboratory practice (GLP) as set forth in EU Directive 2004/10/EC.

In particular, non-clinical studies, both in

vitro and in vivo, must be planned, performed, monitored, recorded, reported and archived in accordance with the GLP principles, which

define a set of rules and criteria for a quality system for the organizational process and the conditions for non-clinical studies.

GLP standards reflect the Organization for Economic Co-operation and Development requirements.

Clinical trials of medicinal products in the EU

must be conducted in accordance with EU and national regulations and the International Conference on Harmonization (ICH) guidelines on

good clinical practices (GCP) as well as the applicable regulatory requirements and the ethical principles that have their origin in the

Declaration of Helsinki.

Additional GCP guidelines from the European Commission, focusing in particular on traceability, apply to clinical

trials of advanced therapy medicinal products.

If the sponsor of the clinical trial is not established within the EU, it must appoint

an entity within the EU to act as its legal representative.

The sponsor must take out a clinical trial insurance policy, and in most EU

member states, the sponsor is liable to provide ‘no fault’ compensation to any study subject injured in the clinical trial.

Certain countries outside of the United States,

including the EU, have a similar process that requires the submission of a clinical study application (CTA) much like the IND prior to

the commencement of human clinical studies.

A CTA must be submitted to each country’s national health authority and an independent

ethics committee, much like the FDA and the IRB, respectively.

Once the CTA is approved by the national health authority and the ethics

committee has granted a positive opinion in relation to the conduct of the trial in the relevant member state(s), in accordance with a

country’s requirements, clinical study development may proceed.

The CTA must include, among other things, a copy

of the trial protocol and an investigational medicinal product dossier containing information about the manufacture and quality of the

medicinal product under investigation.

Currently, CTAs must be submitted to the competent authority in each EU member state in which the

trial will be conducted.

Under the new Regulation on Clinical Trials, which is currently expected to become applicable by early 2022,

there will be a centralized application procedure where one national authority takes the lead in reviewing the application and the other

national authorities have only a limited involvement.

Any substantial changes to the trial protocol or other information submitted with

the CTA must be notified to or approved by the relevant competent authorities and ethics committees.

Medicines used in clinical trials

must be manufactured in accordance with good manufacturing practice (GMP).

Other national and EU-wide regulatory requirements also apply.

Similarly to the United States,

the various phases of non-clinical and clinical research in the EU are subject to significant regulatory controls.

Non-clinical studies are

performed to demonstrate the health or environmental safety of new chemical or biological substances.

Non-clinical studies must be conducted

in compliance with the principles of good laboratory practice (GLP) as set forth in EU Directive 2004/10/EC.

In particular, non-clinical

studies, both in vitro and in vivo, must be planned, performed, monitored, recorded, reported and archived in accordance with the GLP

principles, which define a set of rules and criteria for a quality system for the organizational process and the conditions for non-clinical

These GLP standards reflect the Organization for Economic Co-operation and Development requirements.

Clinical trials of medicinal

products in the EU must be conducted in accordance with EU and national regulations and the International Conference on Harmonization

(ICH) guidelines on good clinical practices (GCP) as well as the applicable regulatory requirements and the ethical principles that have

their origin in the Declaration of Helsinki.

Additional GCP guidelines from the European Commission, focusing in particular on traceability,

apply to clinical trials of advanced therapy medicinal products.

If the sponsor of the clinical trial is not established within the EU,

it must appoint an entity within the EU to act as its legal representative.

The sponsor must take out a clinical trial insurance policy,

and in most EU member states, the sponsor is liable to provide ‘no fault’ compensation to any study subject injured in the

clinical trial.

Certain countries outside

of the United States, including the EU, have a similar process that requires the submission of a clinical study application (CTA) much

like the IND prior to the commencement of human clinical studies.

A CTA must be submitted to each country’s national health authority

and an independent ethics committee, much like the FDA and the Institutional Review Board (“IRB”), respectively.

CTA is approved by the national health authority and the ethics committee has granted a positive opinion in relation to the conduct of

the trial in the relevant member state(s), in accordance with a country’s requirements, clinical study development may proceed.

The CTA must include, among

other things, a copy of the trial protocol and an investigational medicinal product dossier containing information about the manufacture

and quality of the medicinal product under investigation.

Currently, CTAs must be submitted to the competent authority in each EU member

state in which the trial will be conducted.

Under the new Regulation on Clinical Trials, which is currently expected to become applicable

by early 2022, there will be a centralized application procedure where one national authority takes the lead in reviewing the application

and the other national authorities have only a limited involvement.

Any substantial changes to the trial protocol or other information

submitted with the CTA must be notified to or approved by the relevant competent authorities and ethics committees.

Medicines used in

clinical trials must be manufactured in accordance with good manufacturing practice (GMP).

Other national and EU-wide regulatory requirements

Marketing Authorizations

To market a medicinal product in the EU and in

many other foreign jurisdictions, we must obtain separate regulatory approvals.

More concretely, in the EU, medicinal product candidates

can only be commercialized after obtaining a Marketing Authorization (MA).

To obtain regulatory approval of an investigational medicinal

product under EU regulatory systems, we must submit a marketing authorization application (MAA.) The process for doing this depends, among

other things, on the nature of the medicinal product.

To market a medicinal product

in the EU and in many other foreign jurisdictions, we must obtain separate regulatory approvals.

More concretely, in the EU, medicinal

product candidates can only be commercialized after obtaining a Marketing Authorization (MA).

To obtain regulatory approval of an investigational

medicinal product under EU regulatory systems, we must submit a marketing authorization application (“MAA”).

for doing this depends, among other things, on the nature of the medicin al product.

There are two types of Mas:

“Union MA”, which is issued by the European Commission through the Centralized Procedure, based on the opinion of the Committee

for Medicinal Products for Human Use (CHMP) of the European Medicines Agency (EMA) and which is valid throughout the entire territory

The Centralized Procedure is mandatory for certain types of products, such as (i) medicinal products derived from biotechnology

medicinal products, (ii) designated orphan medicinal products, (iii) advanced therapy products (such as gene therapy, somatic cell therapy

or tissue-engineered medicines), and (iv) medicinal products containing a new active substance indicated for the treatment certain diseases,

such as HIV/AIDS, cancer, neurodegenerative diseases, diabetes, other auto-immune and viral diseases.

The Centralized Procedure is optional

for products containing a new active substance not yet authorized in the EU, or for products that constitute a significant therapeutic,

scientific or technical innovation or that the granting of authorization would be in the interest of public health in the EU;

Mas”, which are issued by the competent authorities of the EU member states and only cover their respective territory, are available

for products not falling within the mandatory scope of the Centralized Procedure.

Where a product has already been authorized for marketing

in an EU member state, this National MA can be recognized in another member state through the Mutual Recognition Procedure.

If the product

has not received a National MA in any member state at the time of application, it can be approved simultaneously in various member states

through the Decentralized Procedure.

Under the Decentralized Procedure an identical dossier is submitted to the competent authorities

of each of the member states in which the MA is sought, one of which is selected by the applicant as the Reference member state.

Under the above-described procedures, in order

to grant the MA, the EMA or the competent authorities of the EU member states make an assessment of the risk-benefit balance of the product

on the basis of scientific criteria concerning its quality, safety and efficacy.

Under the Centralized Procedure, the maximum timeframe

for the evaluation of a MAA by the EMA is 210 days.

Where there is a major public health interest and an unmet medical need for a product,

the CHMP may perform an accelerated review of a MA in no more than 150 days (not including clock stops).

Innovative products that target

an unmet medical need and are expected to be of major public health interest may be eligible for a number of expedited development and

review programs, such as the PRIME scheme, which provides incentives similar to the breakthrough therapy designation in the US PRIME is

a voluntary scheme aimed at enhancing the EMA’s support for the development of medicines that target unmet medical needs.

based on increased interaction and early dialogue with companies developing promising medicines, to optimize their product development

plans and speed up their evaluation to help them reach patients earlier.

Product developers that benefit from PRIME designation can expect

to be eligible for accelerated assessment but this is not guaranteed.

The benefits of a PRIME designation include the appointment of a

CHMP rapporteur before submission of a MAA, early dialogue and scientific advice at key development milestones, and the potential to qualify

products for accelerated review earlier in the application process.

Mas have an initial duration of five years.

these five years, the authorization may be renewed for an unlimited period on the basis of a reevaluation of the risk-benefit balance,

unless the EMA decides, on justified grounds relating to pharmacovigilance, to mandate one additional five-year renewal period.

“Union MA”, which is issued by the European Commission through the Centralized Procedure, based on the opinion of the

Committee for Medicinal Products for Human Use (CHMP) of the European Medicines Agency (“EMA”) and which is valid throughout

the entire territory of the EU.

The Centralized Procedure is mandatory for certain types of products, such as (i) medicinal products

derived from biotechnology medicinal products, (ii) designated orphan medicinal products, (iii) advanced therapy products (such as

gene therapy, somatic cell therapy or tissue-engineered medicines), and (iv) medicinal products containing a new active substance

indicated for the treatment certain diseases, such as HIV/AIDS, cancer, neurodegenerative diseases, diabetes, other auto-immune and

viral diseases.

The Centralized Procedure is optional for products containing a new active substance not yet authorized in the EU,

or for products that constitute a significant therapeutic, scientific or technical innovation or that the granting of authorization

would be in the interest of public health in the EU;

Mas”, which are issued by the competent authorities of the EU member states and only cover their respective territory, are

available for products not falling within the mandatory scope of the Centralized Procedure.

Where a product has already been authorized

for marketing in an EU member state, this National MA can be recognized in another member state through the Mutual Recognition Procedure.

If the product has not received a National MA in any member state at the time of application, it can be approved simultaneously in

various member states through the Decentralized Procedure.

Under the Decentralized Procedure an identical dossier is submitted to

the competent authorities of each of the member states in which the MA is sought, one of which is selected by the applicant as the

Reference member state.

Under the above-described

procedures, in order to grant the MA, the EMA or the competent authorities of the EU member states make an assessment of the risk-benefit

balance of the product on the basis of scientific criteria concerning its quality, safety and efficacy.

Under the Centralized Procedure, the maximum timeframe for the evaluation

of a MAA by the EMA is 210 days.

Where there is a major public health interest and an unmet medical need for a product, the CHMP may perform

an accelerated review of a MA in no more than 150 days (not including clock stops).

Innovative products that target an unmet medical need

and are expected to be of major public health interest may be eligible for a number of expedited development and review programs, such

as the PRIME scheme, which provides incentives similar to the breakthrough therapy designation in the US PRIME is a voluntary scheme aimed

at enhancing the EMA’s support for the development of medicines that target unmet medical needs.

It is based on increased interaction

and early dialogue with companies developing promising medicines, to optimize their product development plans and speed up their evaluation

to help them reach patients earlier.

Product developers that benefit from PRIME designation can expect to be eligible for accelerated

assessment, but this is not guaranteed.

The benefits of a PRIME designation include the appointment of a CHMP rapporteur before submission

of a MAA, early dialogue and scientific advice at key development milestones, and the potential to qualify products for accelerated review

earlier in the application process.

Mas have an initial duration

of five years.

After these five years, the authorization may be renewed for an unlimited period on the basis of a reevaluation of the

risk-benefit balance, unless the EMA decides, on justified grounds relating to pharmacovigilance, to mandate one additional five-year renewal

Data and marketing exclusivity

The EU also provides opportunities for market

Upon receiving MA, new chemical entity, or reference product candidates, generally receive eight years of data exclusivity

and an additional two years of market exclusivity.

If granted, the data exclusivity period prevents generic or biosimilar applicants from

relying on the pre-clinical and clinical trial data contained in the dossier of the reference product when applying for a generic or biosimilar

MA in the EU during a period of eight years from the date on which the reference product was first authorized in the EU.

The market exclusivity

period prevents a successful generic or biosimilar applicant from commercializing its product in the EU until 10 years have elapsed from

the initial authorization of the reference product in the EU.

The overall 10-year market exclusivity period can be extended to a maximum

of eleven years if, during the first eight years of those 10 years, the MA holder obtains an authorization for one or more new therapeutic

indications which, during the scientific evaluation prior to their authorization, are held to bring a significant clinical benefit in

comparison with existing therapies.

However, there is no guarantee that a product will be considered by the EU’s regulatory authorities

to be a new chemical entity, and products may not qualify for data exclusivity.

The EU also provides opportunities

for market exclusivity.

Upon receiving MA, new chemical entity, or reference product candidates, generally receive eight years of data

exclusivity and an additional two years of market exclusivity.

If granted, the data exclusivity period prevents generic or biosimilar

applicants from relying on the pre-clinical and clinical trial data contained in the dossier of the reference product when applying for

a generic or biosimilar MA in the EU during a period of eight years from the date on which the reference product was first authorized

The market exclusivity period prevents a successful generic or biosimilar applicant from commercializing its product in the

EU until 10 years have elapsed from the initial authorization of the reference product in the EU.

