What changed in this filing

/stocks — the workspaceLOADING

Item 1. Business

2024-03-21 compared with 2023-03-24 · 319 added, 348 removed, 779 unchanged (46% of the section changed)

We were incorporated in Delaware in August 2018 as a clinical-stage biopharmaceutical company developing targeted immunotherapies for cancer.

THIO, our lead asset, is an investigational dual mechanism of action drug candidate incorporating telomere targeting and immunogenicity.

We completed our selection process for the clinical sites for our Phase 2 study in Australia and Europe and our application to start the Phase 2 study in Australia has been approved on March 1, 2022, by the Australian Regulatory Agency - Bellberry Human Research Ethics Committee.

We are a clinical-stage biopharmaceutical company developing targeted immunotherapies for cancer.

THIO (6-thio-dG or 6-thio-2 ‘-deoxyguanosine), our lead asset, is an investigational dual mechanism of action drug candidate incorporating telomere targeting and immunogenicity.

In July 2022, the first patient was administered with THIO in our Phase 2 human trial (THIO-101) in Australia.

In December 2022, regulatory authorities in three European countries, Hungary, Poland, and Bulgaria, approved the implementation of THIO-101, Phase 2 clinical trial evaluating THIO in patients with NSCLC.

Patients with advanced Non-Small Cell Lung Cancer (NSCLC) will be treated first with THIO followed a few days later by the immune checkpoint inhibitor Libtayo® (cemiplimab) manufactured and commercialized by Regeneron.

Patients with advanced NSCLC will be treated first with THIO followed a few days later by the immune checkpoint inhibitor Libtayo ® (cemiplimab), manufactured and commercialized by Regeneron.

Cemiplimab is a fully human monoclonal antibody targeting the immune checkpoint receptor PD-1 on T-cells.

2 unchanged sentences

In return, we have granted Regeneron exclusive development rights in combination with PD-1 inhibitors for NSCLC for the study period.

Based on the clinical data we aim to generate by the THIO-101 trial, in late 2024 we plan to seek an accelerated approval of THIO in the United States for the treatment of patients with advanced NSCLC.

Even if granted, accelerated approval status does not guarantee an accelerated review or marketing approval by the FDA.

In addition, in the Fourth Quarter of 2023, we plan to initiate a Phase 2 clinical trial in multiple solid tumor indications of THIO administered in sequence with Anti-PD-1 or Anti-PD-L1.

We completed an initial public offering on August 1, 2022 and our shares of common stock commenced trading on NYSE

American under the ticker symbol "MAIA”

on July 28, 2022.

We sold 2,000,000 shares of common stock at $5 per share for

gross proceeds of $10,000,000 in the initial public offering.

On August 3, 2022, we sold an additional 300,000 shares of common

stock at $5 per share for gross proceeds of $1,500,000 upon the full exercise of the underwriter’s overallotment option.

deducting $2,406,170 for cash issuance costs, net proceeds from the initial public offering, including the overallotment, were

Based on the clinical data generated by our THIO-101 trial, in late 2024, we plan to seek an accelerated approval of THIO in the United States for the treatment of patients with advanced NSCLC, but even if granted, accelerated approval status does not guarantee an accelerated review or marketing approval by the Food and Drug Administration (FDA).

In addition, in 2025, we plan to initiate a Phase 2 clinical trial in multiple solid tumor indications of THIO administered in sequence with Anti-PD-1or Anti-PD-L1 agents.

We were incorporated in Delaware in August 2018, and have operations in Chicago, Illinois, with some of our team members setup virtually and working remotely in California, North Carolina, and New Jersey, among others.

Our principal executive office is located at 444 West Lake Street, Suite 1700, Chicago, IL 60606, and our phone number is (312) 416-8592.

In July 2021, we established a wholly-owned Australian subsidiary, MAIA Biotechnology Australia Pty Ltd., to conduct various preclinical and clinical activities for the development of our product candidates.

ln April 2022, we established a wholly owned Romanian subsidiary, MAIA Biotechnology Romania S.R.L.

to conduct various preclinical and clinical activities for the development of our product candidates.

Our website address is www.MAIABiotech.com.

The information contained on our website is not incorporated by reference into this prospectus supplement, and you should not consider any information contained on, or that can be accessed through, our website as part of this prospectus supplement or in deciding whether to purchase our securities.

Our Lead Product Candidate

THIO (6-thio-dG or 6-thio-2’-deoxyguanosine) is a telomere-targeting agent currently in clinical development to evaluate its activity in NSCLC.

THIO is a telomere-targeting agent currently in clinical development to evaluate its activity in NSCLC.

Telomeres, along with the enzyme telomerase, play a fundamental role in the survival of cancer cells and their resistance to current therapies.

THIO is being developed as a second- or later line of treatment for NSCLC for patients that have progressed beyond the standard-of-care regimen of existing checkpoint inhibitors.

In 2019, our research team discovered that THIO produced telomere modifications and disruption, which ultimately induced cancer-specific innate and adaptive immune responses against immunologically “cold”

tumors or tumor types that were unresponsive to immune checkpoint inhibitors.

This hypothesis was tested and demonstrated in syngeneic and humanized mouse models.

1 unchanged sentence

Further, no toxicities were reported in the tumor-free mice.

These new findings were published in the highly reputable, peer-reviewed research scientific journal, Cancer Cell in July 2020.

These new findings were published in the peer-reviewed research scientific journal, Cancer Cell in July 2020.

Based on these recent discoveries, a new therapeutic approach has been designed to advance THIO into a Phase 2 clinical trial (THIO-101) in patients with advanced NSCLC.

Our regulatory strategy includes a planned filing of an Investigational New Drug application (IND) with the U.S.

FDA in the near future.

This would allow U.S.

Our regulatory strategy includes a filing of an Investigational New Drug application (IND) with the United States Food and Drug Administration (U.S.

This was granted and will allow U.S.

sites to participate in the THIO-101 NSCLC trial.

The human safety data generated in Australia and Europe would constitute the basis of the IND application.

Although we plan to rely solely on the safety and efficacy data we generate in our own clinical trials in support of our planned NDA filing, we take added confidence in the potential tolerability of THIO in light of the fact that the THIO doses we plan to test represent a range of 4 to 40 times lower than the maximum tolerated dose tested in the earlier clinical trials sponsored by the National Cancer Institute in the 1970s.

The planned THIO-101 phase 2 trial is intended to be a proof-of-concept study that may be modified depending on interim results to include both primary and secondary endpoints and be consistent with previously approved cancer treatments.

In September 2022, we submitted a pre-IND meeting request to FDA to discuss, among other elements, the existing non-clinical and clinical data to support the conduct of our planned THIO-101 phase 2 trial under an IND to include patients from the United States.

MAIA received feedback in-line with the proposed plans from the FDA regarding its manufacturing, preclinical and clinical development plan.

MAIA also obtained guidance from the FDA on the assessment of its safety and efficacy in the THIO-101 Phase 2 trial that will be incorporated in the U.S.

The human safety data generated in Australia and Europe constituted the basis of the IND application.

Although we plan to rely solely on the safety and efficacy data we generate in our own clinical trials in support of our planned New Drug Application (NDA) filing, and do not plan to rely on clinical data generated by unaffiliated third parties, we take added confidence in the potential tolerability of THIO in light of the fact that the THIO dose selected of 180 mg/cycle is 14 times lower than the maximum tolerated dose tested in the earlier clinical trials sponsored by the National Cancer Institute (NCI) in the 1970s.

The THIO-101 Phase 2 trial is a proof-of-concept study that may be modified depending on interim results to include both primary and secondary endpoints and be consistent with previously approved cancer treatments.

In September 2022, we submitted a pre-IND meeting request to the FDA to discuss, among other elements, the existing non-clinical and clinical data to support the conduct of our planned THIO-101 Phase 2 trial under an IND to include patients from the U.S.

MAIA received feedback in-line with the proposed plans from the FDA regarding its

manufacturing, preclinical and clinical development plan.

MAIA also obtained guidance from the FDA on the assessment of its safety and efficacy in the THIO-101 Phase 2 trial that was incorporated in the U.S.

IND application.

MAIA plans to file its U.S.

IND in the first half of 2023 and commence enrolling patients in the U.S.

in the second half of 2023.

Based on the clinical data we aim to generate in the THIO-101 study and assuming THIO achieves its intended clinical effect with a manageable

safety profile at one of the doses tested in the study, we expect to seek early FDA guidance and agreement for using this clinical trial as basis for requesting an accelerated approval.

The FDA instituted its Accelerated Approval Program to allow for earlier approval of drugs that treat serious conditions, and that fill an unmet medical need based on a surrogate endpoint.

A surrogate endpoint is a marker, such as a laboratory measurement, radiographic image, physical sign or other measure that is thought to predict clinical benefit, but is not itself a measure of clinical benefit.

The use of a surrogate endpoint can considerably shorten the time required prior to receiving FDA approval.

MAIA Biotechnology will still be required to conduct studies to confirm the anticipated clinical benefit.

These studies are known as confirmatory trials.

If the confirmatory trial shows that the drug actually provides a clinical benefit, then the FDA grants traditional approval for the drug.

If the confirmatory trial does not show that the drug provides clinical benefit, FDA has regulatory procedures in place that could lead to removing the drug from the market.

The FDA’s accelerated approval pathway, even if initially granted, does not guarantee an accelerated review or marketing approval by the FDA.

The THIO-101 study protocol may need to be amended to increase the number of patients enrolled, undergo modification of the statistical analysis or change in the trial design and/or primary endpoints.

IND was granted in 2023.

Based on the clinical data we aim to generate in the THIO-101 study and assuming THIO achieves its intended clinical effect with a manageable safety profile at one of the doses tested in the study, we expect to seek early FDA guidance on the possibility of utilizing one or more of FDA’s expedited programs for serious conditions, such as fast track designation, breakthrough therapy designation, priority review and/or accelerated approval designation.

Accelerated approval status does not guarantee an accelerated review or marketing approval by the FDA.

The TH10-101 study protocol may need to be amended to increase the number of patients enrolled, undergo modification of the statistical analysis, or change in the trial design and/or primary endpoints.

On April 11, 2023, we announced positive topline data related to the completion of Part A, safety lead-in portion of the THI0-101 trial which showed that administration of THIO, at the highest dose of 360 mg/cycle in sequential combination with Regeneron’s anti-PD-1 therapy, Libtayo ® was well tolerated with no dose limiting toxicities or significant treatment-related adverse events reported.

On April 18, 2023, we published data in Hepatocellular Carcinoma (HCC) models:

as monotherapy, THIO achieved complete and durable responses in Hepatocellular Carcinoma (HCC), the dominant histology in primary liver cancer (90%), in in vivo models.

When combined with Libtayo ® , duration of response was further potentiated.

Even upon rechallenge with two times more cancer cells and no additional treatment, tumor growth was completely prevented.

Administration of THIO alone and in combination with Libtayo ® generated anticancer immune memory.

On April 20, 2023, we announced preliminary survival data from Part A of THIO-101.

The first two patients enrolled in Part A of the study continued to be alive, approximately 10 and 9 months respectively, from treatment initiation.

Both patients have advanced Stage IV metastatic disease and are heavily pretreated, receiving third and fourth line of therapy respectively after previously failing treatment with an immune checkpoint inhibitor.

They continue to be progression free following their last dose of THIO, 7 and 6 months respectively, with no new treatment.

The current treatment options in patients with advanced relapsed or refractory NSCLC who failed two or more therapy regimens are limited and show minimal benefit.

Furthermore, discontinuation of treatment is rapidly followed by physical decline and death, therefore seeing patients with such survival and no disease progression in this clinical setting, is noteworthy.

In real-world clinical practice, observed survival in such heavily pretreated patients is 3-4 months.