The overall 10-year market exclusivity

period can be extended to a maximum of eleven years if, during the first eight years of those 10 years, the MA holder obtains an authorization

for one or more new therapeutic indications which, during the scientific evaluation prior to their authorization, are held to bring a

significant clinical benefit in comparison with existing therapies.

However, there is no guarantee that a product will be considered by

the EU’s regulatory authorities to be a new chemical entity, and products may not qualify for data exclusivity.

Pediatric Development

In the EU, MAAs for new medicinal products candidates

have to include the results of trials conducted in the pediatric population, in compliance with a pediatric investigation plan (PIP) agreed

with the EMA’s Pediatric Committee (PDCO).

The PIP sets out the timing and measures proposed to generate data to support a pediatric

indication of the drug for which MA is being sought.

The PDCO can grant a deferral of the obligation to implement some or all of the measures

of the PIP until there are sufficient data to demonstrate the efficacy and safety of the product in adults.

Further, the obligation to

provide pediatric clinical trial data can be waived by the PDCO when these data is not needed or appropriate because the product is likely

to be ineffective or unsafe in children, the disease or condition for which the product is intended occurs only in adult populations,

or when the product does not represent a significant therapeutic benefit over existing treatments for pediatric patients.

is obtained in all EU Member States and study results are included in the product information, even when negative, the product is eligible

for six months’ supplementary protection certificate extension (if any is in effect at the time of authorization).

In the EU, MAAs for new medicinal

products candidates have to include the results of trials conducted in the pediatric population, in compliance with a pediatric investigation

plan (PIP) agreed with the EMA’s Pediatric Committee (PDCO).

The PIP sets out the timing and measures proposed to generate data

to support a pediatric indication of the drug for which MA is being sought.

The PDCO can grant a deferral of the obligation to implement

some or all of the measures of the PIP until there are sufficient data to demonstrate the efficacy and safety of the product in adults.

Further, the obligation to provide pediatric clinical trial data can be waived by the PDCO when these data is not needed or appropriate

because the product is likely to be ineffective or unsafe in children, the disease or condition for which the product is intended occurs

only in adult populations, or when the product does not represent a significant therapeutic benefit over existing treatments for pediatric

Once the MA is obtained in all EU Member States and study results are included in the product information, even when negative,

the product is eligible for six months’ supplementary protection certificate extension (if any is in effect at the time of authorization).

Post-Approval Requirements

Similar to the United States, both MA holders

and manufacturers of medicinal products are subject to comprehensive regulatory oversight by the EMA, the European Commission and/or the

competent regulatory authorities of the member states.

The holder of a MA must establish and maintain a pharmacovigilance system and appoint

an individual qualified person for pharmacovigilance who is responsible for oversight of that system.

Key obligations include expedited

reporting of suspected serious adverse reactions and submission of periodic safety update reports (PSURs).

All new MAA must include a risk management plan

(RMP) describing the risk management system that the company will put in place and documenting measures to prevent or minimize the risks

associated with the product.

The regulatory authorities may also impose specific obligations as a condition of the MA.

Such risk-minimization

measures or post-authorization obligations may include additional safety monitoring, more frequent submission of PSURs, or the conduct

of additional clinical trials or post-authorization safety studies.

The advertising and promotion of medicinal products

is also subject to laws concerning promotion of medicinal products, interactions with physicians, misleading and comparative advertising

and unfair commercial practices.

All advertising and promotional activities for the product must be consistent with the approved summary

of product characteristics, and therefore all off-label promotion is prohibited.

Direct-to-consumer advertising of prescription medicines

is also prohibited in the EU.

Although general requirements for advertising and promotion of medicinal products are established under

EU directives, the details are governed by regulations in each member state and can differ from one country to another.

The aforementioned EU rules are generally applicable

in the European Economic Area (EEA) which consists of the 27 EU member states plus Norway, Liechtenstein and Iceland.

For other countries outside of the EU, such as

countries in Latin America or Asia (e.g.

China and Japan), the requirements governing the conduct of clinical studies, product licensing,

pricing and reimbursement vary from country to country.

In all cases, again, the clinical studies are conducted in accordance with GCP

and the applicable regulatory requirements and the ethical principles that have their origin in the Declaration of Helsinki.

to comply with applicable foreign regulatory requirements, we may be subject to, among other things, fines, suspension or withdrawal of

regulatory approvals, product recalls, seizure of products, operating restrictions and criminal prosecution.

Similar to the United States,

both MA holders and manufacturers of medicinal products are subject to comprehensive regulatory oversight by the EMA, the European Commission

and/or the competent regulatory authorities of the member states.

The holder of a MA must establish and maintain a pharmacovigilance system

and appoint an individual qualified person for pharmacovigilance who is responsible for oversight of that system.

Key obligations include

expedited reporting of suspected serious adverse reactions and submission of periodic safety update reports (PSURs).

All new MAA must include

a risk management plan (RMP) describing the risk management system that the company will put in place and documenting measures to prevent

or minimize the risks associated with the product.

The regulatory authorities may also impose specific obligations as a condition of the

Such risk-minimization measures or post-authorization obligations may include additional safety monitoring, more frequent submission

of PSURs, or the conduct of additional clinical trials or post-authorization safety studies.

The advertising and promotion

of medicinal products is also subject to laws concerning promotion of medicinal products, interactions with physicians, misleading and

comparative advertising and unfair commercial practices.

All advertising and promotional activities for the product must be consistent

with the approved summary of product characteristics, and therefore all off-label promotion is prohibited.

Direct-to-consumer advertising

of prescription medicines is also prohibited in the EU.

Although general requirements for advertising and promotion of medicinal products

are established under EU directives, the details are governed by regulations in each member state and can differ from one country to another.

The aforementioned EU rules

are generally applicable in the European Economic Area (“EEA”) which consists of the 27 EU member states plus Norway, Liechtenstein

For other countries outside

of the EU, such as countries in Latin America or Asia (e.g., China and Japan), the requirements governing the conduct of clinical studies,

product licensing, pricing and reimbursement vary from country to country.

In all cases, again, the clinical studies are conducted in

accordance with GCP and the applicable regulatory requirements and the ethical principles that have their origin in the Declaration of

If we fail to comply with applicable foreign regulatory requirements, we may be subject to, among other things, fines, suspension

or withdrawal of regulatory approvals, product recalls, seizure of products, operating restrictions and criminal prosecution.

Privacy and data protection laws

We are also subject to laws and regulations in

non-US countries covering data privacy and the protection of health-related and other personal information.

For instance, EU member states

and other jurisdictions have adopted data protection laws and regulations, which impose significant compliance obligations.

Laws and regulations

in these jurisdictions apply broadly to the collection, use, storage, disclosure, processing and security of personal information that

identifies or may be used to identify an individual, such as names, contact information, and sensitive personal data such as health data.

These laws and regulations are subject to frequent revisions and differing interpretations,

As of May 2018, the General Data Protection Regulation

(GDPR) replaced the Data Protection Directive with respect to the processing of personal data in the European Union.

The GDPR imposes

many requirements for controllers and processors of personal data, including, for example, higher standards for obtaining consent from

individuals to process their personal data, more robust disclosures to individuals and a strengthened individual data rights regime, shortened

timelines for data breach notifications, limitations on retention and secondary use of information, increased requirements pertaining

to health data and pseudonymised (i.e., key-coded) data and additional obligations when we contract third-party processors in connection

with the processing of the personal data.

The GDPR allows EU member states to make additional laws and regulations further limiting the

processing of genetic, biometric or health data.

Failure to comply with the requirements of GDPR and the applicable national data protection

laws of the EU member states may result in fines of up to €20,000,000 or up to 4% of the total worldwide annual turnover of the preceding

financial year, whichever is higher, and other administrative penalties.

Japanese drug regulation

Non-clinical studies and clinical trials

Being a member of the International Conference

on Harmonization (ICH), Japan has pharmaceutical regulations fundamentally similar to those of the United States or EU.

Non-clinical studies are performed to demonstrate

the health safety of new chemical or biological substances.

Non-clinical studies must be conducted in compliance with the principles of

Japanese good laboratory practice (GLP) which reflect the Organization for Economic Co-operation and Development requirements.

Japan and EU have a mutual recognition agreement for GLP, and data generated compliant with EU requirements will be accepted by the Japanese

There is no similar agreement with the United States.

Clinical trials of medicinal products in Japan

must be conducted in accordance with Japanese regulations based on ICH guidelines governing good clinical practices (GCP).

on ethics of the clinical trial and protection of the privacy of the trial subjects.

If the sponsor of the clinical trial is not established

within Japan, it must appoint an entity within the country to act as its caretaker who should be authorized to act on the sponsor’s

The sponsor must take out a clinical trial insurance policy, and, according to the industry agreement, should put in place a common

compensation policy for the injuries from the trial.

Prior to the commencement of human clinical studies,

the sponsor must complete evaluation of the safety of the investigative product, and submit a clinical trial notification and the protocol

to the authorities in advance, upon agreement of the IRB of the participating institutions.

When the authorities do not comment on the

notification, the sponsor may proceed with the clinical trial.

Any substantial changes to the trial protocol

or other information submitted must be cleared by the IRB and notified to the authorities.

Medicines used in clinical trials must be manufactured

in accordance with good manufacturing practice (GMP).

Product approval

To market a medicinal product in Japan, we must

obtain regulatory approval.

To obtain regulatory approval of an investigational medicinal product, we must submit a new drug application.

The process for doing this depends, among other things, on the nature of the medicinal product and there are currently a few different

pathways for approval.

If the product is designed for treating certain “difficult diseases” or those whose patient size is

limited, we may be able to obtain designation as an orphan drug product if it demonstrates unique therapeutic value.

Approval application

for such designated orphan products will be processed on an expedited basis and the authorities’ requirement for clinical data will

be much limited.

Separately, the latest amendment to the law introduced separate pathways for (i) truly innovative products with a unique

mode of action and (ii) those which will satisfy unmet medical needs.

These products will also be processed on an expedited basis.

The evaluation of applications will be based on

an assessment of the risk-benefit balance of the product on the basis of scientific criteria concerning its quality, safety and efficacy.

Once the review organization complete its review task, the matter will be considered by the advisory committee of experts, and the government

will grant approval upon positive recommendation from the committee.

The volume and quality of the clinical data will

be the key determinant of the approval decision.

Clinical trial data generated overseas will be accepted as part of the data package consistent

with the ICH recommendation.

Typically, a limited dose response clinical trial for Japanese subjects is required to ensure that data are

extrapolatable for the Japanese population.

In a more recent development, the authorities encourage manufacturers to organize an international

joint clinical trial with some Japanese participation under a joint protocol, to expedite the clinical trial process.

Regulatory approval

does not expire.

Licensing requirement

Separate from the approval requirement, it is

also mandatory to possess a distribution license of an appropriate class for the manufacturer to commercially distribute the product in

Non-Japanese companies who possess only the product approval may designate an appropriate license holder in Japan to commercially

distribute the product, rather than distributing it on its own.

The license is valid for 5 years.

We are also subject to laws and regulations in non-US countries covering

data privacy and the protection of health-related and other personal information.

For instance, EU member states and other jurisdictions

have adopted data protection laws and regulations, which impose significant compliance obligations.

Laws and regulations in these jurisdictions

apply broadly to the collection, use, storage, disclosure, processing, and security of personal information that identifies or may be

used to identify an individual, such as names, contact information and sensitive personal data such as health data.

These laws and regulations

are subject to frequent revisions and differing interpretations,

As of May 2018, the General

Data Protection Regulation (GDPR) replaced the Data Protection Directive with respect to the processing of personal data in the European

The GDPR imposes many requirements for controllers and processors of personal data, including, for example, higher standards for

obtaining consent from individuals to process their personal data, more robust disclosures to individuals and a strengthened individual

data rights regime, shortened timelines for data breach notifications, limitations on retention and secondary use of information, increased

requirements pertaining to health data and pseudonymized (i.e., key-coded) data and additional obligations when we contract third-party

processors in connection with the processing of the personal data.

The GDPR allows EU member states to make additional laws and regulations

further limiting the processing of genetic, biometric or health data.

Failure to comply with the requirements of GDPR and the applicable

national data protection laws of the EU member states may result in fines of up to €20,000,000 or up to 4% of the total worldwide

annual turnover of the preceding financial year, whichever is higher, and other administrative penalties.

EU Medical device legislation

Medical device legislation is harmonized in the European Union (EU)

through the European Commission’s New Legislative Framework.

The new regulatory framework for medical devices, published in April

2017, is based on the Medical Devices Regulation (MDR) (EU) 2017/745 applicable for medical devices and active implantable medical devices

and the In Vitro Diagnostic Medical Devices Regulation (IVDR) (EU) 2017/746 applicable for in vitro diagnostic medical devices (IVDs).

The dates of application of the MDR were May 26, 2021 (Article 123(2) as amended by Regulation (EU) 2020/561 and Regulation 2023/607)

and May 26, 2022 (Article 113(2)), respectively.

As regulations, the legislation applies to all the EU Member States as drafted and is

applicable in the European Economic Area (EEA) which consists of the 27 EU Member States plus Norway, Liechtenstein, and Iceland.

The new regulatory framework

in EU was triggered by the breast implant scandal (2012) and various similar case scenarios, where the cause identified significant gaps

in the market surveillance and supply chain oversight as well as insufficient controls and compliance to state-of-the-art standards and

documentation.

Europe’s new regulatory framework for IVDs introduced significant changes for IVD manufacturers;

the most important

is the up-classification of IVDs (introduction of 7 classification rules and four risk classes A to D harmonized with the international

classification system), which require independent conformity assessments for most IVD Classes by independent regulatory compliance assessors

(Notified Bodies, NB).

Other changes under the IVDR are the increased NB-involvement, a new risk-based classification system and classification

rules, increased elements and compliance to General Safety and Performance Requirements (GSPR), stricter demands on clinical evidence

(scientific validity, analytical and clinical performance), stronger focus for post-market surveillance (PMS) and post-market performance

follow-up (PMPF), stricter regulatory responsibilities throughout the supply chain for economic operators (like importers or distributors)

and traceability through Unique Device Information (UDI, labelling).

Overall, the IVDR is a significant expansion of the previous EU-Directive

98/79/EC (IVDD), which has been effective for IVDs since 1998.

Since 2022, due to different reasons, the European Commission issued

various updates to the IVDR to introduce transitional provisions for certain IVDs, which are already on the EU market prior to the Date

of Application (legacy devices) and which are not to be substantially changed by function and design (Regulation (EU) 2022/112 and Regulation

(EU) 2023/6074).

The current accepted transitional periods provided for in IVDR Article 120 will end on either December 31, 2027, or December

Currently a new proposal (2024/0021 (COD)) is even proposing extended transitional periods up to December 31, 2029, for some

devices (Class B and Class A sterile) and December 31, 2028, for medium risk IVDs (Class C).

Due to these extended transition timelines

for legacy devices, many IVD manufacturers are not yet setting compliance to IVDR on their highest priority.

For the Proclarix IVDs (Assays

and Risk Calculator software), which are class C devices under IVDR, Proteomedix has already CE marked them in 2019 under IVDD and since

then started to comply with IVDR.

This includes the performance and safety of the device, specifically clinical performance testing and

addressing the clinical evidence for Proclarix.

Irrespective of the amendments

for extended transition timelines to IVDR published since 2022 by the European Commission – Proteomedix AG has selected and streamlined

the interaction with a NB (TÜV SÜD) for a conformity assessment under IVDR and passed this NB conformity assessment for their

Technical Documentation and Quality Management System according to international standard ISO 13485:2016 (“Design and development,

production and distribution of in-vitro diagnostic reagents and stand-alone software for prostate cancer management”) in July 2022.

Proteomedix AG has agreements

signed with Emergo Europe B.V.

acting as their EU Authorized Representative (EU AR, also referred as EC REP).

The IVDR-compliance of Proclarix

devices makes them as one the first IVDs under the new EU regime and this will have several advantages to other devices marketed under

IVDD or without CE mark yet.

Because of the mentioned significant changes introduced with the IVDR, other competitors might face problems

and delays when trying to get to this stage of IVDR compliance.

As mentioned before, every new device or substantially changed device

would not be able to use the amended timelines and must fully comply with IVDR before placing them on the EU market.

Second, clients (users,

laboratories) might expect compliance with the IVDR at some degree as the new normal (of state-of-the-art quality).

Third, for the Proclarix

devices marketed since 2019 in EU, there is automatically systematic post market surveillance data collected from the field, which further

can support the clinical evidence (validity) of the Proclarix devices.

Proteomedix AG also has an

appointed Data Protection Officer (DPO) for data safety in line to requirements from General Data Protection Regulation (EU) 2016/679

(GDPR) and Swiss Data Protection Act although there are no personnel data included or affected in the Proclarix IVDs.

Switzerland and United

Kingdom (UK) Medical Device Regulation

Switzerland and United Kingdom

(UK) are not part of the EU market and in principle, become third countries with different jurisdictions and differing product regulations.

However, these two countries still align to a certain degree on the European CE Mark and CE marked devices currently can be marketed without

significant additional approval in Switzerland and UK.

For Switzerland, the new

EU Regulations (MDR/IVDR) required an update of the Mutual Recognition Agreements to include the EU Regulations, which has so far not

been negotiated by the Switzerland–EU Joint Committee for Switzerland and the EU at international treaty level.

Therefore, trading

of devices can no longer move freely between the Swiss market and the EU market and the sharing of information between authorities (incl.

EUDAMED) or the mutual recognition of certificates of conformity are not possible and must be regulated through Swiss law separately in

The new Swiss law for medical devices, the Medical Devices Ordinance (MedDO) was introduced in 2020 together with certain

obligations for Swiss manufacturers such as registration with Swissmedic.

As a consequence, Swiss manufacturers must appoint an EU-based

AR and/or importer in line with Article 11 and Article 13 of the IVDR.

For UK, IVD manufacturers

must comply with the UK MDR 2002 (Medical device Regulation), which has been revised several times with new guidelines addressed in the

Guidance on the Regulation of In Vitro Diagnostic Medical Devices in Great Britain.

Similar to EU, IVD manufacturers must identify the

appropriate conformity assessment procedure for their device and demonstrate compliance with relevant requirements of the applicable legislation

for IVDs in the UK for the purpose of affixing the UKCA mark to their device (UK MDR 2002 Part IV).

UKCA marking (UK Conformity Assessed

marking) is the UK product marking requirement that will be needed for devices being placed on the market in UK, substituting the EU requirements

for CE Marking (CE marking will continue to be accepted in Northern Ireland).

Most of these IVDs will then require a designated UK Authorized

Body (UKAB)-issued certificate (similar to an EU CE Marking Certificate).

EN ISO 13485:2016 is the designated standard under the UK MDR

2002 that covers QMS requirements for medical device manufacturers.

In the UK, device manufacturers must further appoint a single “UK

Responsible Person” for all of their devices, who will act on the manufacturer’s behalf to perform tasks, including product

registration.

However, for medical devices with a valid CE marking placed on the UK-market, there was a transition time until 1 July 2023

(no requirement to re-label the device with a UKCA mark), and the UK government recently has extended acceptance of CE marked devices

in UK beyond 30 June 2023 (MDR 2002, SI 2002 No 618, as amended).

Therefore, Proteomedix AG

with a valid CE mark for EU (IVDR) and appointed EU-AR, and local registration in Switzerland (Swissmedic) is in full compliance to the

current changed requirements on the EU, Swiss and UK markets.

Proteomedix AG has agreements signed with Emergo Consulting (UK) Ltd.

as their UK Responsible Person.

The requirement to comply with UKCA marking would apply after 30 June 2030.

EU – Impact and

market opportunities on other non-EU markets

With the overall intend from regulators to harmonize regulation, the

CE marking and compliance to European IVDR for the Proclarix can be considered as a state-of-the-art regulatory compliance with high potential

to enter other markets.

Some of these like Australia, New Zealand or Singapore and other markets recognize the CE mark and – though

they might have separate approval procedures – are expected to mainly rely on the CE Certificate.

For example, Australia and New

Zealand have a Trans-Tasman Mutual Recognition Arrangement (TTMRA), which means that CE mark can be recognized and sold without additional

regulatory processes.

Brazil’s medical device market regulator, ANVISA, recently announced updates to the IVD legislation as Resolution

(RDC) 830/2023 similar to the EU definition and classification of IVD under IVDR.

For US, the FDA recently in January 2024 amended their

title of their Quality System regulation part 820 (QSR), and integrated elements and concepts from ISO 13485:2016 into their new Quality

Management System Regulation (QMSR).

These examples demonstrate

that Proclarix with established CE mark (IVDR) and ISO 13485:2016 QMS has high potential to get faster market access in other non-EU countries,

It can be expected that more non-EU country legislations will further adapt their approval or acceptance process to the level of

IVDR or ISO 13485 in the forthcoming years.

Intellectual Property

Exclusive License Agreement with Children’s Hospital Medical

Center, d/b/a Cincinnati Children’s Hospital Medical Center

On June 1, 2021 (the “Effective Date”),

the Company entered into a license agreement with Children’s Hospital Medical Center, d/b/a Cincinnati Children’s Hospital

Medical Center (“CHMC”) to develop and commercialize certain CHMC patents and related technology directed at a VLP vaccine

platform that utilizes nanoparticle delivery technology, which may have potential broad application to develop vaccines for multiple infectious

diseases (“the CHMC Agreement”).

The license is exclusive, worldwide, and is for all uses (other than the “Excluded

Field” of immunization against, and prevention, control, or reduction in severity of gastroenteritis caused by Rotavirus and Norovirus

in China and Hong Kong).

The license is sublicensable with prior CHMC written approval consistent with the terms of the CHMC Agreement.

The CHMC Agreement includes the below patents,

which we refer to as the “Licensed Patents”, and any divisionals, continuations and continuations-in-part thereto (solely

to the extent that the claims in the continuations-in-part are directed to the subject matter specifically claimed in the Licensed Patents,

and they have the same priority date as the Licensed Patents, but do not include any different or additional claims), and any patents

resulting therefrom:

Proteomedix’s biomarkers were discovered using a genetics-guided

discovery approach focusing on the PI3K/PTEN cancer pathway that plays a dominant role in prostate cancer development.

Applying proteomics

technology to a disease-relevant mouse model allowed the identification of proteins specifically linked to the molecular cause of prostate

The biomarkers and the bioinformatics algorithm used in Proclarix are protected by issued and pending patents in Europe, the United

States, and other countries.

Cancer arises from different

genetic mutations that can be linked to specific signaling pathways often referred to as cancer pathways.

Depending on what pathway is

affected in a patient, results in different cancer subtypes that are more or less aggressive and further determines if a patient responds

to a certain drug treatment or not.

Proteomedix’s biomarkers

were discovered by a group of researchers at ETH Zurich using a genetics-guided discovery approach focusing on the PI3K/PTEN cancer pathway

that plays a dominant role in prostate cancer development.

Using a mouse model and mass-spectrometry based proteomics technology including

a glycoprotein enrichment technology led to the identification of proteins directly linked to the molecular cause of cancer and therefore

correlating to the disease status in the prostate.

Different serum glycoproteins were combined to form multiplexed biomarker signatures

predictive for tissue PI3K/PTEN status as well as diagnosis and prognosis of prostate cancer (Figure 5).

The genetic-guided proteomics

approach enabled the fast discovery and validation of several biomarkers which in different combinations correspond to diagnosis, prognosis

and potentially to therapy response.

Proteomics approach to improve prostate cancer disease

The biomarker assays were

transferred from a mass spectrometry-based to an immunoassay-based platform.

Immunoassay-based measurement offers several advantages compared

to other analytical methods.

In general, immunoassays provide a rapid, sensitive, reproducible, cost effective and easily manageable analysis.

The reagents used are stable and the method is established in routine diagnostic laboratories guaranteeing broad compatibility of Proteomedix’s

tests on established automated clinical platforms and thus rapid adoption rates and platform flexibility of the diagnostic tests.

deep knowledge in selecting novel biomarkers, assay development and clinical development enabled Proteomedix to enable several R&D

partnerships.

In 2021, Proteomedix entered

into a research and development partnership with New Horizon Health Limited, Grand Cayman, Cayman Islands.

The partnership builds on complimentary

platform and biomarker developments with utility in cancer patient management.

In 2022, Immunovia AB (Sweden)

partnered with Proteomedix to leverage Proteomedix’s research and development capabilities and advances their research and development

With this partnership, Immunovia gained a more flexible research and development organization, increased its research and development

productivity, and refocused internal resources on commercial build up, thus further accelerating the roll-out of their proprietary IMMray TM

PanCan-d test.

The partnership capitalizes on the combined expertise of two leading innovators in proteomics-based diagnostics, who have

both launched innovative oncology tests, Immunovia with IMMray TM PanCan-d in the U.S.

and Proteomedix with Proclarix® in

Proteomedix has exclusively licensed worldwide rights to one patent

family from ETH Zurich and the State Hospital of St.

Gallen, which describes and protects the use of the proprietary biomarkers for diagnosing

and monitoring prostate cancer.