On June 20, 2023, we announced updates in enrollment in THIO-101 in Europe.

To that date, 29 patients have been dosed in THIO-101.

With the addition of sites in Hungary, Poland, and Bulgaria in March 2023, THIO-101 has rapidly increased the number of patients enrolled and dosed with THIO.

Thirteen sites were activated with another two new additional sites ready to open shortly afterward.

On July 10, 2023, we announced updates on preliminary survival data in the Part A safety lead-in of THIO-101.

The first 2 patients enrolled in the study continued to be alive, approximately 12.2 and 11.5 months respectively, from treatment initiation.

Both patients have advanced Stage IV metastatic disease and failed 2 prior lines of therapy, including one line with an immune checkpoint inhibitor (CPI), and platinum-based chemotherapy.

Following the conclusion of study treatment, they have remained free of disease progression for 10.2 and 8.5 months, respectively, without requiring any additional therapy.

On July 11, 2023, we announced updates on disease control data in the part A safety lead-in of THIO-101.

Of the first 11 patients enrolled in THIO-101 to complete at least 1 post baseline response assessment, 9 (82%) met the primary endpoint of disease control (defined as a Complete Response, Partial Response, or Stable Disease per RECIST 1.1).

All patients enrolled have previously failed 2 or more prior lines of treatment including an immune CPI and platinum-based chemotherapy for advanced NSCLC.

On October 24, 2023, we reported unprecedented interim disease control rate (DCR) of 100% in second-line treatment that far surpasses standard of care (SoC) DCR of 53-64%, presented at ESMO 2023.

DCR is far stronger than overall response rate (ORR) in predicting overall survival benefit, as shown in a recent meta-analysis of 74 clinical trials worldwide in NSCLC.

On December 19, 2023, we announced dose selection for THIO-101, a Phase 2 clinical trial evaluating its lead asset, THIO, in sequential combination with Regeneron’s anti-PD-1 cemiplimab (Libtayo ® ) in patients with advanced non-small cell lung cancer (NSCLC).

During the dose-finding stage of THIO-101, patients were administered either 60mg, 180mg, or 360mg of THIO per cycle, followed by 350mg of cemiplimab (Libtayo ® ).

The selected dose, 180mg/cycle, presented better safety profile and outperformed the other doses in the key measures of efficacy for NSCLC trials.

Subsequently, all future trial participants will be treated with THIO 180mg/cycle.

On January 17, 2024, we announced new interim data for our ongoing THIO-101 Phase 2 trial in non-small cell lung cancer (NSCLC).

In the latest available data from THIO-101 (November 13, 2023), 60 patients had been dosed with THIO in sequential combination with Libtayo ® .

The patients received either 60mg, 180mg, or 360mg of THIO per dose, and 42 had at least one post baseline assessment completed.

The observed disease control was well sustained compared to previous scans.

On February 7, 2024, we announced publication of international Patent Cooperation Treat (PCT) application titled “Dinucleotides and Their Use in Treating Cancer.” The new dinucleotides disclosed in the patent application are telomere-targeting molecules, such as THIO fragments or other THIO analogues.

These compounds are key next-generation telomere-targeting agents, an important extension of MAIA’s innovative cancer treatment platform.

The PCT system streamlines the process for obtaining patent protection globally.

Under the PCT, applicants can seek patent protection in a large number of countries.

On February 22, 2024, we announced completion of enrollment in Phase 2 THIO-101 go-to-market clinical trial.

The trial reached the enrollment target of 41 patients for the 180mg/dose on February 19, 2024.

As of the latest data available for the trial, 79 patients had received either 60mg (24 patients), 180mg (41 patients) or 360mg (14 patients).

The original trial design targeted up to 182 patients, including all patients in the safety lead-in and 41 patients in each of the 3 tested doses (60mg, 180mg, and 360mg).

Following the selection of 180 mg/cycle as the optimal dose in December 2023, all patients were subsequently enrolled at the 180mg/cycle dose and trial enrollment was completed ahead of schedule.

On March 6, 2024, we announced interim efficacy data for THIO-101 Phase 2 trial in NSCLC.

In the latest data available (January 8, 2024), the overall response rate (ORR), characterized as partial or complete response to therapy, was 38% (3 out of 8 patients) in the efficacy evaluable population for combination THIO 180mg + cemiplimab in third-line treatment for NSCLC patients who failed treatment with immune checkpoint inhibitors in prior lines of therapy, with or without chemotherapy.

Our Science--Driven Telomere Targeting Approach

Telomeres are regions of repetitive DNA nucleotide sequences that are associated with specialized proteins at the ends of linear chromosomes in cells.

THIO’s mechanism of action comprises telomere targeting and induction of anti-cancer immunogenicity.

The enzyme telomerase recognizes THIO’s metabolite formed in situ and incorporates it into the structure of the cancer cell’s telomeres, creating a faulty structure, which breaks apart the telomere spatial structure.

THIO’s mechanism of action comprises telomere targeting and induction of anti-cancer immunogenicity.

As a result, the THIO-modified telomeric structure unwinds, recognized as DNA damage, and the cancer cells die.

We believe THIO transforms “cold”

tumors into “hot”

tumors rendering them responsive to immunotherapy (checkpoint inhibitors) and this process takes place promptly within 24 to 72 hours.

We believe THIO transforms “cold” tumors into “hot” tumors rendering them responsive to immunotherapy (checkpoint inhibitors) and this process takes place promptly within 24 to 72 hours.

We also believe we can improve the immunotherapy efficacy and we can restore the immunotherapy efficacy in patients who have progressed or developed resistance to prior immunotherapy.

8 unchanged sentences

We are also currently developing potential next-generation small molecule telomere modifying agents with the goal of identifying additional proprietary drug candidates, across multiple cancer types.

We have generated eighty-two (82) new telomere-targeting compounds of which sixty (60) compounds have been evaluated in vitro.

Currently, seven (7) molecules have been selected for further evaluation in additional in vitro and in vivo models.

Human clinical trials prior to approval are typically conducted in three sequential Phases that may overlap or be combined.

In Phase 1, the drug or biologic is initially introduced into healthy human subjects and tested for safety, dosage tolerance, absorption, metabolism, distribution and excretion.

In Phase 2, the drug or biologic is evaluated in a limited patient population to identify possible adverse effects and safety risks, to preliminarily evaluate the efficacy of the product for specific targeted diseases and to determine dosage tolerance, optimal dosage and dosing schedule for patients having the specific disease.

In Phase 3, larger-scale clinical trials are undertaken to evaluate clinical efficacy and safety and the overall risk/benefit ratio of the product.

Post-approval studies, or Phase 4 clinical trials, may be conducted voluntarily, or as a condition of FDA’s approval of a drug.

These studies may be used to confirm preliminary efficacy results, gain additional experience from the treatment of certain patient populations, or to support additional indications or labeling changes.

We completed our selection process for the clinical sites for our Phase 2 study in Australia and Europe and our application to start the Phase 2 study in Australia was approved on March 1, 2022, by the Australian Regulatory Agency—Bellberry Human Research Ethics Committee.

In July 2022, the first patient was administered with THIO in our Phase 2 human trial (THIO-101) in Australia.

In March 2022, the FDA granted Orphan Drug Designation (ODD) to THIO for the treatment of HCC, in May 2022, the FDA granted the second ODD to THIO for the treatment of small cell lung cancer, and in late 2023, a third ODD for Malignant Gliomas Brain

The FDA’s Office of Orphan Products Development may grant orphan designation status to drugs and biologics that are intended for the treatment, diagnosis or prevention of rare diseases, or conditions that affect fewer than 200,000 people in the U.S.

ODD provides certain benefits, including financial incentives, to support clinical development and the potential for up to seven years of market exclusivity for the drug for the designated orphan indication in the U.S.

if the drug is ultimately approved for its designated indication.

Our Second Generation Molecule Candidates

Our THIO program drives our development pipeline of second-generation telomere targeting agents.

We have initiated an early-stage research and discovery program aimed at identifying new compounds capable of acting through similar mechanisms of activity as THIO, such as the targeting and modifying telomeric structures of cancer cells through cancer-cell intrinsic telomerase activity.

The main objective for this program is to discover new compounds with potentially improved specificity towards cancer cells relative to normal cells and with increased anticancer activity.

The main objective for this program is to discover new compounds with potentially improved specificity towards cancer cells relative to normal cells and with potentially increased anticancer activity.

This program may also allow us to strengthen our patent portfolio.

Our current 2nd-generation pipeline of potential telomere-targeting agents includes seven compounds that have successfully undergone in vitro inhibitory testing in five cancer models.

The data from those studies showed a significantly lower 50% inhibitory concentration (IC50) for those compounds compared to THIO, as reflected in the following figure:

IC50, µM

THIO(6 thio dG)

IC50 is the half maximal inhibitory concentration, and it is a measure of the potency of a substance in inhibiting a specific biological or biochemical function, such as cell proliferation.

MC38, LLC, Hep55-1C, H2081,

and HEK293 are Non-Small Cell Lung Carcinoma, Colorectal, Hepatocellular carcinoma, Small Cell Lung Carcinoma, and Immortalized Human Kidney cell line, respectively.

*- Data unavailable

The figures below represent dose-response curves from which IC50 values were derived for second generation compounds #5 (X97848), and #12 (X97855) in HEK293 cells:

The graph below demonstrates the dose response curves for our number five next generation compound, designated as 6S-dG-dimer, in ovarian cancer-derived cell line CoC1/DDP, in comparison with cisplatin (current standard of care in this setting).

The corresponding IC50 values are shown next to the plot.

In mid-January 2023, MAIA nominated one lead new molecular entity candidate (designated as MAIA-2021-20) and one back-up new molecular entity candidate (MAIA-2022-12) for further advancement into preclinical GLP-toxicity and other studies, and may advance one of these candidates into human clinical trials upon completion of the required preclinical evaluations.

MAIA also has filed a broad provisional patent application covering the composition of matter for the new telomere-targeting molecules in the fourth quarter of 2022.

Although the program is in early stages and we may not be able to identify suitable compounds, we believe we will be able to create a second generation of THIO-like compounds.

Our pipeline includes several potential targeted immuno-oncology candidates for relapsed and refractory cancers.

Pipeline products are under investigation and have not been proven to be safe or effective.

There is no guarantee any product will be approved in the sought-after indication or will meet the developmental milestones set forth above.

Our current 2nd-generation pipeline of potential telomere-targeting agents includes seven compounds that have successfully undergone in vitro inhibitory testing in five cancer models.

The data from those studies showed a significantly lower 50% inhibitory concentration (IC50) for those compounds compared to THIO.

Based on those data, we have progressed those seven compounds to in vivo testing.

In January 2023, we nominated one lead new molecular entity candidate (designated as MAIA-2021-20) and one back-up new molecular entity candidate (MAIA-2022-12) for further advancement into preclinical GLP-toxicity and other studies and may advance one of these candidates into human clinical trials upon completion of the required preclinical evaluations.

A third candidate (MAIA-2021-029) was selected in June 2023.

MAIA also filed a broad provisional patent application covering the composition of matter for the new telomere-targeting molecules in the fourth quarter of 2022.

Our robust pipeline includes several targeted immuno-oncology candidates for relapsed and refractory cancers.

Our goal is to be the leader in the discovery, development and commercialization of cancer telomere targeting agents and other similar small molecules.

35 unchanged sentences

Acute Myeloid Leukemia (AML)

A Survey of Telomerase Activity in Human Cancer –

JW Shay, S Bacchetti –

European Journal of Cancer, 33,5,787-791, 1997.

A Survey of Telomerase Activity in Human Cancer – JW Shay, S Bacchetti – European Journal of Cancer, 33,5,787-791, 1997.