The parent international patent application WO 2009138392 A1 was filed on May 12, 2009, claims a priority

date of May 14, 2008 (priority date) and was granted in China (CN201027373B), Europe (EP2281201B1), Japan (JP6025607B) and the United

States (US10151755B2/ US9377463B2).

Proteomedix has also obtained a non-exclusive license from ETH Zurich

for certain patents pertaining to specific enrichment of glycoproteins, including EP1514107 (expired June 3, 2023) and US7183118 (to expire

May 3, 2024), that ETH Zurich licensed from the Institute for Systems Biology (ISB), Seattle.

The license enables Proteomedix to use the

glycoprotein technology for the development of new diagnostic products.

In addition, a new patent covering the latest development and clinical

results was filed by Proteomedix on July 11, 2017, claiming a priority of July 15, 2016.

The patent covers the specific test format and

algorithm contained in Proteomedix’s first product (Proclarix) for the improved diagnosis of prostate cancer.

An international application

(WO2018011212A1) was filed, and the patent was granted in Europe (EP3270163B1), Japan (JP6979712B2), South Korea (KR102408276B1), Australia

(AU2017294979B2), United States (US11320435B2, with term extension of 377 days) and China (CN109477836B) with the application still pending

in Canada (CA3028874A1).

A patent application

describing and claiming a method combining Proclarix and magnetic resonance imaging to diagnose prostate cancer was filed by

Proteomedix on June 29, 2021.

The patent was originally filed in Switzerland and subsequently as PCT application (WO2023274742A1)

and as national applications in the United States and China.

A patent application

describing and claiming a method measuring a blood-based protein combination with prognostic utility in prostate cancer patients was

filed by Proteomedix on June 29, 2021.

The patent was originally filed in Switzerland followed by an international application

(WO2018011212A1).

National applications were filed in Europe, United States and China.

The brand “Proteomedix”

was filed on June 4, 2010, and registered under no.

602190 in Switzerland on June 22, 2010.

This application served as the basis for the

international trademark application.

The product name “Proclarix” was filed on July 1, 2019, and registered under no.

in Switzerland on July 22, 2019.

This application served as the basis for the international trademark application.

The product name “Prosgard”

was filed on July 1, 2019, and registered under no.

733975 in Switzerland on July 22, 2019.

Exclusive License Agreement with Children’s

Hospital Medical Center, d/b/a Cincinnati Children’s Hospital Medical Center

On June 1, 2021 (the “Effective

Date”), the Company entered into a license agreement with Children’s Hospital Medical Center, d/b/a Cincinnati Children’s

Hospital Medical Center (“CHMC”), to develop and commercialize certain CHMC patents and related technology directed at a VLP

vaccine platform that utilizes nanoparticle delivery technology, which may have potential broad application to develop vaccines for multiple

infectious diseases (“the CHMC Agreement”).

However, as Onconetix has now deprioritized its infectious disease vaccine programs

based on a change in clinical focus, we are exploring ways in which CHMC’s VLP platform can be used in therapeutic and diagnostic

applications in oncology.

The license is exclusive,

worldwide, and is for all uses (other than the “Excluded Field” of immunization against, and prevention, control, or reduction

in severity of gastroenteritis caused by Rotavirus and Norovirus in China and Hong Kong).

The license is sublicensable with prior CHMC

written approval consistent with the terms of the CHMC Agreement.

The CHMC Agreement includes

the below patents, which we refer to as the “Licensed Patents”, and any divisionals, continuations and continuations-in-part

thereto (solely to the extent that the claims in the continuations-in-part are directed to the subject matter specifically claimed in

the Licensed Patents, and they have the same priority date as the Licensed Patents, but do not include any different or additional claims),

and any patents resulting therefrom:

Application No.

11 unchanged sentences

[March 2042] #

expiration if patent issues:

* Projected expiration if patent

20 years from earliest non-provisional application filing date.

# Non-provisional

application not yet filed.

# Non-provisional application

not yet filed.

Expiration projected 21 years from provisional application filing date.

Dependent on timely conversion to

non-provisional application and issuance of patent.

is a pending application.

Dependent on timely conversion to non-provisional

application and issuance of patent.

** This is a pending application.

Claim type will be determined after U.S.

prosecution is complete.

The claim type sought includes compositions

of the vaccine and vaccine platform.

The CHMC Agreement also grants the Company a non-exclusive

limited license to use and copy internally any technical information in existence and known before the Effective Date by CHMC solely as

necessary for the use and practice of the Licensed Patents (the “CHMC Technology”).

The term of the CHMC Agreement begins on the Effective

Date and extends on a jurisdiction by jurisdiction and product by product basis until the later of:

(i) the last to expire Licensed Patent;

(ii) ten (10) years after the first commercial sale;

or, (iii) entrance onto the market of a biosimilar or interchangeable product.

has reserved the right to practice, have practiced, and transfer the Licensed Patents and CHMC Technology for research and development

purposes, including education, research, teaching, publication and public service, but not to use or practice the Licensed Patents or

CHMC Technology in Field of Use for any commercial or profit purpose.

The Licensed Patents granted to the Company under

the CHMC Agreement are also subject to any rights of the United States federal, state and/or local Government(s), as well as nonprofit

entities, if certain patents or technologies were created in the course of Government-funded or non-profit entity-funded research.

CHMC Agreement also contains compulsory licensing provisions under which CHMC must notify the Company in writing whenever CHMC may become

aware of third parties that are interested in obtaining rights to the Licensed Patents or CHMC Technology for purposes that are beyond

the scope of the Company’s development and commercialization plan.

The Company may elect to pursue the new purposes itself (and

negotiate commercially reasonable development targets), or enter into sublicense negotiations with the interested third party.

if the Company fails to meet its development targets for the new purposes or fails to enter into a sublicense agreement with the interested

third party within nine (9) months of the notice from CHMC, then the new purpose will be excluded from the license grant and CHMC will

be free to pursue licensing of the Licensed Patents or CHMC Technology within the Excluded Field to an interested third party.

Any patented modification, alteration or improvement

of any invention claimed in a Licensed Patents or CHMC Technology which is conceived or reduced to practice solely by the Company (“Company

Improvement”) is owned by the Company;

however, for any such Company Improvement, the Company will automatically grant to CHMC a

worldwide, perpetual, sublicensable, nonexclusive, paid-up, royalty-free license to use any Company Improvements solely for clinical or

non-clinical, non-commercial research, testing, educational and patient care purposes.

The CHMC Agreement also provides the Company with

an option to license any CHMC or jointly patented modification, alteration or improvement of any invention claimed in a Licensed Patent

(“CHMC Improvement” and “Joint Improvement, respectively”), with option fee for each Improvement that the Company

elects to include in the license grant of the CHMC Agreement.

The Company is required to pay CHMC an aggregate

of up to $59.75 million upon the achievement of specified development milestones, of approximately $0.5 million, regulatory milestones,

of approximately $1.25 million and commercial milestones, of approximately $58 million (excluding any royalty arrangements).

the Company enters into a sublicense agreement with a third party who is not an affiliate, then the Company is obligated to pay CHMC a

percentage of all non-royalty sublicensing revenue.

Specifically, the Company must pay twenty-five percent (25%) for revenue received

from the sublicensee prior to first net sale of a licensed product, fifteen percent (15%) for revenue received after first net sale of

a licensed product or five percent after the first sale of a second licensed product.

No annual maintenance fee is required.

Pursuant to the CHMC Agreement, the Company paid

to CHMC a one-time $25,000 initial license fee;

thereafter, in fiscal year ended December 31, 2022, the Company paid $200,000 in deferred

license fees.

Under the CHMC Agreement, the Company is obligated

to use commercially reasonable efforts to bring licensed products to market through diligent research and development, testing, manufacturing

and commercialization and to use best efforts to make all necessary regulatory filings and obtain all necessary regulatory approvals,

and achieve milestones relating to development and sales, and report to CHMC on progress.

The Company will also be obligated to pay the

agreed upon development milestone payments to CHMC.

Development milestones include:

(i) IND filings

of each Licensed Product;

(ii) BLA or equivalent allowed for Licensed Product in U.S.

(iii) first commercial sale of licensed

product in the U.S.;

(iv) first commercial sale of licensed product in the E.U.;

The claim type sought includes compositions of the vaccine and vaccine

The CHMC Agreement also grants

the Company a non-exclusive limited license to use and copy internally any technical information in existence and known before the Effective

Date by CHMC solely as necessary for the use and practice of the Licensed Patents (the “CHMC Technology”).

The term of the CHMC Agreement

begins on the Effective Date and extends on a jurisdiction by jurisdiction and product by product basis until the later of:

to expire Licensed Patent;

(ii) ten (10) years after the first commercial sale or (iii) entrance onto the market of a biosimilar or interchangeable

CHMC has reserved the right to practice, have practiced, and transfer the Licensed Patents and CHMC Technology for research and

development purposes, including education, research, teaching, publication and public service, but not to use or practice the Licensed

Patents or CHMC Technology in the Field of Use for any commercial or profit purpose.

The Licensed Patents granted

to the Company under the CHMC Agreement are also subject to any rights of the United States federal, state and/or local Government(s),

as well as nonprofit entities, if certain patents or technologies were created in the course of Government-funded or non-profit entity-funded

The CHMC Agreement also contains compulsory licensing provisions under which CHMC must notify the Company in writing whenever

CHMC may become aware of third parties that are interested in obtaining rights to the Licensed Patents or CHMC Technology for purposes

that are beyond the scope of the Company’s development and commercialization plan.

The Company may elect to pursue the new purposes

itself (and negotiate commercially reasonable development targets) or enter into sublicense negotiations with the interested third party.

However, if the Company fails to meet its development targets for the new purposes or fails to enter into a sublicense agreement with

the interested third party within nine (9) months of the notice from CHMC, then the new purpose will be excluded from the license grant

and CHMC will be free to pursue licensing of the Licensed Patents or CHMC Technology within the Excluded Field to an interested third

patented modification, alteration or improvement of any invention claimed in a Licensed Patents or CHMC Technology which is conceived

or reduced to practice solely by the Company (“Company Improvement”) is owned by the Company;

however, for any such Company

Improvement, the Company will automatically grant to CHMC a worldwide, perpetual, sublicensable, nonexclusive, paid-up, royalty-free

license to use any Company Improvements solely for clinical or non-clinical, non-commercial research, testing, educational and patient

care purposes.

The CHMC Agreement also provides the Company with an option to license any CHMC or jointly patented modification, alteration

or improvement of any invention claimed in a Licensed Patent (“CHMC Improvement” and “Joint Improvement, respectively”),

with option fee for each Improvement that the Company elects to include in the license grant of the CHMC Agreement.

Company is required to pay CHMC an aggregate of up to $59.75 million upon the achievement of specified development milestones, of approximately

$0.5 million, regulatory milestones, of approximately $1.25 million and commercial milestones of approximately $58 million (excluding

any royalty arrangements).

In the event the Company enters into a sublicense agreement with a third party who is not an affiliate, then

the Company is obligated to pay CHMC a percentage of all non-royalty sublicensing revenue.

Specifically, the Company must pay twenty-five

percent (25%) for revenue received from the sublicensee prior to first net sale of a licensed product, fifteen percent (15%) for revenue

received after first net sale of a licensed product or five percent after the first sale of a second licensed product.

No annual maintenance

fee is required.

to the CHMC Agreement, the Company paid to CHMC a one-time $25,000 initial license fee;

thereafter, in fiscal year ended December 31,

2022, the Company paid $200,000 in deferred license fees.

Under the CHMC Agreement, the Company is obligated to use commercially

reasonable efforts to bring licensed products to market through diligent research and development, testing, manufacturing, and commercialization

and to use best efforts to make all necessary regulatory filings and obtain all necessary regulatory approvals, and achieve milestones

relating to development and sales, and report to CHMC on progress.

The Company will also be obligated to pay the agreed upon development

milestone payments to CHMC.

milestones include:

(i) IND filings of each Licensed Product;

(ii) Biologics License Applications (“BLAs”) or equivalent

allowed for Licensed Product in U.S.

(iii) first commercial sale of licensed product in the U.S.;

(iv) first commercial sale

of licensed product in the E.U.;

(v) first commercial sale of licensed product in Japan;

(vi) first commercial sale in Rest of World (ROW);

(vi) first commercial sale in Rest of World

(vii) conclusion of the first calendar year.

Pursuant to the terms of the CHMC Agreement,

if the Company fails to achieve milestones or make milestone payments on certain milestones, and cannot mutually agree with CHMC on an

amendment to the milestones, then CHMC will have the option of converting any and all of such exclusive licenses to nonexclusive licenses.

In addition to the fees discussed above, beginning

on the first Net Sale, the Company will pay CHMC running royalties on a quarterly basis as a percentage of Net Sales (as defined in the

CHMC Agreement) of the Company, its affiliates and any subsidiaries.