Telomerase Active in Human Liver Tissues;

12 unchanged sentences

Small Cell Lung Cancer

Incidence, Prevalence, Mortality (Global Cancer Observatory / WHO);

Sales (Global Data).

The table below reflects the current market for check-point inhibitors because there is no current market for THIO-like molecules.

14 unchanged sentences

Pfizer / Merck AG

TBD (tislelizumab)

Novartis / BeiGene

TEVIMBRA (tislelizumab)

JEMPERLI (dostarlimab)

1 unchanged sentence

Intellectual Property

Our global patent and patent-pending estate covers several areas.

Telomerase mediated telomere altering compounds and treatment of therapy-resistant cancers are part of our portfolio.

Further, THIO’s immunogenic treatment strategy, which focuses on sequential combination with checkpoint inhibitors has been filed.

We maintain five (5) issued patents and have twenty-nine (29) pending applications.

Our goal is to obtain, maintain and enforce patent protection wherever appropriate for our product candidates, formulations, processes, methods and any other proprietary technologies, and operate without infringing on the proprietary rights of other parties, both in the United States and in other countries.

3 unchanged sentences

To help protect our proprietary know-how that is not patentable, we seek to put in place appropriate internal policies for the management of confidential information requiring all our employees, consultants, advisors, and other contractors to enter into confidentiality agreements that prohibit the disclosure of confidential information, and which will require disclosure and assignment to us of the ideas, developments, discoveries, and inventions important to our business.

Risk Factors –

Risks Related to our Intellectual Property ”

for additional information.

See “ Risk Factors – Risks Related to our Intellectual Property ” for additional information.

We file for patents, both directly and in collaboration with our licensing partners, in the United States with counterparts in certain countries in Europe and certain key market countries in the rest of the world, thereby covering the major pharmaceutical markets.

2 unchanged sentences

Title / PCT Application Number

Telomerase Mediated Telomere Altering Compounds / PCT/US2014/33330 (WO2014/168947), issued in the US, MX, NZ and RU (all method of use) pending in BR, CA, CN, EP, HK and SG.

Telomerase Mediated Telomere Altering Compounds / PCT/US2014/33330 (WO2014/168947), issued in the US (patent no.

10,463,685), CA, MX, NZ and RU (all method of use) pending in BR, CN, EPO, HK and SG.

6-Thio-2'-Deoxyguanosine (6-Thio-dG) Results in Telomerase Dependent Telomere Dysfunction and Cell Death in Various Models of Therapy-Resistant Cancer Cells /

PCT/US2017/34706 (WO2017/205756), pending in the US (method of use)

PCT/US2017/34706 (WO2017/205756), pending in the US (method of use), AU, CA, and EPO.

Use of 6-thio-dG to Treat Therapy-Resistant Telomerase positive Pediatric Brain Tumors /

6 unchanged sentences

All patents are method of use.

On December 23, 2020, we entered into a second agreement with UTSW, which set forth the agreement between the parties pursuant to the Company exercising its option rights in the UTSW1 Agreement and obtaining additional license rights.

Pursuant this second

license with UTSW, which we refer to as the UTSW2 Agreement, we obtained (1) an exclusive, worldwide license to develop and commercialize the following UTSW patent family:

On December 23, 2020, we entered into a second agreement with UTSW, which granted the Company option rights in the UTSW1 Agreement and obtaining additional license rights.

This second license with UTSW, which we refer to as the UTSW2 Agreement, we obtained (1) an exclusive, worldwide license to develop and commercialize the following UTSW patent family:

Title / PCT Application Number

Sequential Treatment of Cancers Using 6-Thio-dG and Checkpoint Inhibitors / PCT/US2021/022090, pending in the US and PCT (method of use)

Sequential Treatment of Cancers Using 6-Thio-dG and Checkpoint Inhibitors / PCT/US2021/022090, pending in the US and PCT (method of use), AU, BR, CA, CN, EPO, IL,JP, KR, MX, RU, SG, US

and (2) a non-exclusive worldwide license to develop and commercialize related technology rights.

2 unchanged sentences

This patent is generally directed to methods of using THIO in combination with immune checkpoint inhibitors.

On July 13, 2022, MAIA Biotechnology filed PCT/US23/70177, US 18/352,220, and TW 112126229, Dinucleotides and their use in treating cancer, for Dinucleotide compounds that target telomers in cancer cells and method for using the dinucleotide compounds in treating cancers alone and in combination with other anticancer-agents and therapies, such as in combination with checkpoint inhibitors and radiation therapy.

Pending PCT, US, and TW.

On May 30, 2023, MAIA Biotechnology filed US 63/469,782, Tumor Redox-Activated 6-Thiopurine containing dimer compounds, for 6-thiopurine containing compounds that target telomers in cancer cells and methods for using the compounds in treating cancers alone and in combination with other anticancer agents and therapies.

Pending in US.

On October 22, 2023, MAIA Biotechnology and Regeneron filed US ser no.

18/382,521, Treatment of Non-Small Cell Lung Cancer with 6-THIO-dG and Cemiplimab, that discloses the use of treating Non-Small Cell Lung Cancer with 6-THIO-dG followed by cemiplimab.

Pending in US.

This application is under petition to be converted to a provisional application.

On October 29, 2023, MAIA Biotechnology filed US ser.

63/546,242, Telomere-Targeting Phosphatidyl-THIO Conjugates, for Telomere-targeting phosphatidyl-THIO conjugates that target telomers in cancer cells and methods for using the telomere-targeting phosphatidyl-THIO conjugates compounds to treat cancers.

Pending in US.

We continually assess and refine our intellectual property strategy as we develop new technologies and therapeutic candidates.

7 unchanged sentences

and Incyte Corporation, including development and commercialization of major oncology brands, organizational capability building, talent recruiting and development, and functional leadership.

Our Chief Medical Officer and Head of Development, Mihail Obrocea, M.D., is a former practicing academic medical hematologist/oncologist and experienced pharmaceutical physician executive that brings over 20 years of successful cancer drug development track record from Juno Therapeutics Inc.

(acquired by Celgene/BMS), Pharmacyclics Inc., AbbVie Bio Corp., Mannkind Corp., MedImmune, Inc.

and Pfizer, Inc., among others.

His experience includes clinical development of cell therapies (CAR-T), cancer vaccines, antibodies, and antibody drug conjugates (ADCs) and small molecules across a wide range of tumor types and clinical indications.

• Our Chief Scientific Officer, Sergei M.

1 unchanged sentence

who is an internationally recognized scientist and expert in the areas of modern drug discovery and development, oncology, telomerase, immune-regulatory therapeutics, nucleosides, nucleotides, DNA and RNA analogues, lipid and other conjugates, small molecules and nucleic acid based therapeutic agents.

He is the co-inventor of a novel telomere-by-telomerase-targeting therapeutic approach to potential cancer treatment and responsible for leading the research team that characterized THIO’s telomere targeting activity.

Our Chief Financial Officer, Joseph F.

McGuire has served as Chief Financial Officer for several privately held and publicly traded companies in the health care, financial services, investment, and manufacturing industries.

In these roles, his responsibilities included SEC financial reporting, investor relations, corporate governance, legal and audit liaison, and team building.

Most recently, Mr.

McGuire was the chief financial officer at Avadim Health, Inc.

(“Avadim”).

McGuire began his career with Price Waterhouse, where he was a certified public accountant, and later held management positions with Dean Witter Reynolds and Paine Webber, Inc.

We have engaged the following advisors, who are leading, internationally recognized experts in oncology, telomeres and telomerase research, to be a part of our Scientific Advisory Board (“SAB”), which provides independent non-binding scientific advice to our management team in the roles detailed below under each member’s name:

Tom Gajewski, M.D., Ph.D.

Professor of Cancer Immunotherapy (University of Chicago)

One of the key pioneers in cancer immunotherapies and accomplished in the field

Key investigator on all phase 2 and phase 3 trials in Melanoma (with Keytruda®, Opdivo®, etc.)

Past president of the Society for Immunotherapy of Cancer (SITC)

Served on the program committees for the American Society for Clinical Oncology (ASCO) and the American Association for Cancer Research (AACR)

Serves as an editor for Cancer Research and Journal for Immunotherapy of Cancer

On our SAB, will cover translational research for all cancers, for clinical development

• Our Head of Finance and principal financial and accounting officer, Jeffrey Himmelreich, has extensive finance, accounting and public company reporting experience.

Prior to his recent appointment, since September 2023, Mr.

Himmelreich acted as the Company’s Director of Accounting and Financial Reporting, where he provided oversight for the Company’s filings with the U.S.

Securities and Exchange Commission (“SEC”) and other related financial, accounting or reporting matters.

From July 2021 to September 2023, Mr.

Himmelreich acted as the Chief Financial Officer of Microtech Knives, Inc., a private manufacturer of hand tools.

Further, from December 2018 to July 2021, Mr.

Himmelreich served as the Director of Finance and Accounting at Avadim Health Inc., a healthcare-related private company, during which time he assisted with SEC filings of Avadim Health Inc.

for a proposed initial public offering.

Himmelreich has a Bachelor of Science (B.S.) in Accounting from the Indiana University of Pennsylvania, and a Master of Business Administration from Pennsylvania State University.

Tudor Ciuleanu, M.D., Ph.D.

5 unchanged sentences

• Editor for the Journal of Clinical Oncology (JCO), Romanian edition

On our SAB, will lead clinical activities in Europe across tumor types –

NSCLC, CRC, Gastric, HCC, Head and Neck, Urological cancers, and Lymphomas

• On our SAB, will lead clinical activities in Europe across tumor types – NSCLC, CRC, Gastric, HCC, Head and Neck, Urological cancers, and Lymphomas

Jerry Shay, Ph.D.

3 unchanged sentences

• Highly influential biomedical researcher with over 30 issued patents and more than 500 peer reviewed publications

Southland Financial Corporation Distinguished Chair in Geriatric Research and a Distinguish Professor at University of Texas Southwestern, having received the University of Texas Regent’s Outstanding Teaching Award and the Minnie Steven Piper Foundation Professor Award

• Southland Financial Corporation Distinguished Chair in Geriatric Research and a Distinguish Professor at University of Texas Southwestern, having received the University of Texas Regent’s Outstanding Teaching Award and the Minnie Steven Piper Foundation Professor Award

• Awarded the Eunice Kennedy Shriver NIH Alliance Pioneer Award in 2017

8 unchanged sentences

• Principal investigator of a number of important national and international studies, both clinical and pre-clinical

Former Director of two major cancer centers, The Royal Children’s Hospital Melbourne and Andrew Love Cancer Centre –

Barwon Health

• Former Director of two major cancer centers, The Royal Children’s Hospital Melbourne and Andrew Love Cancer Centre – Barwon Health

• On our SAB, will assist in translational research in Brain Cancers for clinical development

Gunnur Dikmen, M.D., Ph.D.

Professor at Hacettepe University Medical Faculty, Department of Medical Biochemistry, as well as the director of the Hacettepe University hospital’s emergency laboratory.

– Professor at Hacettepe University Medical Faculty, Department of Medical Biochemistry, as well as the director of the Hacettepe University hospital’s emergency laboratory.

• Broad range of experimental and clinical experience in molecular & cell biology and clinical biochemistry, translating research results from bench to bedside and from academia to clinical laboratory to mentor the next generation of multidisciplinary research projects by providing new therapeutic approaches for cancer and telomere related diseases.

3 unchanged sentences

Adam Yopp, M.D.

–Associate Professor and Division Chief of Surgical Oncology and Colorectal Surgery, at Harold C.

Simmons NCI-designated Comprehensive Cancer Center at UT Southwestern Medical Center in Dallas.

3 unchanged sentences

• On our SAB, will assist with developing THIO for the treatment of liver cancer.

Remus Vezan, M.D., Ph.D.