Similarly, in the event the Company enters into a sublicense agreement,

the Company shall pay CHMC a percentage of all non-royalty sublicensing revenues received from the sublicensee.

There is a 5% royalty

rate for products and processes for P-Particle VLP Bivalent vaccine for norovirus and rotavirus;

a 4% royalty rate for products and processes

for Universal Flu Vaccine(s);

Pursuant to the terms of the CHMC Agreement, if the Company fails to achieve milestones

or make milestone payments on certain milestones and cannot mutually agree with CHMC on an amendment to the milestones, then CHMC will

have the option of converting any and all of such exclusive licenses to nonexclusive licenses.

In addition to the fees discussed above, beginning on the first Net

Sale, the Company will pay CHMC running royalties on a quarterly basis as a percentage of Net Sales (as defined in the CHMC Agreement)

of the Company, its affiliates, and any subsidiaries.

Similarly, in the event the Company enters into a sublicense agreement, the Company

shall pay CHMC a percentage of all non-royalty sublicensing revenues received from the sublicensee.

There is a 5% royalty rate for products

and processes for P-Particle VLP Bivalent vaccine for norovirus and rotavirus;

a 4% royalty rate for products and processes for Universal

Flu Vaccine(s);

and a 2% royalty rate for all other products or processes for other indications.

To date, no payments have

been made related to the milestones or royalties.

Before any Valid Claims (as defined in the CHMC Agreement) exist, the running royalty

rates are reduced by fifty percent (50%).

The CHMC Agreement also contains an anti-stacking

provision pursuant to which in the event the Company is legally required to pay royalties to one or more third parties whose patent rights

dominate the Licensed Patents, and would therefore be infringed by exercise of the license rights granted in the CHMC Agreement, the Company

may reduce running royalty payments by fifty percent (50%).

In the event the Company grants sublicenses, the Company is obligated to pay

CHMC as follows:

(i) specified percentage of revenue received prior to first Net Sale of first Licensed Product;

(ii) specified percentage

for revenue received after first Net Sales of first Licensed Product but before first Net Sales of second Licensed Product;

or (iii) specified

percentage for revenues received after first Net Sales of second Licensed Product.

CHMC reserved the first and sole right, using

in-house or outside legal counsel selected by CHMC, to prepare, file, prosecute, maintain and extend patents and patent applications,

and the Company agreed to reimburse CHMC for its legal and administrative costs incurred in the course of doing such.

The Company also

agreed to reimburse CHMC for incurred legal fees of approximately $177,100 as of the Effective Date.

CHMC will provide the Company a reasonable

opportunity to comment during prosecution and will consider the Company’s comments, but CHMC retained control over all final decisions.

If CHMC elects to not be responsible for the prosecution or maintenance of any such patents, the Company will receive a sixty (60) days’

To date, no payments have been made related

to the milestones or royalties.

Before any Valid Claims (as defined in the CHMC Agreement) exist, the running royalty rates are reduced

by fifty percent (50%).

CHMC Agreement also contains an anti-stacking provision pursuant to which in the event the Company is legally required to pay royalties

to one or more third parties whose patent rights dominate the Licensed Patents and would therefore be infringed by exercise of the license

rights granted in the CHMC Agreement, the Company may reduce running royalty payments by fifty percent (50%).

In the event the Company

grants sublicenses, the Company is obligated to pay CHMC as follows:

(i) specified percentage of revenue received prior to first Net

Sale of first Licensed Product;

(ii) specified percentage for revenue received after first Net Sales of first Licensed Product but before

first Net Sales of second Licensed Product;

or (iii) specified percentage for revenues received after first Net Sales of second Licensed

CHMC reserved the first and sole right, using in-house or outside legal

counsel selected by CHMC, to prepare, file, prosecute, maintain, and extend patents and patent applications, and the Company agreed to

reimburse CHMC for its legal and administrative costs incurred in the course of doing such.

The Company also agreed to reimburse CHMC

for incurred legal fees of approximately $177,100 as of the Effective Date.

CHMC will provide the Company a reasonable opportunity to

comment during prosecution and will consider the Company’s comments, but CHMC retained control over all final decisions.

elects to not be responsible for the prosecution or maintenance of any such patents, the Company will receive sixty (60) days’ prior

written notice upon which the Company may elect, at the Company’s expense, to assume the responsibilities and obligations to prosecute

2 unchanged sentences

but the final decision with respect to such matter will remain with the Company.

The CHMC Agreement contains no CHMC representations

or warranties.

The CHMC Agreement also requires the Company to indemnify CHMC and other related parties against all claims, suit, actions,

demands, judgments, or investigations arising out of any product the Company produces under the CHMC Agreement, as set forth in the CHMC

Agreement, and requires the Company, beginning with the earlier of the first clinical trial or commercial sale or other commercialization

to obtain liability insurance.

CHMC will have the first and sole right but not

the obligation, at its own expense, to initiate an infringement suit or other appropriate actions against third party infringers and receives

all therefrom.

For joint suits initiated against third party infringers and receives damages or profits recovered therefrom.

CHMC does not, within six (6) months after becoming aware of infringement, secure cessation of the infringement, the Company will have

the right to initiate suit at its own expense.

Any damages or profits that the Company recovers will be treated as Net Sales subject to

royalties after the Company has been compensated for its costs in handling such action.

In the event of a joint infringement suit, the

Company and CHMC will agree in writing who will control the action and how cost and recoveries will be shared.

The Company may terminate the CHMC Agreement for

convenience, at any time prior to first commercial sale of a product or process by providing one hundred and eighty (180) days’

written notice to CHMC.

CHMC Agreement contains no CHMC representations or warranties.

The CHMC Agreement also requires the Company to indemnify CHMC and other

related parties against all claims, suit, actions, demands, judgments, or investigations arising out of any product the Company produces

under the CHMC Agreement, as set forth in the CHMC Agreement, and requires the Company, beginning with the earlier of the first clinical

trial or commercial sale or other commercialization to obtain liability insurance.

will have the first and sole right but not the obligation, at its own expense, to initiate an infringement suit or other appropriate

actions against third party infringers and receives all therefrom.

For joint suits initiated against third party infringers and receives

damages or profits recovered therefrom.

In the event CHMC does not, within six (6) months after becoming aware of infringement, secure

cessation of the infringement, the Company will have the right to initiate suit at its own expense.

Any damages or profits that the Company

recovers will be treated as Net Sales subject to royalties after the Company has been compensated for its costs in handling such action.

In the event of a joint infringement suit, the Company and CHMC will agree in writing who will control the action and how cost and recoveries

will be shared.

Company may terminate the CHMC Agreement for convenience at any time prior to first commercial sale of a product or process by providing

one hundred and eighty (180) days’ written notice to CHMC.

It may also terminate for a CHMC uncured material breach.

CHMC may terminate the CHMC Agreement for an uncured

Company material breach or insolvency or bankruptcy.

In the event the Company’s material breach is for failure to meet any of the

milestone payments, the Company is entitled to a nonexclusive license to continue developing indications that have already entered development

at any stage or in which the Company has invested in developing.

CHMC may also terminate the CHMC Agreement to the fullest extent permitted

by law in the countries of the worldwide territory, in the event the Company or its affiliates challenge or induce others set up challenges

to the validity or enforceability of any of the Licensed Patents and the Company will be obligated reimburse CHMC for its costs, including

reasonable attorneys’ fees.

In addition to the CHMC Agreement, the Company also

entered into a sponsored research agreement dated June 30, 2022 with CHMC for research related to the CHMC Agreement (the “CHMC

Pursuant to this research agreement, the Company is obligated to pay CHMC an aggregate amount not -to-exceed

Option Agreement between Oxford University Innovation Limited

and Blue Water Vaccines Inc.

On December 18, 2018, the Company entered into

an option agreement with Oxford University Innovation Limited (“OUI”), pursuant to which the Company paid an option fee of

between $25,000, to OUI in exchange for a period of exclusivity, in advance of a fundraising of fifteen million dollars ($15,000,000).

Under the option agreement, the Company has the right to exercise the option for the grant of the right to the Company to an exclusive,

worldwide license to PCT Patent Application number PCT/GB/2017/052510, any patents granted in response to that application, any corresponding

foreign patents and applications deriving priority from that application, and any addition, continuation, continuation-in-part, division,

reissue, renewal or extension based thereon, and related know-how and confidential information (the “OUI Technology”).

Exercise of the option by the Company was conditional

upon the Company submitting a business plan for the subsequent two years, including a development plan for the OUI Technology and a financial

projection, demonstrating the Company’s ability to develop the OUI Technology and evidence of the Company’s solvency and receipt

of fifteen million dollars ($15,000,000) in funds for the development of the OUI Technology.

The Company has agreed that, as a condition

precedent to the license becoming effective, it must provide funding for three years of salary for Dr.

Craig Thompson in Oxford’s

Department of Zoology of four hundred and twenty thousand pounds (£420,000).

No additional funds are required to fulfill the three-year

salary commitment, at this time, and none are anticipated prior to the completion of the three year term.

License Agreement between Oxford University Innovation Limited

and Blue Water Vaccines Inc.

On July 16, 2019, the Company entered into an

exclusive, worldwide agreement (“OUI Agreement”) with Oxford University Innovation Limited (“OUI”), pursuant to

which the Company obtained an exclusive worldwide license for all fields to PCT Patent Application number PCT/GB/2017/052510, entitled

“Immunogenic Composition,” any patents granted in response to that application, any corresponding foreign patents and applications

deriving priority from that application, and any addition, continuation, continuation-in-part, division, reissue, renewal or extension

based thereon, and a nonexclusive license to related know-how and confidential information, as set forth in the below chart (the “Licensed

Technology”):

Application No.

Granted Claim Type

Foreign Counterparts

Compositions and method of treatment

Pending applications in Australia, Canada, China, EU and Japan

expiration if patent issues:

20 years from earliest non-provisional application filing date.

is a pending application.

Claim type will be determined after U.S.

prosecution is complete.

The claim type sought includes compositions

of the compositions and method of treatment.

The OUI Agreement has a term concluding ten years

following the last to expire of all licensed patents and patent applications as defined under the terms of the OUI Agreement.

was conditional upon the Company entering into a separate agreement with Oxford University to provide funding for three years’ salary

Craig Thompson in the University’s Department of Zoology, which amounted to four hundred and twenty thousand pounds (£420,000),

which was paid by the Company in January 2020.

No additional funds are required to fulfill the three-year salary commitment, at this time,

and none are anticipated prior to the completion of the three year term.

Improvements to the Licensed Technology as defined

in the OUI Agreement belong to OUI and are included in the Licensed Technology.

All Company Improvements of belong to the Company.

Company granted to OUI, and OUI subsequently granted to Oxford University, a non-transferable, irrevocable, perpetual, royalty-free license

to use and publish the Licensed Technology and the Company’s Improvements upon the Licensed Technology for non-commercial use.

a Licensed Product is covered by the Medicines Access Policy of Oxford University to promote, the Company shall adhere to the requirements

of the Medicines Access Policy.

The Company is required to pay OUI milestone payments

of up to an aggregate of $51.25 million upon the achievement of specified development milestones, of approximately $2.25 million, regulatory

milestones, of approximately $9.5 million and commercial milestones, of approximately $39.5 million (excluding any royalty arrangements).

An annual maintenance fee, or minimum sum, $10,000 to $20,000 will be required beginning in 2023 through launch, increasing to $250,000,

which would be the highest “minimum sum” of royalties in any year prior until expiration or revocation of the last valid claim

covering a licensed product, in which case the annual maintenance fee will no longer be required and the “step down” royalty

rate will apply.

The Company did not pay a signing fee to OUI and

is obligated to pay a 6% royalty on all net sales of licensed products, as defined in the OUI Agreement, as well as royalties of 25% on

any sums received by the Company from any sublicensee (including all up-front, milestone and other one-off payments received by the Company

from any sub-licenses or other contracts granted by the Company with respect to the licensed technology).

After the expiration or revocation

of the last Valid Claim (as defined in the OUI Agreement) covering a Licensed Product, a “step down” royalty rate shall apply

to such Licensed Technology and no minimum sum will be payable by the Company.

If the Company has to pay royalties to a third party to

use a proprietary manufacturing process proprietary adjuvants in order to make or have made a Licensed Product, the Company will be able

to deduct from all royalty payments, up to a maximum amount of twenty-five percent (25%) of the royalties due to OUI.

The OUI Agreement

entitles the Company to supply a commercially reasonable quantity (not exceeding 5% of units sold in any quarter) of licensed products

for promotional sampling.

In the event that royalties paid to OUI do not

amount to the “minimum sum”, as discussed above, under the OUI Agreement for a particular year, the Company is obligated to

make up the difference between the royalties actually paid and such minimum sum.

The minimum sums vary over time, and reduces to $0 once

the “step down” applies.