– Vice President, Global Clinical Development at BeiGene

• Completed his medical training (M.D.

and Ph.D.) at the University of Medicine and Pharmacy Cluj, Romania and University of Bern, Switzerland

• Seasoned leader in drug development of novel therapeutic modalities, including cell and gene therapies, with over 20 years of academic and biopharmaceutical industry experience, and had a seminal contribution to the development and approval of multiple products, including TECARTUS®, YESCARTA® or IMBRUVICA®

• On our SAB, will assist in development and strategy for approval of THIO in multiple tumor types.

Our SAB is primarily compensated by way of the grant of stock options as determined by the Company as appropriate in recognition of the specific services or areas of expertise of each member.

5 unchanged sentences

• Maintenance of telomeres is essential for unlimited cellular proliferation and confers immortality in cancer cells.

Telomeres in human cells consist of double-stranded and single-stranded repeats of the sequence TTAGGG, which terminate in a single-stranded 3´- extension overhang of the G-rich strand.

Their major function is to cap and protect the ends of chromosomes and thus to provide genetic stability.

This capping function is mediated by a special architecture in which the 3´- overhang participates with telomere-binding proteins in a large loop structure called T-loop.

The image on the right reflects the general location of telomeres as the end-cap of the chromosomes, which are located in the nucleus of the cell.

Adapted from Transcendental Meditation and lifestyle modification increase telomerase , December 6, 2015.

The most successful anti-cancer drugs in the market today typically interfere with only one of the specific capabilities or “hallmarks”

cancer cells use for tumor growth and progression.

The most successful anti-cancer drugs in the market today typically interfere with only one of the specific capabilities or “hallmarks” cancer cells use for tumor growth and progression.

In contrast, our lead drug candidate, THIO, targets two major hallmark pathways:

• Targeting cancer cell telomeric DNA structure and functional integrity;

Activating the immune system that turns immunologically “cold”

tumors into “hot”

tumors that are responsive to therapy.

• Activating the immune system that turns immunologically “cold” tumors into “hot” tumors that are responsive to therapy.

THIO synergizes with immune activating agents, like checkpoint inhibitors, for the potential to attack and destroy tumors.

6 unchanged sentences

In human cells, the telomerase holoenzyme consists of a high-molecular-weight complex with a template region-containing RNA subunit, hTR, and a protein component, the catalytic subunit human telomerase reverse transcriptase (hTERT).

In most normal somatic cells, telomerase activity is absent and telomere repeats are lost with cell division and with aging.

In most normal

somatic cells, telomerase activity is absent and telomere repeats are lost with cell division and with aging.

Telomerase is especially important in fetal tissues, reproductive cells and other tissues where extensive cell proliferation is necessary.

4 unchanged sentences

Since most cancer cells are reliant on telomerase for their survival, and telomerase is undetectable or only transiently present at low levels in normal cells, telomeres of cancer cells and telomerase are attractive targets for the development of new cancer therapeutics.

“Proof of Principle”

for validation of telomere structural integrity-targeting as a therapeutic concept was demonstrated in vitro in human tumor cells using dominant negative mutant forms of hTERT.

“Proof of Principle” for validation of telomere structural integrity-targeting as a therapeutic concept was demonstrated in vitro in human tumor cells using dominant negative mutant forms of hTERT.

In these experiments, telomerase activity was abolished, which was associated with continuous telomere shortening, subsequently leading to the cancer cells death.

3 unchanged sentences

Differentiated Activity of THIO, a Telomere-Targeting Agent

THIO (6-thio-2’-deoxyguanosine or 6-thio-dG) is a small molecule telomere targeting agent that uses the enzyme telomerase for DNA integration predominantly in the telomeric structure.

Based on pre-clinical studies, THIO’s telomere targeting activity is believed to be primarily cancer-specific in tumor cells with active telomerase, but not in normal cells.

Based on our extensive review of publicly-available information, to our knowledge THIO’s direct telomere targeting action utilizing telomerase is different from other commercially available cancer therapies and those currently in publicly disclosed clinical trials.

Telomeres, along with the enzyme

telomerase, play a fundamental role in the survival of cancer cells and their resistance to current therapies.

THIO (6-thio-2’-deoxyguanosine or 6-thio-dG) is a small molecule telomere targeting agent that uses the enzyme telomerase for DNA integration predominantly in the telomeric structure.

Based on pre-clinical studies, THIO’s telomere targeting activity is believed to be primarily cancer-specific in tumor cells with active telomerase, but not in normal cells.

Telomeres, along with the enzyme telomerase, play a fundamental role in the survival of cancer cells and their resistance to current therapies.

The statements above are not intended to give any indication that THIO has been proven effective or that it will receive regulatory approval.

In non-clinical studies, published initially in 2014 along with subsequent studies, THIO was found to be converted, in cells, into the substrate recognized by telomerase, and then incorporated into telomeres of the cancer cells.

Once incorporated, THIO compromised the cancer cell’s telomere structure and function, leading to “uncapping”

of the telomeres, induction of DNA damage responses, and rapid cancer cell death.

Once incorporated, THIO compromised the cancer cell’s telomere structure and function, leading to “uncapping” of the telomeres, induction of DNA damage responses, and rapid cancer cell death.

These profound structural modifications of cancer cell telomeres were irreparable.

10 unchanged sentences

Administration of low doses of THIO, aimed to activate the immune system via THIO-induced telomeric DNA modification, followed by checkpoint inhibitor therapy (anti-PD-L1 or anti-PD1), eliminated advanced tumors in preclinical models with confirmation of cancer cell type specific immune memory.

This potential for THIO to induce immune memory, if confirmed in human clinical trials, would be a distinct feature of THIO’s mechanism of action, offering the possibility that the immune system may continue to be active against the cancer cells over extended periods of time, potentially reducing the need for additional treatment.

These pre-clinical results provided the basis for our new clinical therapeutic strategy for sequentially administering THIO as a telomere-targeted agent first, to activate the immune system against the specific cancer, followed by immunotherapy or other immune-activating therapy.

Limitations of Other Therapeutic Approaches

In contrast to THIO, which targets telomeres, a challenge for the potential clinical application of pharmaceutically useful telomerase inhibitors (e.g., Imetelstat), is the therapeutic window (the range of dosage of a drug or of its concentration in a bodily system that provides safe effective therapy) and the often-observed delay between initiation of treatment and phenotypic response (called the “lag period”).

Since the antiproliferative effect of any direct telomerase inhibitor is dependent on the telomere length of any given tumor cell, clinical response will be delayed until the telomeres become critically short, and thus can no longer protect the chromosomes, and as a result, the cancer cell dies.

1 unchanged sentence

A Telomere Targeting Agent

THIO (6-thio-2’-deoxyguanosine) is a synthetically-modified small molecule nucleoside that was originally designed to be an improved chemotherapy drug developed to work around purine analog resistance, which was standard-of-care therapy in the 1970s.

Sponsored by the National Cancer Institute, THIO was extensively investigated in at least 19 clinical trials with over 600 cancer patient subjects (adult and pediatric) treated, both as monotherapy or in combination with other commonly used standard agents of the time.

See “THIO Clinical Trials”

below for more information about these trials.

See “THIO Clinical Trials” below for more information about these trials.

A traditional treatment strategy was used where patients were treated to maximum tolerated dose (MTD), a common approach for cancer therapy drug development.

6 unchanged sentences

These factors have only been discovered since 2014 (with the most recent in 2019), as illustrated in the following graphic:

THIO’s detailed telomere targeting mechanism and resulting immune activation.

At high drug exposure (MTD), THIO can be immunosuppressive.

Proper administration of THIO to activate the immune system followed by immunotherapy to achieve best response.

Telomeres are vital DNA-structures discovered by Jack Szostak’s laboratory, for which he received the Nobel Prize in 2009, which are present at the ends of each chromosome which protect the genome from degradation, unnecessary recombination, repair, and interchromosomal fusion.

Telomeres, along with the enzyme telomerase, are both crucial for the survival of cancer cells.

2 unchanged sentences

57% to 100% of primary human cancers are TERT+ dependent upon tumor type, indicating a significant potential therapeutic utilization for THIO in almost all tumor types.

THIO’s cancer-specific disturbance of telomeric structure by telomerase leads to disruption in the cell cycle, followed by rapid cell death.

Based on extensive review of publicly-available information, THIO’s direct telomere targeting action utilizing telomerase is different from other commercially available cancer therapies and those currently in publicly disclosed clinical trials.

In 2019, the MAIA research team showed that in mouse models THIO-produced telomere modification and disruption induced cancer-specific innate and adaptive immune response against immunologically “cold”

or unresponsive tumor types.

THIO’s cancer-specific disturbance of telomeric structure by telomerase leads to disruption in the cell cycle, followed by rapid cell death.

When THIO was administered at low doses, in syngeneic and humanized mouse models of telomerase-expressing cancers, followed by a break to allow for the activation of the immune system against the specific cancer, then followed by a standard-of-care immunotherapy agent like a check point inhibitor (CPI), either PD-1 or PD-L1, complete tumor regression was observed, with no observed toxicities.

These effects have been replicated in multiple preclinical models, utilizing all leading checkpoint inhibitors or radiation therapy.

Based on these studies, we hypothesized that THIO, administered in advance of immune-activating therapies (e.g., checkpoint inhibitors, radiation therapy, etc.), at dose levels significantly lower than the levels evaluated in previous clinical trials, will “

prime”

the tumor environment and initiate an overall anti-tumor immune response.

This represents an entirely new therapeutic approach for THIO and forms the basis for the new clinical strategy for planned future trials.

1 unchanged sentence

The following summarizes the relevant preclinical studies.

Extensive preclinical studies have been performed to validate THIO’s primary mechanism of action:

targeting telomeres directly and causing cancer cell death via telomerase-mediated DNA damage.

To our knowledge, THIO alone has shown significant telomere targeting activity in numerous non-small cell lung cancer (NSCLC) and multiple other cancer-based cell lines in vitro and in vivo , including but not limited to small cell lung cancer (SCLC), melanoma, colorectal cancer (CRC), glioblastoma multiforme (GBM), diffuse intrinsic pontine glioma (DIPG), neuroblastoma, pancreatic, hepatocellular carcinoma (HCC), as well as head and neck cancer, breast cancer and prostate cancer.

in summary, EC 50 values (the concentrations at which half of the total number of cancer cells are dead) were approximately 0.4 µM to 1.5 µM.

THIO was not cytotoxic in normal, untransformed telomerase-negative cells at concentrations up to 100 µM.

in summary, EC 50 values (the concentrations at which half of the total number of cancer cells are dead) were approximately 0.4 µM to 1.5 µM.

THIO was not cytotoxic in normal, untransformed telomerase-negative cells at concentrations up to 100 µM.

in summary, the doses that resulted in cancer cell death were in the range of 2.5 - 5.0 mg/kg, depending on the tumor type and the schedule of the drug administration ranging from 1 to 3 days per cycle.

In March 2022, the U.S.

Food and Drug Administration (FDA) granted Orphan Drug Designation (ODD) to THIO for the treatment of hepatocellular carcinoma, and in May 2022, the FDA granted ODD to THIO for the treatment of small cell lung cancer.

Orphan Drug Designation provides certain benefits, including financial incentives, to support clinical development and the potential for up to seven years of market exclusivity for the drug for the designated orphan indication in the U.S.

if the drug is ultimately approved for its designated indication.

1 unchanged sentence

In vivo , THIO, at 3 mg/kg/dose, (which corresponds to a 20 mg/patient/day low-dose), administered followed by a one-day break, followed by an immune checkpoint inhibitor (either anti-programmed cell death protein 1 (PD-1) or anti-programmed death ligand 1 (PD-L1) products), resulted in complete tumor regression in NSCLC and CRC syngeneic mouse tumor models.

At this low dose, THIO was able to transform immunologically “cold’

tumors, (tumors that do not respond to the CPI treatment), into immunologically “hot”

tumors, which then responded well to the following sequential treatment with a CPI.

At this low dose, THIO was able to transform immunologically “cold’ tumors, (tumors that do not respond to the CPI treatment), into immunologically “hot” tumors, which then responded well to the following sequential treatment with a CPI.

These potent anti-tumor phenotypic effects were also accompanied by the efficient induction of the tumor-specific CD8+ cells, as well as CD4+, and natural killer (NK)-cells (Mender, 2020b).

7 unchanged sentences

In the second column, with the telomerase inhibitor BIBR, the cancer cells also grew.

In the third column, in which the telomere targeting agent THIO was administered at a concentration of 2.5µM, cancer cell growth was visibly inhibited.

In the fourth column, in which THIO was administered at a concentration of 5µM, cancer cells were also visibly inhibited.

In the third column, in which the telomere targeting agent THIO was administered at a concentration of 2.5µM, cancer cell growth was visibly inhibited.

In the fourth column, in which THIO was administered at a concentration of 5µM, cancer cells were also visibly inhibited.

The same concentrations of THIO were also administered in vivo in rodent models (mice), caring tumors, derived from either brain, or liver, or melanoma, or neuroblastoma, or colorectal cancer cells were treated with THIO (at 2 mg/kg to 5 mg/kg doses), significant reduction in tumor masses resulting from the treatment with THIO was observed.

Note that THIO’s activity seen in preclinical models has yet to be demonstrated in humans.

• THIO demonstrated potential to selectively cause cancer cell death with active enzyme telomerase versus normal cells in vitro .

3 unchanged sentences

et al., Cancer Discovery (2015)

*TIF –

telomere damages induced foci

*TRF2 –

protein associated with telomeres

* Gamma-H2AX –

protein associated with induction of DNA damage

*CRC –

colorectal cancer

*hTERT –

protein components of telomerase enzyme

THIO, as a single agent, showed in vitro telomere targeting activity in cancer cells that are resistant to tyrosine kinase inhibitors (TKIs), checkpoint inhibitors, IL-2, IFNα, YERVOY ® (ipilimumab) and a host of chemotherapies.

*TIF – telomere damages induced foci

*TRF2 – protein associated with telomeres

* Gamma-H2AX – protein associated with induction of DNA damage

*CRC – colorectal cancer

*hTERT – protein components of telomerase enzyme

• THIO, as a single agent, showed in vitro telomere targeting activity in cancer cells that are resistant to tyrosine kinase inhibitors (TKIs), checkpoint inhibitors, IL-2, IFNα, YERVOY ® (ipilimumab) and a host of chemotherapies.

The below graphic, in NSCLC and Melanoma models respectively, demonstrates in vivo telomere targeting activity of THIO in mice models of lung cancer, derived from PERC16 cells, and melanoma derived from WM4265 cells.

1 unchanged sentence

– intraperitoneal injection

*IL-2 –

cytokine interleukin 2

*IFN-a –

interferon alfa

*IL-2 – cytokine interleukin 2

*IFN-a – interferon alfa

• THIO was observed to penetrate the blood-brain barrier and inhibits tumor growth, inducing in-tumor telomere dysfunction and cancer cell death, in in vitro models of difficult to treat pediatric brain cancer, where no therapy exists.

3 unchanged sentences

1504-1514, 2018.

*TIF –

telomere damage induced foci

*MB004 –

brain cancer cell line

THIO transformed “cold”

tumors into “hot”

tumors that were responsive to immunotherapy.

*TIF – telomere damage induced foci

*MB004 – brain cancer cell line

• THIO transformed “cold” tumors into “hot” tumors that were responsive to immunotherapy.

THIO utilized a telomere targeting pathway that synergized with checkpoint inhibitors and other immune-activating therapies.

The tumor-specific immune activation, resulting from THIO’s primary mode of action, overcame resistance to current check point inhibitor (CPI) standard-of-care therapy, as illustrated in the following Colorectal Cancer model.

The below graphic demonstrates telomere targeting activity of THIO alone, and in sequential combination with immune checkpoint inhibitor (anti-PD-L1 compound, atezolizumab), in mice model of colorectal cancer, derived from MC-38 cells.

14 unchanged sentences

This summary should address the methodology used, the results, and a discussion of the relevance of the findings to the investigated therapeutic and the possible unfavourable and unintended effects in humans.

It is therefore hypothesized that THIO, administered in advance of immune-activating therapies (e.g., checkpoint inhibitors, radiation therapy, etc.), at dose levels significantly lower than the levels evaluated in previous clinical trials, will “

prime”

environment and initiate an overall anti-tumor immune response.

6 unchanged sentences

Studies utilizing THIO as a single agent have been published in peer-reviewed journals.

As part of the existing data base of clinical experience with the drug, we expect to reference the older NCI studies in the public domain as well as reference NCI’s original IND filing in support of an IND filing, pursuant to FDA regulations.

The following tables summarize the THIO single agent peer-reviewed published data available from the previous clinical trials.

14 unchanged sentences

and Siegel, S.

“Phase I evaluation of beta-2'-deoxythioguanosine in pediatric patients with leukemia.”

Cancer Treat Rep 69(6):

Phase 2 –

Single Agent Studies

“Phase I evaluation of beta-2'-deoxythioguanosine in pediatric patients with leukemia.” Cancer Treat Rep 69(6):

Phase 2 – Single Agent Studies

Adverse Events

22 unchanged sentences

O., Knospe, W.

“Phase II Study of beta-2'-deoxythioguanosine in adult acute leukemia.

(Study SEG-248)”

Cancer Treat Rep 61(7):

“Phase II Study of beta-2'-deoxythioguanosine in adult acute leukemia.

(Study SEG-248)” Cancer Treat Rep 61(7):

1379-1381 Douglass, H.

2 unchanged sentences

and Carbone, P.

“Chemotherapy of advanced measurable colon and rectal carcinoma with oral 5-fluorouracil, alone or in combination with cyclophosphamide or 6-thioguanine, with intravenous 5-fluorouracil or beta-2'-deoxythioguanosine or with oral 3(4-methyl-cyclohexyl)-1(2-chlorethyl)-1-nitrosourea:

A Phase II-III study of the Eastern Cooperative Oncology Group (EST 4273).”

Cancer 42(6):

A Phase II-III study of the Eastern Cooperative Oncology Group (EST 4273).” Cancer 42(6):

The previous human experience presents significant limitations as it dates to the 1970s and early 1980s when the implementation of ICH Good Clinical Practices was not yet in effect.

The published studies did not disclose certain data points in line with the current ICH Good Clinical Practices, such as efficacy endpoints and serious adverse events.

, whether those endpoints were reached, whether the data was found to be statistically significant and serious adverse events.

The published studies did not disclose certain data points in line with the current ICH Good Clinical Practices, such as efficacy endpoints and serious adverse events, whether those endpoints were reached, whether the data was found to be statistically significant and serious adverse events.

Further, we do not know whether those prior studies were powered for statistical significance in the way our planned studies will be powered.

9 unchanged sentences

THIO Developmental Initiatives and Objectives

Based on the existing data regarding pre-clinical information on THIO, we believe it is possible to enter the next human clinical study in the near term with the new low dose immunogenic approach with THIO.

We plan to approach the FDA to request a modified toxicity requirement to allow us a reduced time and expenditure to IND in the United States, however, the FDA may not grant such request.

We are currently working with experts to evaluate the extent and quality of the existing data supporting THIO and had a pre-IND meeting with the FDA for guidance in 2022.

Phase 2 and 3 Programs

7 unchanged sentences

The following chart sets forth the design of the THIO-101 trial:

This “dose-finding”

trial will assess the safety, mechanism of activity, and immune system activation of four THIO doses tested out in separate arms administered in parallel.

This “dose-finding” trial is designed to assess the safety, mechanism of activity, and immune system activation of three THIO doses tested out in separate arms administered in parallel.

Each dosing arm will be further evaluated for efficacy based on Overall Response Rate (ORR), Duration of Response (DoR) and Progression Free Survival (PFS) to determine to optimal (safe and effective) dose of THIO administered in sequence with cemiplimab.

Additional patients may be recruited for further clinical evaluation in any of the THIO arms based on safety and clinical benefit.

Each arm of the trial will enroll a minimum of 22 and up to 41 evaluable patients.

Subsequently, we expect to target earlier lines of therapy (1 st line) in pivotal Phase 3 confirmatory studies in NSCLC.

FDA’s November 2022 feedback indicated that our protocol generally sounds reasonable, subject to certain modifications to the

protocol and requests for additional information.

We intend to incorporate FDA’s feedback and provide the requested information as part of our IND submission to FDA, which we anticipate filing in the near future.

Subsequently, we expect to target earlier lines of therapy (1 st line) in a pivotal Phase 3 confirmatory studies in NSCLC.

As of February 2024, dose selection and enrollment had been completed, but monitoring and assessment of dosed subjects are ongoing as patients continue to with the postbaseline scans and data matures.

In an effort to obtain FDA and/or EMEA approval of THIO in combination with other standard of care approved cancer immunotherapies, we will have to conduct head-to-head studies which will compare standard of care treatment alone to standard of care treatment combined with THIO.

2 unchanged sentences

In the event THIO demonstrates early clinical efficacy, we plan to expand our clinical development program in multiple tumor types and assess several regulatory approval pathways utilizing our other development programs.

The clinical development plan includes the initiation of an additional “basket trial”

in multiple cancer types.

The clinical development plan includes the initiation of an additional “basket trial” in multiple cancer types.

This study uses a special design which allows different cancer indications to be studied under the same single trial umbrella.

Some of the indications considered are:

• colorectal cancer (CRC)

• hepatocellular carcinomas (HCC)

5 unchanged sentences

• prostate cancer

Ultimately, we envision positioning THIO as the foundational priming treatment for all immune-activating agents over time based upon THIO’s tumor-specific immune-activation approach that enables key clinical strategies that could dramatically expand the immunotherapy market.

Second Generation of Telomere Targeting Agents

4 unchanged sentences

Strategic Collaborations and Key Agreements

Through our licensing agreements with The University of Texas Southwestern Medical Center (“UTSW”), we have commercial rights to certain U.S.

patents, as well as their foreign counterparts, for the use of THIO in treating telomerase-expressing lung and colon cancer cells.

We are currently using this technology to study a treatment regimen comprising the use of THIO treatment followed by cemiplimab (Regeneron) treatment in NSCLC.

We are currently using this technology to study a treatment regimen comprising the use of THIO treatment followed by cemiplimab treatment in NSCLC.

In addition, we have licensed a number of pending U.S.

2 unchanged sentences

In 2021, we entered into a Clinical Supply Agreement with Regeneron Pharmaceuticals, Inc.

(REGN) to supply cemiplimab for the THIO-101 study.

(Regeneron) to supply cemiplimab for the THIO-101 study.

Regeneron will contribute the drug supply without cost, which represents a significant direct cost savings for our program.

1 unchanged sentence

All other tumor types remain open, and we are in discussions with other pharmaceutical companies to evaluate additional agreements that may be appropriate to support the expanded development of THIO.

The supply agreement will remain in force until all of the obligations of the parties’

related to the studies contemplated by the agreement are completed, or until terminated by either party.

The supply agreement will remain in force until all of the obligations of the parties’ related to the studies contemplated by the agreement are completed, or until terminated by either party.

The agreement may be terminated in the event of unsafe use of cemiplimab, material breach, regulatory action or corruption.

In addition, our management believes that strong partnership interest will develop from other pharmaceutical companies who have checkpoint inhibitor franchises or those with cancer immunotherapy interest.

We expect to continue discussions with several

companies that have expressed interest and plan to expand discussions to capitalize on these opportunities.