The minimum sums and milestone fees are indexed to the RPI (Retail Prices index for all items which

is published in the United Kingdom by the Office for National Statistics, or any replacement of it) and will be increased or decreased

as appropriate as set forth in the OUI Agreement.

The Company is obligated to use its best efforts

to develop and market Licensed Products in accordance with its development plan report to OUI on progress and achieve the following milestones

and must pay OUI nonrefundable milestone fees as follows when it achieves them:

initiation of first Phase I study;

initiation of first

Phase II study;

initiation of first Phase III/pivotal registration studies;

first submission of application for regulatory approval (BLA/NDA);

marketing authorization in the United States;

marketing authorization in any EU country;

marketing authorization in Japan;

first marketing

authorization in any other country;

first commercial sale in Japan;

first commercial sale in any ROW country;

first year that annual sales

equal or exceed certain thresholds.

Upon consultation with the Company and at the

Company’s expense, OUI shall prosecute, use all reasonable endeavors to maintain and renew the patents throughout the duration of

the OUI Agreement.

The Company and OUI agreed to inform each other in writing of any misappropriation or infringement of any rights to

the licensed technology;

however, the Company has the first right to take legal action at its own cost in relation to any such misappropriation

or infringement, but must discuss any proposed legal action with OUI and take into account any legitimate interest of OUI in the legal

action that it takes.

If the Company notifies OUI that it does not intend to take legal action in such matters, OUI may take any legal

action at its own cost.

All profits or damages recovered after unrecovered costs and expenses are deducted are treated as net sales for

which royalties would be due.

OUI makes no warranties at all with regard to

the Licensed Technology or whether use of it will infringe third party rights.

The Company is required to indemnify OUI and Oxford University

from all third party claims, damages, and liabilities asserted by third parties arising directly or indirectly from use of the Licensed

marketing of Licensed Products;

or breach of the OUI Agreement.

The OUI Agreement is governed by English law and the parties

agreed to submit to the exclusive jurisdiction of English Courts for resolution of any disputes arising out of or in connection with the

OUI Agreement, with the exception of actions relating to intellectual property disputes or confidential information which may be brought

in any court of competent jurisdiction.

Either party may terminate the OUI Agreement for

an uncured material breach.

The Company may terminate the OUI Agreement for any reason at any time upon six months’ written notice

expiring after the third anniversary of the OUI Agreement.

OUI may terminate immediately if the Company has a petition presented for its

winding-up or passes a resolution for winding up other than for a bona fide amalgamation or reconstruction or compounds with its creditors

or has a receiver or administrator appointed.

OUI may also terminate if the Company opposes or challenges the validity of any of the patents

or applications in the Licensed Technology;

raises the claim that the know-how of the Licensed Technology is not necessary to develop

and market Licensed Products;

or in OUI’s reasonable opinion, is taking inadequate or insufficient steps develop or market Licensed

Products and does not take any further steps that OUI requests by written notice within a reasonable time.

Pursuant to the terms of the OUI Agreement, the

Company entered into a sponsored research agreement (the “OUI SRA”), dated December 18, 2019 with Oxford University for research

related to the OUI Agreement for a period of three years for a total of £420,000.

The Company prepaid the full amount to Oxford

of $554,802 for the services in January 2020.

Pursuant to an amendment to the SRA (the “OUI SRA Amendment”), dated May 16,

2022, the term of the research under the SRA was extended for an additional 18 months, culminating on June 18, 2024.

The OUI SRA Amendment

also requires that the Company provide additional funding in connection with the research in the amount of £53,500.

Exclusive License Agreement between St.

Jude Children’s

Research Hospital, Inc.

& Blue Water Vaccines Inc.

On January 27, 2020 (the “Effective Date”),

the Company entered into an exclusive, worldwide license agreement with St.

Jude Children’s Research Hospital, Inc.

Jude”), pursuant to which St.

Jude granted the Company an exclusive license to develop licensed products and produce vaccines for

use in humans (“St.

Jude Agreement”) under U.S.

Provisional Patent Application No.

61/537,290 (U.S.

9,265,819 issued

on February 23, 2016), and U.S.

Provisional Patent Application No.

62/817,748 (filed March 13, 2019), and any issued patents, divisions,

continuations, continuations-in-part, to the extent that the claims are directed to subject matter described in the above-referenced patent

applications and are entitled to the priority date of the existing patent rights, re-examinations, substitutions, renewals, restorations,

additions, or registrations thereof, as well as non-United States counterparts thereof, and extensions and supplementary protection certificates

thereon (“Patent Rights”), all as set forth in the below chart:

Application No.

Granted Claim Type

Foreign Counterparts

Compositions and method of treatment

Pending Applications in:

Brazil, Canada, China, Europe,

Hong Kong, Japan and Korea

expiration if patent issues:

20 years from earliest non-provisional application filing date.

National stage entry of WO 2020/183420 (PCT/IB2020/052250).

is a pending application.

Claim type will be determined after U.S.

prosecution is complete.

The claim type sought includes compositions

and method of treatment.

The license is sublicensable consistent with the

terms and conditions of the St.

Jude Agreement, provided that the Company remains responsible for the performance by each of its sublicensees.

The license is subject to any government rights the United States has reserved, and St.

Jude retained the right to make, have made, provide

and use for St.

Jude’s non-commercial research and clinical purposes, including the right to distribute St.

Jude’s biological

material disclosed and claimed in the Patent Rights for non-profit academic research use to non-commercial entities as is customary in

the scientific community and to sell the biological materials as research reagents for research use only by the scientific community.

In the event the Company enters into a sublicense

agreement with a third party who is not an affiliate, then the Company is obligated to pay St.

Jude fifteen percent of any sublicense

consideration, subject to specified exclusions, but including any upfront or milestone fees and including any premium paid by sublicensee

over Fair Market Value (as defined in the agreement) for the Company’s stock.

In exchange for the licenses, the Company paid

Jude an initial license fee of $15,000 and is required to pay an annual maintenance fee of $10,000 beginning on the first anniversary

of the Effective Date (which is waived if all of the developmental milestones scheduled for completion before such annual fee is due have

been achieved), milestone payments, patent reimbursement, and running royalties based on net sales of licensed products under the St.

Jude Agreement.

Under the St.

Jude Agreement, the Company is obligated

to use commercially reasonable efforts to develop and commercialize the licensed product(s).

If the Company fails to achieve the development

milestones contained in the St.

Jude Agreement, and if the Company and St.

Jude fail to agree upon a mutually satisfactory revised time

Jude will have the right to terminate the St.

Jude Agreement.

On May 11, 2022, the Company and St.

into a first amendment to the St.

Jude Agreement (the “St.

Jude Amendment”).

Jude Amendment provides for a revised

development milestone timeline and a one-time license fee of $5,000.

Jude Amendment also provides for an increase in the aggregate

milestone payments that are due upon the achievement of specified developmental milestones, from $1.0 million to $1.9 million;

specifically,

development milestones of $0.3 million, regulatory milestones of $0.6 million, and commercial milestones of $1.0 million.

The milestones include the following events:

complete IND enabling study by 2022;

(ii) Initiate animal toxicology study by last half of 2022;

(iii) file IND by last half of 2023;

(iv) complete Phase I Clinical Trial by last half of 2024;

(v) commence Phase II Clinical Trial by 2025;

(vi) commence Phase III Clinical

Trial by 2027;

and, (vii) regulatory approval, U.S.

or foreign equivalent by 2032.

Upon achievement of certain development and commercialization

milestones, the Company is required to make milestone payments to St.

Jude between the achievement of certain milestones (commencement

of a Phase III clinical trial through first commercial sale).

As of the date of this Report, none of these milestones have been achieved.

Additionally, the Company is obligated to make

running 5% royalty payments payable, for each licensed product(s) sold by the Company, its affiliates or sublicensees, based on the net

sales for the duration of the St.

Jude Agreement.

Furthermore, the Company is obligated to pay a percentage between 15% of other consideration

received for any sublicenses.

The Company is responsible for and shall bear

all expenses relating to the filing, prosecution, and maintenance of all patent rights licensed under the St.

Jude Agreement.

has the first right to enforce any patent against infringement, and shall keep St.

Jude informed of the status of such;

however, before

the Company may commence any action with respect to any such alleged infringement, the Company shall take into consideration the views

Jude and the potential effect on the public interest.

Prior to initial human testing or first commercial

sale of a licensed product, and thereafter so long as the licensed products are being sold in any particular country, the Company (and

its sublicenses) is required to obtain and maintain insurance to cover its indemnity obligations, and to obtain and maintain product liability

insurance coverage.

Jude represented and warranted that it has

good and marketable title to the Patent Rights, but made no other representations and warranties.

The term of the agreement commenced

on the Effective Date, and shall continue, in each country, until the date of expiration of the last to expire valid claim included within

the Patent Rights in that country.

Either party may terminate the St.

Jude Agreement in the event the other party (a) files or has filed

against it a petition under the Bankruptcy Act (among other things) or (b) fails to perform or otherwise breaches its obligations under

Jude Agreement, and has not cured such failure or breach within sixty (60) days.

The Company may terminate for any reason on thirty

(30) days written notice.

In addition to the St.

Jude Agreement, the Company

also entered into a sponsored research agreement (the “St.

Jude SRA”) dated May 3, 2021 with St.

Jude for research related

Jude Agreement.

Pursuant to the St.

Jude SRA, the Company is obligated to pay St.

Jude an aggregate amount of $73,073 in two

parts, Phase I for $57,624 and Phase II for $15,449.

This sponsored research project began during the year ended December 31, 2021.

The Company entered into a second sponsored research

agreement with St.

Jude, dated August 29, 2022, pursuant to which the Company is obligated to pay St.

Jude an amount of $75,603 which

is due within 30 days of the effective date of the agreement.

Exclusive License Agreement between the University of Texas Health

Science Center at San Antonio & Blue Water Vaccines Inc.

On November 18, 2022, the Company entered into

a patent and technology license agreement (the “UT Health Agreement”), with the University of Texas Health Science Center

at San Antonio (“UT Health”).

Under the terms of the UT Health Agreement, the Company holds an exclusive, worldwide license

(other than the excluded field of vectors) to certain specified patent rights relating to the development of a live attenuated, oral Chlamydia

vaccine candidate, as set forth in the chart below:

Patent Application No.

Granted Claim Type

Compositions and method of treatment

‌[11/2/2042]*

expiration if patent issues:

20 years from earliest non-provisional application filing date.

is a pending application.

Claim type will be determined after U.S.

prosecution is complete.

The claim type sought includes compositions

of the compositions and method of treatment.

An initial non-refundable license fee of $100,000

was due upon execution of the UT Health Agreement and subsequent annual license fees of $20,000 per year for each of the four years ending

on December 31, 2026;

$40,000 per year for each of the two years ending on December 31, 2028, and $60,000 for the year ending December

31, 2029 and each year thereafter.

See Note 7 to our financial statements included elsewhere in this Report for information on milestone

payments as well as royalty obligations required under the UT Health Agreement.

The UT Health Agreement will expire upon the expiration

of the last date of expiration or termination of the patent rights, unless terminated earlier.

The Company may terminate the UT Health

Agreement for convenience, by providing 90 days’ written notice to UT Health.

UT Health may terminate the UT Health Agreement in

the event the Company (a) becomes arrears in payment due and does not make payment within 30 days after notification from UT Health or

(b) is in breach of any non-payment provision and does not cure such breach within 60 days after notification from UT Health or (c) UT

Health delivers notice to the Company of three or more actual material breaches of the UT Health Agreement in any 12-month period or (d)

in the event the Company or its affiliates initiates any proceeding or action to challenge the validity, enforceability, or scope of any

of the licensed patents.

Pursuant to the UT Health Agreement, as disclosed in Note 7 to our

financial statements included elsewhere in this Report, the Company is obligated to pay certain milestone and royalty payments in the

future, as the related contingent events occur.

Specifically, the Company is obligated to pay UT Health a royalty on net sales, being

5% or 3% depending on whether the product is covered by a valid claim or not, as defined in the agreement.

The Company is also obligated

to pay a 20% royalty on any sums received by the Company from any sublicensee.

In addition, the Company is required to pay UT Health milestone

payments of up to an aggregate of approximately $2.2 million;

specifically, upon the achievement of specified development milestones of

approximately $0.7 million and regulatory milestones of approximately $1.5 million.

Manufacturing and Supply

We currently do not own or operate any manufacturing

facilities, but our strategic partnership with Ology Bioservices, Inc.

(which was later acquired by National Resilience, Inc.) (“Ology”)

provides us with access to substantial resources to facilitate an independent supply path to the market.

Ology is a leading global contract

manufacturer with deep domain expertise and experience in large and small-scale production of clinical, as well as commercial-stage products.