We expect to continue discussions with several companies that have expressed interest and plan to expand discussions to capitalize on these opportunities.

The checkpoint inhibitor market is large, and our goal is to ultimately position THIO as the foundational priming treatment to be used prior to all checkpoint inhibitors.

3 unchanged sentences

Title / PCT Application Number

Telomerase Mediated Telomere Altering Compounds / PCT/US2014/33330 (WO2014/168947)

Telomerase Mediated Telomere Altering Compounds / PCT/US2014/33330 (WO2014/168947), issued in the US (patent no.

10,463,685), CA, MX, NZ and RU (all method of use) pending in BR, CN, EPO, HK and SG.

6-Thio-2'-Deoxyguanosine (6-Thio-dG) Results in Telomerase Dependent Telomere Dysfunction and Cell Death in Various Models of Therapy-Resistant Cancer Cells /

PCT/US2017/34706 (WO2017/205756)

PCT/US2017/34706 (WO2017/205756), pending in the US (method of use), AU, CA, and EPO.

Use of 6-thio-dG to Treat Therapy-Resistant Telomerase positive Pediatric Brain Tumors /

PCT/US2019/023596 (WO2019/183482)

Treatment of Drug Resistant Proliferative Diseases with Telomerase Mediated Telomere Altering Compounds / PCT/US2017/023858 (WO/2017/165675)

PCT/US2019/023596 (WO2019/183482), pending in the US (method of use)

Treatment of Drug Resistant Proliferative Diseases with Telomerase Mediated Telomere Altering Compounds / PCT/US2017/023858 (WO/2017/165675), pending in the US (method of use)

Under the UTSW1 Agreement, we agreed to pay UTSW a minimal license fee, deferred license fees, milestone fees, and running royalties beginning on the first net sale (among others).

For additional details regarding our relationship with UTSW, see the section entitled “

Business —

Intellectual Property —License Agreement 1 with The Board of Regents of The University of Texas System / The University of Texas Southwestern Medical Center .”

The UTSW1 Agreement includes an exclusive license to US patent no.

For additional details regarding our relationship with UTSW, see the section entitled “ Business — Intellectual Property —License Agreement 1 with The Board of Regents of The University of Texas System / The University of Texas Southwestern Medical Center .” The UTSW1 Agreement includes an exclusive license to US patent no.

10,463,685 (expires April 8, 2034), and pending US patent application nos.

4 unchanged sentences

Title / PCT Application Number

Sequential Treatment of Cancers Using 6-Thio-dG and Checkpoint Inhibitors / PCT/US2021/022090

Sequential Treatment of Cancers Using 6-Thio-dG and Checkpoint Inhibitors / PCT/US2021/022090, pending in the US and PCT (method of use), AU, BR, CA, CN, EPO, IL,JP, KR, MX, RU, SG, US

Under the UTSW2 Agreement, we agreed to pay UTSW a minimal license fee, deferred license fees, milestone fees, and running royalties beginning on the first net sale (among others).

For additional details regarding our relationship with UTSW, see the section entitled “

Business —

Intellectual Property —License Agreement 2 with The Board of Regents of The University of Texas System / The University of Texas Southwestern Medical Center .”

The UTSW2 Agreement includes an exclusive license to pending US patent application no.

For additional details regarding our relationship with UTSW, see the section entitled “ Business — Intellectual Property —License Agreement 2 with The Board of Regents of The University of Texas System / The University of Texas Southwestern Medical Center .” The UTSW2 Agreement includes an exclusive license to pending US patent application no.

17/200,539 (having an earliest expiration of March 12, 2041, if a patent is granted).

License Agreement 1 with The Board of Regents of The University of Texas System /The University of Texas Southwestern Medical Center

On December 8, 2020 (the “Effective Date”), we entered into an amended and restated agreement (of our prior November 29, 2018 agreement) with The Board of Regents of The University of Texas System on behalf of The University of Texas Southwestern Medical Center, (collectively, UTSW) to develop and commercialize certain UTSW owned and/or controlled patents and related technology directed to methods of using THIO (“the UTSW1 Agreement”).

The license is exclusive as to worldwide Patent Rights for all uses in the Field, which is defined as all therapeutic, prophylactic and diagnostic fields of use for all indications, including

1 unchanged sentence

The license is sublicensable with prior UTSW written approval consistent with the terms of UTSW1 Agreement.

The UTSW1 Agreement includes an exclusive license to the “Patent Rights”

of the worldwide patent families including all provisional applications and any divisionals, continuations, continuations-in-part and foreign counterpart applications that are entitled to claim priority thereto, and any patents resulting therefrom, of the following:

The UTSW1 Agreement includes an exclusive license to the “Patent Rights” of the worldwide patent families including all provisional applications and any divisionals, continuations, continuations-in-part and foreign counterpart applications that are entitled to claim priority thereto, and any patents resulting therefrom, of the following:

Title / PCT Application Number

Telomerase Mediated Telomere Altering Compounds / PCT/US2014/33330 (WO2014/168947)

6-Thio-2'-Deoxyguanosine (6-Thio-dG) Results in Telomerase Dependent Telomere Dysfunction and Cell Death in Various Models of Therapy-Resistant Cancer Cells /PCT/US2017/34706 (WO2017/205756)

Use of 6-thio-dG to Treat Therapy-Resistant Telomerase positive Pediatric Brain Tumors /PCT/US2019/023596 (WO2019/183482)

Treatment of Drug Resistant Proliferative Diseases with Telomerase Mediated Telomere Altering Compounds / PCT/US2017/023858 (WO/2017/165675)

The UTSW1 Agreement also grants the Company a non-exclusive worldwide license under the Technology Rights to develop, manufacture, have manufactured, distribute, have distributed, use, offer for Sale, Sell, lease, loan and/or import Licensed Products in the Field, wherein Technology Rights means Licensor’s rights in technical information, know-how, processes, procedures, compositions, devices, methods, formulas, protocols, techniques, designs, drawings or data created before the Effective Date by Inventors at UTSW which are necessary or reasonably useful for practicing Patent Rights.

Telomerase Mediated Telomere Altering Compounds / PCT/US2014/33330 (WO2014/168947), issued in the US (patent no.

10,463,685), CA, MX, NZ and RU (all method of use) pending in BR, CN, EPO, HK and SG.

6-Thio-2'-Deoxyguanosine (6-Thio-dG) Results in Telomerase Dependent Telomere Dysfunction and Cell Death in Various Models of Therapy-Resistant Cancer Cells /

PCT/US2017/34706 (WO2017/205756), pending in the US (method of use), AU, CA, and EPO.

Use of 6-thio-dG to Treat Therapy-Resistant Telomerase positive Pediatric Brain Tumors /PCT/US2019/023596 (WO2019/183482), pending in the US (method of use)

Treatment of Drug Resistant Proliferative Diseases with Telomerase Mediated Telomere Altering Compounds / PCT/US2017/023858 (WO/2017/165675), pending in the US (method of use)

The UTSW1 Agreement also grants the Company the first right to negotiate an exclusive license under any patent rights covering or claiming any improvement, which is any patentable invention and is conceived or reduced to practice solely by Dr.

3 unchanged sentences

or (iii) if Technology Rights are licensed and no Patent Rights are applicable, twenty (20) years after the Effective Date.

The Company may terminate the UTSW1 Agreement for convenience, at any time prior by providing ninety (90) days’

written notice to UTSW.

The Company may terminate the UTSW1 Agreement for convenience, at any time prior by providing ninety (90) days’ written notice to UTSW.

UTSW may terminate the UTSW1 Agreement if the Company (i) becomes in arrears in any payments due, and fails to make the required payment within 30 days after delivery of written notice from UTSW, (ii) is in breach of any material non-payment provision, and does not cure such breach within 60 days after delivery of written notice, (iii) UTSW delivers notice to the Company of three or more actual breaches in any 12-month period, even in the event that the Company cures such breaches in the allowed period, (iv) becomes insolvent or bankrupt, then termination is immediate.

4 unchanged sentences

In the event that the Company assigns the agreement to a third party, the Company is obligated to pay UTSW an assignment fee in the mid-six figures within 15 days of such assignment.

The agreement cannot be assigned without UTSW’s consent.

Under the UTSW1 Agreement, the Company is obligated to use diligent efforts to bring licensed products to market through a funded, ongoing and active research and development, manufacturing, regulatory, marketing or sales program (all as commercially reasonable) and provide semi-annual reports to UTSW on its progress.

5 unchanged sentences

(ii) first commercial sale in the U.S.

of licensed product for treating a non-oncology indications;

of licensed product for treating a non-oncology

(iii) first time aggregate Net Sales (as defined in the UTSW1 Agreement) of licensed product for treating an oncology indications exceeds low-nine figure sales in a contract year;

(iv) first time aggregate Net Sales of licensed product for treating a non-oncology indications exceeds low nine-figure sales in a contract year;

(v) first time aggregate Net Sales of licensed product for treating

an oncology indications exceeds low ten-figure sales in a contract year;

(v) first time aggregate Net Sales of licensed product for treating an oncology indications exceeds low ten-figure sales in a contract year;

(vi) first time aggregate Net Sales of licensed product for treating a non-oncology indications exceeds low ten-figure sales in a contract year.

6 unchanged sentences

The royalty obligations continue on a country-by-country basis until the later of expiration of the last Valid Claim in each country or ten (10) years after the First Commercial Sale (as defined in UTSW1 Agreement) in each country.

In the event that the Company or its sublicensee challenges the Patent Rights, then the Company will be obligated to pay multiples of the applicable royalty rate of the Net Sales and, should the outcome of such challenge determine that any claim of the Patent Rights challenged is both valid and infringed then the Company will pay royalties at the rate of multiples of the applicable royalty rate of the Net Sales sold thereafter and reimburse UTSW for all fees and costs associated with defending such challenge, including attorney’s fees and expert fees.

The UTSW1 Agreement also contains an anti-stacking provision pursuant to which in the event the Company or its sublicensee pays royalties or other payments to a third party who owns or controls intellectual property deemed necessary to develop, manufacture, have manufactured, distribute, have distributed, use, lease, loan, import, offer for sale and/or sell any licensed products and licensed services, the Company may reduce payments to UTSW by a certain percentage of the royalty, milestone or other payments paid to such third party.

3 unchanged sentences

UTSW maintains direct control over the prosecution and maintenance activities of the Patent Rights, and the Company is obligated to reimburse past and ongoing patent expenses as noted above.

UTSW will permit the Company to comment on submissions to government patent agencies, during prosecution and will consider the Company’s comments, but UTSW retained control over all final decisions.

The UTSW1 Agreement contains a representation that UTSW has the rights and authority to grant to Company the licensed rights and is to its knowledge unaware of any third-party infringer or any infringement of third-party intellectual property rights.

2 unchanged sentences

If the Company does not file suit within six months after a written request by UTSW, then UTSW may bring suit to enforce any Patent Right and retain all recoveries from such enforcement.

If UTSW pursues such infringement action, it may, as part of the resolution of such efforts, grant nonexclusive license rights to the alleged infringer notwithstanding Licensee’s exclusive license rights.

In accordance with the terms of the UTSW1 Agreement, on April 24, 2020 Company sublicensed all Company rights and obligations under the UTSW1 Agreement to Company affiliate THIO Therapeutics, Inc.

License Agreement 2 with The Board of Regents of The University of Texas System /The University of Texas Southwestern Medical Center

On December 23, 2020 (the “Effective Date”), we entered into a second agreement with The Board of Regents of The University of Texas System on behalf of The University of Texas Southwestern Medical Center, (collectively, UTSW), which set forth the agreement between the parties pursuant to the Company exercising its option rights in the UTSW1 Agreement and obtaining additional license rights (“the UTSW2 Agreement”).

The license is exclusive as to worldwide Patent Rights for all uses in the Field,

which is defined as all therapeutic, prophylactic and diagnostic fields of use for all indications, including discovery and development uses.

The license is exclusive as to worldwide Patent Rights for all uses in the Field, which is defined as all therapeutic, prophylactic and diagnostic fields of use for all indications, including discovery and development uses.

The license is sublicensable with prior UTSW written approval consistent with the terms of UTSW2 Agreement.

The UTSW2 Agreement includes an exclusive license to the “Patent Rights”

of the worldwide patent family including all provisional applications and any divisionals, continuations, continuations-in-part and foreign counterpart applications that are entitled to claim priority thereto, and any patents resulting therefrom, of the following

The UTSW2 Agreement includes an exclusive license to the “Patent Rights” of the worldwide patent family including all provisional applications and any divisionals, continuations, continuations-in-part and foreign counterpart applications that are entitled to claim priority thereto, and any patents resulting therefrom, of the following

Title / PCT Application Number

Sequential Treatment of Cancers Using 6-Thio-dG and Checkpoint Inhibitors / PCT/US2021/022090

The UTSW2 Agreement also grants the Company a non-exclusive worldwide license under the Technology Rights to develop, manufacture, have manufactured, distribute, have distributed, use, offer for Sale, Sell, lease, loan and/or import Licensed Products in the Field, wherein Technology Rights means UTSW’s rights in technical information, know-how, processes, procedures, compositions, devices, methods, formulas, protocols, techniques, designs, drawings or data created before the Effective Date by inventors at UTSW which are necessary or reasonably useful for practicing Patent Rights.

Sequential Treatment of Cancers Using 6-Thio-dG and Checkpoint Inhibitors / PCT/US2021/022090, pending in the US and PCT (method of use), AU, BR, CA, CN, EPO, IL,JP, KR, MX, RU, SG, US

The terms of the UTSW2 Agreement are similar in many respects to those set forth in the UTSW1 Agreement.

Pursuant to the UTSW2 Agreement, the Company paid to UTSW a nominal one-time upfront license fee.

The UTSW2 Agreement recognizes the accrual of low five-figures in patent expenses relative to the Patent Rights of this agreement and provides for deferral of this fee and related ongoing patent expense fees on a schedule connected to the Company’s fundraising through Series A funding.

Once the Company has raised mid seven-figures, the patent expense fees are be paid in full for all patent expenses incurred by UTSW for the Company’s licensed technologies which accrued between December 12, 2019, and the date at which the mid seven-figures has been raised.

Until the Company has reimbursed all patent expenses it is obligated to report its fundraising progress to UTSW on a quarterly basis.

3 unchanged sentences

In the event the Company assigns the UTSW2 Agreement to a third party, the Company is obligated to pay UTSW low six-figures within 15 days of such assignment, which is cumulative of the UTSW1 Agreement assignment fee, such that if both agreements are assigned to a third party, a total of high six-figures would be owed to UTSW.

The agreement cannot be assigned without UTSW’s consent.

The Company will also pay UTSW running royalties on a yearly basis as a percentage of Net Sales of the Company or its sublicensee.

3 unchanged sentences

In the event that the Company or its sublicensee challenges the Patent Rights, then the Company will be obligated to pay multiple times the applicable royalty rate of the Net Sales and, should the outcome of such challenge determine that any claim of the Patent Rights challenged is both valid and infringed then the Company will pay royalties at the rate of multiple times the applicable royalty rate of the Net Sales sold thereafter and reimburse UTSW for all fees and costs associated with defending such challenge, including attorney’s fees and expert fees.

The UTSW2 Agreement also contains an anti-stacking provision pursuant to which in the event the Company or its sublicensee pays royalties or other payments to a third party who owns or controls intellectual property deemed necessary to develop, manufacture, have manufactured, distribute, have distributed, use, lease, loan, import, offer for sale and/or sell any licensed products and licensed services, the Company may reduce payments to UTSW by a certain percentage of the royalty, milestone or other payments paid to such third party.

have manufactured, distribute, have distributed, use, lease, loan, import, offer for sale and/or sell any licensed products and licensed services, the Company may reduce payments to UTSW by a certain percentage of the royalty, milestone or other payments paid to such third party.

However, such adjustment in royalty payments to UTSW may not be reduced by more than a minimum percentage of the royalty obligation in any contract year.

8 unchanged sentences

government or imposing certain obligations on us, such as a license to the U.S.

government under such intellectual property, “march-in”

rights, certain reporting requirements and a preference for U.S.-based companies, and compliance with such regulations may limit our exclusive rights and our ability to contract with non-U.S.

government under such intellectual property, “march-in” rights, certain reporting requirements and a preference for U.S.-based companies, and compliance with such regulations may limit our exclusive rights and our ability to contract with non-U.S.

manufacturers.

See Risks Relating to Our Intellectual Property - Intellectual property discovered through government funded programs may be subject to federal regulations such as “march-in”

rights, certain reporting requirements and a preference for U.S.-based companies.

See Risks Relating to Our Intellectual Property - Intellectual property discovered through government funded programs may be subject to federal regulations such as “march-in” rights, certain reporting requirements and a preference for U.S.-based companies.

Compliance with such regulations may limit our exclusive rights and limit our ability to contract with non-U.S.

11 unchanged sentences

Smaller or early-stage companies may also prove to be significant competitors, particularly through collaborative arrangements with large and established companies.

These early stage and more established competitors also compete with us in recruiting and retaining qualified scientific and management personnel and establishing clinical trial sites and patient registration for clinical trials, as well as in acquiring technologies complementary to, or necessary for, our programs.

These early stage and more established competitors also compete with us in

recruiting and retaining qualified scientific and management personnel and establishing clinical trial sites and patient registration for clinical trials, as well as in acquiring technologies complementary to, or necessary for, our programs.

Government Regulation

Government authorities in the United States, at the federal, state and local level, and in other countries, extensively regulate, among other things, the research, development, testing, manufacture, quality control, approval, labeling, packaging, storage, record-keeping, promotion, advertising, distribution, post-approval monitoring and reporting, marketing and export and import of products such as

those we are developing.

Any pharmaceutical candidate that we develop must be approved by the United States Food and Drug Administration, or FDA, before it may be legally marketed in the United States and by the appropriate foreign regulatory agency before it may be legally marketed in foreign countries.

5 unchanged sentences

• Submission to the FDA of an Investigational New Drug Application, or an IND, which must become effective before human clinical trials may begin;

Performance of several phases of adequate and well-controlled human clinical trials according to the FDA’s current good clinical practices, or GCPs, to establish the safety and efficacy of the proposed drug or biologic for its intended use;

• Performance of several phases of adequate and well-controlled human clinical trials according to the FDA’s current good clinical practices, or GCPs, to establish the safety and efficacy of the proposed drug or biologic for its intended use;

• Submission to the FDA of a New Drug Application, or an NDA, for a new drug product, or a Biologics License Application, or a BLA, for a new biological product;

Satisfactory completion of an FDA inspection of the manufacturing facility or facilities where the drug or biologic is to be produced to assess compliance with the FDA’s current good manufacturing practice standards, or cGMP, to assure that the facilities, methods and controls are adequate to preserve the drug’s or biologic’s identity, strength, quality and purity;

• Satisfactory completion of an FDA inspection of the manufacturing facility or facilities where the drug or biologic is to be produced to assess compliance with the FDA’s current good manufacturing practice standards, or cGMP, to assure that the facilities, methods and controls are adequate to preserve the drug’s or biologic’s identity, strength, quality and purity;

• Potential FDA audit of the nonclinical and clinical trial sites that generated the data in support of the NDA or BLA;

19 unchanged sentences

In this case, the IND sponsor and the FDA must resolve any outstanding concerns before clinical trials can begin.

A clinical hold may occur at any time during the life of an IND and may affect one or more specific studies or all studies conducted under the IND.

Clinical trials involve the administration of the drug or biological candidate to healthy volunteers or patients having the disease being studied under the supervision of qualified investigators, generally physicians not employed by or under the trial sponsor’s control.

clinical hold may occur at any time during the life of an IND and may affect one or more specific studies or all studies conducted under the IND.

Clinical trials are conducted under protocols detailing, among other things, the objectives of the clinical trial, dosing procedures, subject selection and exclusion criteria, and the parameters to be used to monitor subject safety.

Each protocol must be submitted to the FDA as part of the IND.

Clinical trials must be conducted in accordance with the FDA’s good clinical practices requirements.

Further, each clinical trial must be reviewed and approved by an independent institutional review board, or IRB, at or servicing each institution at which the clinical trial will be conducted.

13 unchanged sentences

The FDA or the sponsor or its data safety monitoring board may suspend a clinical trial at any time on various grounds, including a finding that the research subjects or patients are being exposed to an unacceptable health risk.

Similarly, an IRB can suspend or terminate approval of a clinical trial at its institution if the clinical trial is not being conducted in accordance with the IRB’s requirements or if the drug or biologic has been associated with unexpected serious harm to patients.

Concurrent with clinical trials, companies usually complete additional animal studies and develop additional information about the chemistry and physical characteristics of the drug or biologic as well as finalize a process for manufacturing the product in commercial quantities in accordance with cGMP requirements.

7 unchanged sentences

Once the submission is accepted for filing, the FDA begins an in-depth review of the NDA or BLA.

After the NDA or BLA submission is accepted for filing, the FDA reviews the application to determine, among other things, whether the proposed product is safe and effective for its intended use, and whether the product is being manufactured in accordance with cGMP to assure and preserve the product’s identity, strength, quality and purity.

The FDA reviews a BLA to determine, among other things, whether the product is safe, pure and potent and the facility in which it is manufactured, processed, packaged or held meets standards designed to assure the product’s continued safety, purity and potency.

In addition to its own review, the FDA may refer applications for novel drug or biological products or drug or biological products which present difficult questions of safety or efficacy to an advisory committee, typically a panel that includes clinicians and other experts, for review, evaluation and a recommendation as to whether the application should be approved and under what conditions.

The FDA is not bound by the recommendations of an

advisory committee, but it considers such recommendations carefully when making decisions.

The FDA is not bound by the recommendations of an advisory committee, but it considers such recommendations carefully when making decisions.

During the approval process, the FDA also will determine whether special marketing conditions or restrictions under a risk evaluation and mitigation strategy, or REMS, are necessary to assure the safe use of the drug or biologic.

4 unchanged sentences

Additionally, before approving an NDA or BLA, the FDA will typically inspect one or more clinical trial sites to assure their compliance with cGCP during the conduct of studies of the subject drug.

If during the review of the application the FDA identifies questions or concerns regarding the application, data, manufacturing process or manufacturing facilities, it may issue a deficiency letter which the sponsor must adequately address to the FDA’s satisfaction.

The NDA or BLA review and approval process is lengthy and difficult, and the FDA may refuse to approve an NDA or BLA if the applicable regulatory criteria are not satisfied or may require additional clinical data or other data and information.

1 unchanged sentence

Data obtained from clinical trials are not always conclusive and may be susceptible to varying interpretations, which could delay, limit or prevent regulatory approval.

The FDA will issue a “complete response letter”

(CRL) if the agency decides not to approve the NDA or BLA.

The FDA will issue a “complete response letter” (CRL) if the agency decides not to approve the NDA or BLA.

The complete response letter usually describes the specific deficiencies in the NDA or BLA identified by the FDA.

4 unchanged sentences

Further, the FDA may require that certain contraindications, warnings or precautions be included in the product labeling.

In addition, the FDA may require Phase 4 testing which may involve clinical trials designed to further assess a product’s safety and effectiveness and may require testing and surveillance programs to monitor the safety of approved products that have been commercialized.

Companion Diagnostics

The FDA issued a final guidance document in July 2014 addressing agency policy in relation to in vitro companion diagnostic tests.