We have entered into agreements with Ology to secure capacity, technical expertise and resources to support the production of our products

and processes that are intended to scale to commercial scale at Ology or other commercial manufacturing sites.

In July 2019, we entered into a development and

manufacturing master services agreement with Ology, which we refer to, as amended, as the Ology Agreement, pursuant to which Ology is

obligated to perform manufacturing process development and clinical manufacture and supply of components.

Under the Ology Agreement, we will pay Ology agreed

upon fees for Ology’s performance of manufacturing services, and we will reimburse Ology for its out-of-pocket costs associated

with purchasing raw materials, plus a customary handling fee.

The Company entered into an initial Project Addendum on October 18, 2019

and the Company was required to pay Ology an aggregate of approximately $4 million.

Due to unforeseen delays associated with COVID-19,

the Company and Ology entered into a letter agreement dated January 9, 2020 to stop work on the project, at which point, the Company had

paid Ology $100,000 for services.

The second Project Addendum was executed May 21, 2021 and the Company is obligated to pay Ology an aggregate

amount of approximately $2.8 million, plus reimbursement for materials and outsourced testing, which will be billed at cost plus 15%.

During 2022, the Company entered into three amendments to the Ology

Agreement, to adjust the scope of work defined in the second Project Addendum.

The amendments resulted in a net increase to the Company’s

obligations under the second Project Addendum of $154,000.

During the years ended December 31, 2022 and 2021,

the Company incurred research and development expenses related to the Ology Agreement of approximately $1,329,000 and $328,000, respectively,

and had approximately $476,000 and $669,000 recorded as related accounts payable and accrued expenses, respectively, at December 31, 2022,

and approximately $164,000 and $115,000 recorded as related accounts payable and accrued expenses, respectively, at December 31, 2021.

Either party may terminate a Project Addendum

and/or the Ology Agreement upon the material breach of any provision of this Agreement by the other Party if such breach is not cured

by the breaching party within thirty (30) calendar days after receipt by the breaching Party of written notice of such default.

may terminate the Ology Agreement or the associated Project Addendum for any or no reason upon sixty (60) days’ prior written notice

As of March 6, 2023, we had 12 employees.

None of our employees are

represented by a collective bargaining agreement, and we have never experienced any work stoppage.

We believe we have good relations with

our employees.

Properties and Facilities

We are currently leasing an office located at

201 E Fifth Street, Suite 1900, Cincinnati, OH 45202, which is renewed on a monthly basis.

We also lease office space located at 150

Worth Avenue, Palm Beach, FL 33480, which lease expires on April 30, 2023.

All of our research and development is performed on the premises

of our third-party providers.

Buyback Program

On November 10, 2022, the Company’s Board

of Directors approved a share repurchase program to allow for the Company to repurchase up to 5 million shares of common stock, with discretion

to management to make purchases subject to market conditions.

The maximum purchase price is $2.00 per share and there is no expiration

date for this program.

Fundraising Activities

April Private Placement

On April 19, 2022, we consummated the closing of a Private Placement

(the “April Private Placement”), in which we received approximately $6.9 million in net cash proceeds, pursuant to the terms

and conditions of the Securities Purchase Agreement, dated as of April 13, 2022 (the “April Purchase Agreement”), by and among

the Company and certain purchasers named on the signature pages thereto.

At the closing of the April Private Placement, the Company issued

590,406 shares of common stock, pre-funded warrants to purchase an aggregate of 590,406 shares of common stock and preferred investment

options to purchase up to an aggregate of 1,180,812 shares of common stock.

The purchase price of each share and associated preferred

investment option was $6.775 and the purchase price of each prefunded warrant and associated preferred investment option was $6.774.

aggregate gross proceeds to the Company from the April Private Placement were approximately $8.0 million, before deducting placement agent

fees and other offering expenses.

Wainwright & Co., LLC (“Wainwright”) acted as the exclusive placement agent for

the April Private Placement.

In connection with the April Private Placement,

we entered into a registration rights agreement with the purchasers, dated as of April 13, 2022 (the “April Registration Rights

Agreement”), pursuant to which we filed a registration statement covering the resale of registrable securities under the April Registration

Rights Agreement, which was declared effective on May 20, 2022.

Upon the occurrence of any Event (as defined in

the April Registration Rights Agreement), which, among others, includes the purchasers being prohibited from reselling the securities

acquired in the April Private Placement for more than ten (10) consecutive calendar days or more than an aggregate of fifteen (15) calendar

days during any 12-month period, we are obligated to pay to each purchaser, on each monthly anniversary of each such Event, an amount

in cash, as partial liquidated damages and not as a penalty, equal to the product of 2.0% multiplied by the aggregate subscription amount

paid by such purchaser pursuant to the April Purchase Agreement.

Wainwright served as the exclusive placement agent

for the April Private Placement and received a cash fee of 7.5% of the aggregate gross proceeds of the offering and received warrants

(the “April Wainwright Warrants”) to purchase up to 70,849 shares of our common stock, which was equivalent to 6.0% of the

shares and prefunded warrants sold in the April Private Placement.

We also agreed to pay Wainwright a management fee equal to 1.0% of

the aggregate gross proceeds from the offering and reimburse certain out-of-pocket expenses up to an aggregate of $85,000.

We also agreed,

upon any exercise for cash of any preferred investment options, to issue to Wainwright warrants to purchase the number of shares equal

to 6.0% of the aggregate number of placement shares underlying the preferred investment options that have been exercised (the “April

Contingent Warrants”).

The maximum number of April Contingent Warrants issuable under this provision is 70,849.

August Private Placement

On August 11, 2022, the Company consummated the

closing of a private placement (the “August Private Placement”), pursuant to the terms and conditions of a securities purchase

agreement, dated as of August 9, 2022.

CHMC may terminate

the CHMC Agreement for an uncured Company material breach or insolvency or bankruptcy.

In the event the Company’s material breach

is for failure to meet any of the milestone payments, the Company is entitled to a nonexclusive license to continue developing indications

that have already entered development at any stage or in which the Company has invested in developing.

CHMC may also terminate the CHMC

Agreement to the fullest extent permitted by law in the countries of the worldwide territory, in the event the Company or its affiliates

challenge or induce others set up challenges to the validity or enforceability of any of the Licensed Patents and the Company will be

obligated reimburse CHMC for its costs, including reasonable attorneys’ fees.

Manufacturing

We currently do not own or

operate any manufacturing facilities.

For Proclarix, we outsource manufacturing to a CMO in Germany.

The manufacturing of Proclarix is

outsourced to a CMO in Germany.

All of the key reagents used in Proteomedix’s IVD kits (i.e., antigens and antibodies) are proprietary

and owned exclusively by Proteomedix.

These reagents are produced by an independent supplier in Germany and shipped to the CMO for manufacturing

of the IVD kits.

The development and production of the Proclarix risk calculator software and the hosting of the Proclarix risk calculator

software are performed by external suppliers.

For ENTADFI, we utilize third-party manufacturers for the pharmaceuticals, bottle fill,

finish, labeling, bottle serialization, warehousing, and distribution.

with Cardinal Health

On September 21, 2023, the

Company entered into an Exclusive Distribution Agreement (the “Exclusive Distribution Agreement”), effective as of September

20, 2023 (the “Effective Date”), with Cardinal Health 105, LLC (“Cardinal Health”).

Pursuant to, and subject

to the terms and conditions of, the Exclusive Distribution Agreement, the Company engaged Cardinal Health as its exclusive third-party

logistics distribution agent for sales of ENTADFI and any other products the parties mutually agree to.

The term of the Distribution Agreement is three

years from the Effective Date and automatically renews for additional terms of one year each unless terminated pursuant to the terms

of the Exclusive Distribution Agreement.

Under the terms of the Exclusive Distribution Agreement, the Company must pay to Cardinal Health

a one-time start-up fee of $15,500, and if we proceed with commercialization of ENTADFI, upon its launch, a monthly account management

fee of $7,000, and other fees for various services, including post-launch program implementation, information systems, warehouse operations

and financial services.

As of April 5, 2024, we had 12 full-time and 11 subcontracted employees.

None of our employees are represented by a collective bargaining agreement, and we have never experienced any work stoppage.

we have good relations with our employees.

and Facilities

currently lease an office located at 201 E Fifth Street, Suite 1900, Cincinnati, OH 45202, which is renewed on a monthly basis.

Additionally, Proteomedix

leases office and lab space located at Wagistrasse 23, 8952 Schlieren, Switzerland.

This lease expires on June 30, 2025, subject to renewal

for successive two-year terms.

The lease will automatically renew unless terminated.

Either party may terminate the lease with 12 months’

written notice.

were incorporated on October 22, 2018 under the laws of the State of Delaware.

Our principal executive offices are located at 201 E

Fifth Street, Suite 1900, Cincinnati, OH 45202, and our telephone number is (513) 620-4101.

Our corporate website address is www.onconetix.com .

We make available free of charge on or through our Internet website our annual report on Form 10-K, quarterly reports on Form 10-Q, current

reports on Form 8-K, proxy statements on Schedule 14A, and amendments to those reports filed or furnished pursuant to Section 13(a) or

15(d) of the Exchange Act as soon as reasonably practicable after we electronically file such materials with, or furnish them to, the

Alternatively, you may also access our reports at the SEC’s website at www.sec.gov.

November 10, 2022, the Company’s Board of Directors approved a share repurchase program to allow for the Company to repurchase

up to 5 million shares of common stock, with discretion to management to make purchases subject to market conditions.

The maximum purchase

price is $2.00 per share and there is no expiration date for this program.

the fiscal year ended December 31, 2023, the Company repurchased 57,670 shares of common stock, for an aggregate of approximately $59,000,

at an average price of $1.02 per share.

2022 Private Placement

April 19, 2022, we consummated the closing of a Private Placement (the “April 2022 Private Placement”), in which we received

approximately $6.9 million in net cash proceeds, pursuant to the terms and conditions of the Securities Purchase Agreement, dated as

of April 13, 2022 (the “April Purchase Agreement”), by and among the Company and certain purchasers named on the signature

pages thereto.

At the closing of the April 2022 Private Placement, the Company issued 590,406 shares of common stock, pre-funded warrants

to purchase an aggregate of 590,406 shares of common stock and preferred investment options to purchase up to an aggregate of 1,180,812

shares of common stock.

The purchase price of each share of common stock together with the associated preferred investment option was

$6.775, and the purchase price of each pre-funded warrant and associated preferred investment option was $6.774.

The aggregate net cash

proceeds to the Company from the April 2022 Private Placement were approximately $6.9 million, after deducting placement agent fees and

other offering expenses.

Wainwright & Co.,

LLC (“Wainwright”) acted as the exclusive placement agent for the April 2022 Private Placement and received a cash fee of

approximately $600,000, which was equivalent to 7.5% of the aggregate gross proceeds of the offering, and received warrants (the “April

Wainwright Warrants”) to purchase up to 70,849 shares of our common stock, which was equivalent to 6.0% of the shares and pre-funded

warrants sold in the April 2022 Private Placement.

We also paid Wainwright a management fee equal to approximately $80,000, which

is equivalent to 1.0% of the aggregate gross proceeds from the offering, and reimbursed certain out-of-pocket expenses up to an aggregate

amount of $85,000.

We also agreed, upon any exercise for cash of any preferred investment options, to issue to Wainwright warrants to

purchase the number of shares equal to 6.0% of the aggregate number of placement shares underlying the preferred investment options that

have been exercised (the “April Contingent Warrants”), up to a maximum of 70,849 shares.

The maximum number of April Contingent

Warrants were exchanged for August Contingent Warrants (as defined below) in connection with the August 2022 Private Placement (as defined

connection with the April 2022 Private Placement, we entered into a registration rights agreement with the purchasers, dated as of April

13, 2022 (the “April Registration Rights Agreement”), pursuant to which we filed a registration statement covering the resale

of registrable securities under the April Registration Rights Agreement, which was declared effective on May 20, 2022.

the occurrence of any Event (as defined in the April Registration Rights Agreement), which, among others, includes the purchasers being

prohibited from reselling the securities acquired in the April 2022 Private Placement for more than ten (10) consecutive calendar days

or more than an aggregate of fifteen (15) calendar days during any 12-month period, we are obligated to pay to each purchaser, on each

monthly anniversary of each such Event, an amount in cash, as partial liquidated damages and not as a penalty, equal to the product of

2.0% multiplied by the aggregate subscription amount paid by such purchaser pursuant to the April 2022 Purchase Agreement.

2022 Private Placement

On August 11, 2022, the Company consummated the closing of a private

placement (the “August 2022 Private Placement”), pursuant to the terms and conditions of a securities purchase agreement,

dated as of August 9, 2022.

At the closing of the August 2022 Private Placement, the Company issued 1,350,000 shares of common stock,

3 unchanged sentences

investment option was $2.715, and the purchase price of each pre-funded warrant together with the associated preferred investment option

The aggregate net cash proceeds to the Company from the August Private Placement were approximately $8.7 million, after deducting

placement agent fees and other offering expenses.

In addition, the investors in the August Private Placement, who are the same investors

from the April Private Placement, agreed to cancel preferred investment options to purchase up to an aggregate of 1,180,812 shares of

the Company’s common stock issued in April 2022.

The pre-funded warrants have an exercise price of $0.001 per share, are exercisable

on or after August 11, 2022, and are exercisable until the pre-funded warrants are exercised in full.

On September 20, 2022, 945,000 of

the pre-funded warrants were exercised, and as such the Company issued 945,000 shares of common stock on that date.

The preferred investment

options are exercisable at any time on or after August 11, 2022 through August 12, 2027, at an exercise price of $2.546 per share, subject

to certain adjustments as defined in the agreement.

Wainwright acted as the exclusive placement agent

for the August Private Placement.

The Company agreed to pay Wainwright a placement agent fee and management fee equal to 7.5% and 1.0%,

respectively, of the aggregate gross proceeds from the August Private Placement and reimburse certain out-of-pocket expenses up to an

aggregate of $85,000.

In addition, the Company issued warrants to Wainwright (the “August Wainwright Warrants”) to purchase

up to 220,997 shares of common stock.

The August Wainwright Warrants are in substantially the same form as the preferred investment options,

except that the exercise price is $3.3938.

The form of the preferred investment options is a warrant, and as such the preferred investment

options, the pre-funded warrants, and the August Wainwright Warrants are collectively referred to as the “August Private Placement

Further, upon any exercise for cash of any preferred investment options, the Company agreed to issue to Wainwright additional

warrants to purchase the number of shares of common stock equal to 6.0% of the aggregate number of shares of common stock underlying the

preferred investment options that have been exercised, also with an exercise price of $3.3938 (the “August Contingent Warrants”).

The maximum number of August Contingent Warrants issuable under this provision is 298,346, which includes 70,849 of April Contingent Warrants

that were modified in connection with the August Private Placement.

In connection with the August Private Placement,

the Company entered into a Registration Rights Agreement with the purchasers, dated as of August 9, 2022 (the “August Registration

Rights Agreement”).

The August Registration Rights Agreement provides that the Company shall file a registration statement covering

the resale of all of the registrable securities (as defined in the August Registration Rights Agreement) with the SEC no later than the

30th calendar day following the date of the August Registration Rights Agreement and have the registration statement declared effective

by the SEC as promptly as possible after the filing thereof, but in any event no later than the 45th calendar day following August 9,

2022 or, in the event of a full review by the SEC, the 80th day following August 9, 2022.

The registration statement on Form S-1 required

under the Registration Rights Agreement was filed with the SEC on August 29, 2022, and became effective on September 19, 2022.

Upon the occurrence of any Event (as defined in

the August Registration Rights Agreement), which, among others, prohibits the purchasers from reselling the securities for more than ten

consecutive calendar days or more than an aggregate of fifteen calendar days during any 12-month period, and should the registration statement

cease to remain continuously effective, the Company is obligated to pay to each purchaser, on each monthly anniversary of each such Event,

an amount in cash, as partial liquidated damages and not as a penalty, equal to the product of 2.0% multiplied by the aggregate subscription

amount paid by such purchaser in the August Private Placement.

Legal Proceedings

From time to time we may be involved in various

disputes and litigation matters that arise in the ordinary course of business.

We are currently not a party to any material legal proceedings.

Boustead Settlement

On April 15, 2022, the Company received a demand letter (the “Demand

Letter”) from Boustead Securities, LLC (“Boustead”).

The Demand Letter alleged that the Company breached its underwriting

agreement with Boustead, in connection with the Company’s February 2022 initial public offering.

The Demand Letter alleged that,

by engaging H.C.

Wainwright & Co., LLC as placement agent for the April Private Placement, the Company breached Boustead’s right

of first refusal (“ROFR”) to act as placement agent granted to Boustead under the underwriting agreement and, as a result

of selling securities in the April Private Placement, breached the Company’s obligation under the underwriting agreement not to

offer, sell, issue, agree or contract to sell or issue or grant or modify the terms of any option for the sale of, any securities prior

to February 17, 2023 (the “Standstill”).

On October 9, 2022, the Company and Boustead entered into a Settlement

Agreement and Release effective as of September 28, 2022, pursuant to which Boustead agreed to waive the ROFR and the Standstill and to

release the Company from certain claims with respect to the April Private Placement, the August Private Placement, and all future private,

public equity or debt offerings of the Company.

As consideration for such waiver, the Company agreed to pay Boustead a cash fee of $1,000,000

plus $50,000 in legal expenses and release Boustead from all claims, subject to certain exceptions.

In addition, the Company agreed to

issue to Boustead 93,466 shares of restricted common stock in exchange for the cancellation of 111,111 warrants that were issued to Boustead

in connection with the initial public offering.

Concurrent with the execution of the Settlement Agreement, the Company and Boustead Capital

Markets, LLP (“Boustead Capital”) entered into a three-month Advisory Agreement (the “Advisory Agreement”) for

which consideration equal to 200,000 shares of restricted common stock, with no vesting provisions, was issued to Boustead Capital upon

execution of the Advisory Agreement.

Changes in and Disagreements with Accountants

Corporation Information

We were incorporated in Delaware on October 26,

Our principal executive offices are located at 201 E Fifth Street, Suite 1900, Cincinnati, OH 45202, and our telephone number is

(513) 620-4101.

Our corporate website address is www.bluewatervaccines.com .

The information contained on or accessible through

our website is not part of this Annual Report on Form 10-K.

Available Information

We maintain a website at www.bluewatervaccines.com .

You may access our annual reports on Form 10-K, quarterly reports on Form 10-Q, current reports on Form 8-K, and amendments to those reports

filed or furnished pursuant to Section 13(a) or 15(d) of the Exchange Act with the SEC free of charge at our website as soon as reasonably

practicable after such material is electronically filed with, or furnished to, the SEC.

The reference to our website address does not

constitute incorporation by reference of the information contained on our website, and you should not consider the contents of our website

in making an investment decision with respect to our common stock.

The aggregate net cash proceeds to the Company from the August 2022 Private Placement were approximately $8.7 million, after

deducting placement agent fees and other offering expenses.

In addition, the investors in the August 2022 Private Placement, who are the

same investors from the April 2022 Private Placement, agreed to cancel preferred investment options to purchase up to an aggregate of

1,180,812 shares of the Company’s common stock issued in April 2022.

The pre-funded warrants had an exercise price of $0.001 per

During 2022, an aggregate of 1,686,640 of the pre-funded warrants were exercised.

The remaining 646,640 of pre-funded warrants

were exercised during the year ended December 31, 2023.

The preferred investment options are exercisable at any time on or after August

11, 2022 through August 12, 2027, at an exercise price of $2.546 per share, subject to certain adjustments as defined in the agreement.

During the year ended December 31, 2023, 2,486,214 of these preferred investment options were exercised at a reduced exercise price of

$1.09, in connection with the Warrant Inducement Transaction discussed below.

Wainwright acted as the exclusive

placement agent for the August 2022 Private Placement.

The Company agreed to pay Wainwright a placement agent fee of approximately $750,000

and a management fee of approximately $100,000, which equal to 7.5% and 1.0%, respectively, of the aggregate gross proceeds from the August

2022 Private Placement and reimbursed certain out-of-pocket expenses up to an aggregate of $85,000.

In addition, the Company issued warrants

to Wainwright (the “August Wainwright Warrants”) to purchase up to 220,997 shares of common stock.

The August Wainwright Warrants

are in substantially the same form as the preferred investment options, except that the exercise price is $3.3938.

The form of the preferred

investment options is a warrant, and as such the preferred investment options, the pre-funded warrants, and the August Wainwright Warrants

are collectively referred to as the “August 2022 Private Placement Warrants”.

Further, upon any exercise for cash of any preferred

investment options, the Company agreed to issue to Wainwright additional warrants to purchase the number of shares of common stock equal

to 6.0% of the aggregate number of shares of common stock underlying the preferred investment options that have been exercised, also with

an exercise price of $3.3938 (the “August Contingent Warrants”).

The maximum number of August Contingent Warrants issuable

under this provision is 298,346, which includes 70,849 of April Contingent Warrants that were modified in connection with the August 2022

Private Placement.

In connection with the August 2022 Private Placement, the Company entered

into a Registration Rights Agreement with the purchasers, dated as of August 9, 2022 (the “August Registration Rights Agreement”).

The August Registration Rights Agreement provides that the Company shall file a registration statement covering the resale of all of the

registrable securities (as defined in the August Registration Rights Agreement) with the SEC no later than the 30th calendar day following

the date of the August Registration Rights Agreement and have the registration statement declared effective by the SEC as promptly as

possible after the filing thereof, but in any event no later than the 45th calendar day following August 9, 2022 or, in the event of a

full review by the SEC, the 80th day following August 9, 2022.

The registration statement on Form S-1 required under the Registration

Rights Agreement was filed with the SEC on August 29, 2022 and became effective on September 19, 2022.

the occurrence of any Event (as defined in the August Registration Rights Agreement), which, among others, prohibits the purchasers from

reselling the securities for more than ten consecutive calendar days or more than an aggregate of fifteen calendar days during any 12-month

period, and should the registration statement cease to remain continuously effective, the Company is obligated to pay to each purchaser,

on each monthly anniversary of each such Event, an amount in cash, as partial liquidated damages and not as a penalty, equal to the product

of 2.0% multiplied by the aggregate subscription amount paid by such purchaser in the August 2022 Private Placement.

Inducement Transaction

July 31, 2023, the Company entered into a common stock preferred investment options exercise inducement offer letter (the “Inducement Letter”)

with a certain holder (the “Holder”) of existing preferred investment options (“PIOs”) to purchase shares of

the Company’s common stock at the original exercise price of $2.546 per share, issued on August 11, 2022 (the “Existing PIOs”).

Pursuant to the Inducement Letter, the Holder agreed to exercise for cash its Existing PIOs to purchase an aggregate of 2,486,214 shares

of the Company’s common stock, at a reduced exercised price of $1.09 per share, in exchange for the Company’s agreement to

issue new PIOs (the “Inducement PIOs”) on substantially the same terms as the Existing PIOs as described below, to purchase

up to 4,972,428 shares of the Company’s common stock (the “Inducement PIO Shares”).

August 1, 2023, the Company and the Holder entered into a letter agreement to amend the Inducement Letter to clarify, among other things,

that (i) the Inducement PIOs shall be immediately exercisable at any time on or after the date of issuance and have a term of exercise

of five (5) years from the date of issuance, and (ii) the Company shall not be required to hold a meeting of stockholders to approve

the issuance of the Inducement PIO Shares.

Except for the change in exercise period, the terms of the Inducement PIOs remain unchanged.

August 2, 2023, the Company consummated the Warrant Inducement.

The Company received aggregate net proceeds of approximately $2.3 million

from the Warrant Inducement, after deducting placement agent fees and other offering expenses payable by the Company.

Company engaged Wainwright to act as its placement agent in connection with the Warrant Inducement and paid Wainwright a cash fee equal

to 7.5% of the gross proceeds received from the exercise of the Existing PIOs as well as a management fee equal to 1.0% of the gross

proceeds from the exercise of the Existing PIOs.

The Company also agreed to reimburse Wainwright for its expenses in connection with

the exercise of the Existing PIOs and the issuance of the Inducement PIOs, up to $50,000 for fees and expenses of legal counsel and other

out-of-pocket expenses and agreed to pay Wainwright for non-accountable expenses in the amount of $35,000.

In addition, the exercise

for cash of the Existing PIOs triggered the issuance to Wainwright or its designees, warrants to purchase 149,173 shares of common stock,

which were issuable in accordance with the terms of Contingent Warrants issuable to Wainwright in connection with the August 2022 Private

Placement, and have the same terms as the Inducement PIOs, except for an exercise price equal to $1.3625 per share.

The Company also

agreed to issue warrants to Wainwright upon any exercise for cash of the Inducement PIOs, that number of shares of common stock equal

to 6.0% of the aggregate number of such shares of common stock underlying the Inducement PIOs that have been exercised, also with an

exercise price of $1.3625.

The maximum number of warrants issuable under this provision is 298,346.

time to time we may be involved in various disputes and litigation matters that arise in the ordinary course of business.

We are currently

not a party to any material legal proceedings.

Compared sentence by sentence after normalising whitespace, quotation marks, case and digits, so re-formatting and restated figures do not read as changed language. Wording changes appear as one removal and one addition. The current filing and the prior one are authoritative.

What changed 10-K

Item 1. Business