Many drugs for cancer indications involving patient-specific genetic mutations or biomarkers are approved by FDA with limitations that the specific genetic mutation must be confirmed in each patient by use of an FDA-approved diagnostic test, commonly referred to as a “companion diagnostic.” The FDA issued a final guidance document in July 2014 addressing agency policy in relation to in vitro companion diagnostic tests.

The guidance explains that for some drugs and therapeutic biologics, the use of a companion diagnostic test is essential for the safe and effective use of the product, such as when the use of a product is limited to a specific patient subpopulation that can be identified by using the test.

According to the guidance, the FDA generally will not approve such a product if the companion diagnostic is not also approved or cleared for the appropriate indication, and accordingly the therapeutic product and the companion diagnostic should be developed and approved or cleared contemporaneously.

and a Guidance, Developing and Labeling In vitro Companion Diagnostic Devices for a Specific Group of Oncology Therapeutic Products (2020), which “describes considerations for the development and labeling of in vitro companion diagnostic devices (referred to as “companion diagnostics”

herein) to support the indicated uses of multiple drug or biological oncology products, when appropriate.”

As stated in its Guidance, the FDA may decide that it is appropriate to approve such a product without an approved or cleared in vitro companion diagnostic device when the drug or therapeutic biologic is intended to treat a serious or life-threatening condition for which no satisfactory alternative treatment exists and the FDA determines that the benefits from the use of a product with an unapproved or uncleared in vitro companion diagnostic device are so pronounced as to outweigh the risks from the lack of an approved or cleared in vitro companion diagnostic device.

The FDA has also issued a Guidance, Principles for Codevelopment of an In Vitro Companion Diagnostic Device with a Therapeutic Product (2016), which is “is intended to be a practical guide to assist therapeutic product sponsors and IVD sponsors in developing a therapeutic product and an accompanying IVD companion diagnostic,” and a Guidance, Developing and Labeling In vitro Companion Diagnostic Devices for a Specific Group of Oncology Therapeutic Products (2020), which “describes considerations for the development and labeling of in vitro companion diagnostic devices (referred to as “companion diagnostics” herein) to support the indicated uses of multiple drug or biological oncology products, when appropriate.”

unapproved or uncleared in vitro companion diagnostic device are so pronounced as to outweigh the risks from the lack of an approved or cleared in vitro companion diagnostic device.

The FDA encourages sponsors considering developing a therapeutic product that requires a companion diagnostic to request a meeting with both relevant device and therapeutic product review divisions to ensure that the product development plan will produce sufficient data to establish the safety and effectiveness of both the therapeutic product and the companion diagnostic.

To date, no product targeting TERT+ cancer patients has been approved by FDA, and the applicability to THIO of FDA’s Companion Diagnostics Guidance and policy is yet to be determined.

If a companion diagnostic is required to be developed and approved in order to receive approval of THIO, the cost and length of time to fully develop and receive approval (if at all) of THIO may both be increased, as described in more detail in the section Risk Factors –

Risks Relating

to Government Regulation.

Because the FDA’s policy on companion diagnostics is set forth only in guidance, this policy is subject to change and is not legally binding.

To date, no product targeting TERT+ cancer patients has been approved by FDA, and the applicability to THIO of FDA’s Companion Diagnostics Guidance and policy is yet to be determined.

Because the FDA’s policy on companion diagnostics is set forth only in guidance, this policy is subject to change and is not legally binding.

Expedited Development and Review Programs

14 unchanged sentences

Orange Book Listing

Once a drug product is approved under an NDA, the product is listed in the FDA’s publication, “Approved Drug Products with Therapeutic Equivalence Evaluations,”

commonly known as the Orange Book.

Once a drug product is approved under an NDA, the product is listed in the FDA’s publication, “Approved Drug Products with Therapeutic Equivalence Evaluations,” commonly known as the Orange Book.

An NDA-approved drug product will be designated in the Orange Book as a Reference Listed Drug (RLD).

Sponsors of approved NDA’s are required to list with the FDA patents whose claims cover the product’s active ingredient, formulation, or an approved method of using the drug.

Patent Term Extensions

1 unchanged sentence

The Hatch-Waxman Act permits 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 or therapeutic candidate’s approval date.

The patent term restoration period is generally one half of the time between the effective date of an IND and the submission date of a NDA, plus the time between the submission date of a NDA and the approval of that application, except that the review period is reduced by any time during which the applicant failed to exercise due diligence.

Only one patent applicable to an approved product or therapeutic candidate is eligible for the extension and the application for extension must be made prior to expiration of the patent.

The USPTO, in consultation with the FDA, reviews and approves the application for any patent term extension or restoration.

Only one patent applicable to an approved product or therapeutic candidate is eligible for the extension and the application for extension

must be made prior to expiration of the patent.

The United States Patent and Trademark Office (USPTO), in consultation with the FDA, reviews and approves the application for any patent term extension or restoration.

In the future, we intend to apply for restorations of patent term for some of our currently owned or licensed patents to add patent life beyond their current expiration date, depending on the expected length of clinical trials and other factors involved in the submission of the relevant NDA.

6 unchanged sentences

Instead, a generic applicant must demonstrate that its product is bioequivalent to the innovator drug.

Drugs approved in this way are commonly referred to as “generic equivalents”

to the listed drug and can often be substituted by pharmacists under prescriptions written for the original listed drug.

Drugs approved in this way are commonly referred to as “generic equivalents” to the listed drug and can often be substituted by pharmacists under prescriptions written for the original listed drug.

Section 505(b)(2) NDA Approval Process

As an alternative path to FDA approval for modifications to formulations or uses of products previously approved by the FDA, an applicant may submit an NDA under Section 505(b)(2) of the FDCA.

Section 505(b)(2) was enacted as part of the Hatch-Waxman Amendments to the FDCA and enables the applicant to rely, in part, on the FDA’s previous approval of a similar product, and/or published literature, in support of its application.

Section 505(b)(2) permits the filing of an NDA where at least some of the information required for approval comes from studies not conducted by, or for, the applicant and for which the applicant has not obtained a right of reference.

If the Section 505(b)(2) applicant can establish that reliance on FDA’s previous findings of safety and effectiveness is scientifically appropriate, it may eliminate the need to conduct certain preclinical studies or clinical trials of the new product.

The FDA may also require companies to perform additional studies or measurements, including clinical trials, to support the change from the approved reference drug.

9 unchanged sentences

This last certification is known as a paragraph IV certification.

If an ANDA is submitted to FDA with a Paragraph IV Certification, the generic applicant must also provide a “Paragraph IV Notification”

to the holder of the NDA for the RLD and to the owner of the listed patent(s) being challenged by the ANDA applicant, providing a detailed written statement of the bases for the ANDA applicant’s position that the relevant patent(s) is invalid or would not be infringed.

If an ANDA is submitted to FDA with a Paragraph IV Certification, the generic applicant must also provide a “Paragraph IV Notification” to the holder of the NDA for the RLD and to the owner of the listed patent(s) being challenged by the ANDA applicant, providing a detailed written statement of the bases for the ANDA applicant’s position that the relevant patent(s) is invalid or would not be infringed.

If the patent owner brings a patent infringement lawsuit against the ANDA applicant within 45 days of the Paragraph IV Notification, FDA approval of the ANDA will be automatically stayed for 30 months, or until 7-1/2 years after the NDA approval if the generic application was filed between 4 years and 5 years after the NDA approval.

Any such stay will be terminated earlier if the court rules that the patent is invalid or would not be infringed.

The applicant may, in certain circumstances, elect to submit a “section viii”

statement with respect to a listed method of use patent, certifying that the proposed generic labeling does not contain (or carves out) any language that would infringe a method of use patented listed in the Orange Book for the RLD.

The applicant may, in certain circumstances, elect to submit a “section viii” statement with respect to a listed method of use patent, certifying that the proposed generic labeling does not contain (or carves out) any language that would infringe a method of use patented listed in the Orange Book for the RLD.

The ANDA or Section 505(b)(2) application also will not be approved until any applicable non-patent exclusivity listed in the Orange Book for the reference drug has expired as described in further detail below.

1 unchanged sentence

New Chemical Entity (NCE) Exclusivity

The Hatch-Waxman amendments provides a period of five years of non-patent marketing exclusivity for the first approved drug containing a new chemical entity (“NCE”) as an active ingredient.

An NCE is an active moiety that has not been approved by the FDA in any other NDA.

A fixed combination drug product may receive NCE exclusivity if one of its active ingredients is an NCE, but not if all of its active ingredients have previously been approved.

An “active moiety”

is defined as the molecule or ion responsible for the drug substance’s physiological or pharmacologic action.

an application for filing after four years if the application includes a paragraph IV certification to a listed patent.

An “active moiety” is defined as the molecule or ion responsible for the drug substance’s physiological or pharmacologic action.

During the five-year exclusivity period, the FDA cannot accept for filing any ANDA or 505(b)(2) NDA seeking approval of a product that contains the same active moiety, except that the FDA may accept such an application for filing after four years if the application includes a paragraph IV certification to a listed patent.

In the case of such applications accepted for filing between four and five years after approval of the reference drug, the 30-Month Stay of approval triggered by a timely patent infringement lawsuit is extended by the amount of time necessary to extend the stay until 7-1/2 years after the approval of the reference drug NDA.

9 unchanged sentences

If a product or therapeutic candidate that has Orphan Drug Designation subsequently receives the first FDA approval for the disease for which it has such designation, the approved product is entitled to orphan product exclusivity, which means that the FDA may not approve any other marketing applications for the same drug for the same indication, except under limited circumstances, for seven years.

Orphan product exclusivity, however, could also block the approval of one of our therapeutic candidates for seven years if a competitor obtains approval of the same drug as defined by the FDA, or if our therapeutic candidate is determined to be contained within a competitor’s approved drug for the same indication or disease.

In addition, an orphan drug credit is available for qualifying costs incurred between the date the FDA designates a drug as an orphan drug and the date the FDA approves the drug.

3 unchanged sentences

The data do not need to support a label change for pediatric use;

rather, the additional protection is granted if the pediatric clinical trial is deemed to have fairly responded to the FDA’s Written Request.

Although the FDA may issue a Written Request for studies on either approved or unapproved indications, it may only do so where it determines that information relating to that use of a product or therapeutic candidate in a pediatric population, or part of the pediatric population, may produce health benefits in that population.

2 unchanged sentences

Post-Approval Requirements

Following approval of a new drug or biologic product, the manufacturer and the approved product are subject to pervasive and continuing regulation by the FDA, including, among other things, continuing cGMP compliance, monitoring and recordkeeping activities, reporting of adverse experiences with the product, product sampling and distribution restrictions, complying with promotion and advertising requirements, which include restrictions on promoting drugs for unapproved uses or patient populations (i.e., “off-label use”) and limitations on industry-sponsored scientific and educational activities.

Although physicians may prescribe legally available products for off-label uses, manufacturers may not market or promote such uses.

The FDA and other agencies actively enforce the laws and regulations prohibiting the promotion of off-label uses, and a company that is found to have improperly promoted off-label uses may be subject to significant liability.

new NDA or a NDA supplement, which may require the applicant to develop additional data or conduct additional preclinical studies and clinical trials.

If there are any modifications to the product, including changes in indications, labeling or manufacturing processes or facilities, the applicant may be required to submit and obtain FDA approval of a new NDA or a NDA supplement, which may require the applicant to develop additional data or conduct additional preclinical studies and clinical trials.

Once an NDA or BLA approval is granted, the FDA may withdraw the approval if compliance with regulatory requirements and standards is not maintained or if problems occur after the product or therapeutic reaches the market.

17 unchanged sentences

• notifying the FDA and gaining its approval of specified manufacturing or labeling changes;

and complying with FDA promotion and advertising requirements, which include, among other things, standards for direct-to-consumer advertising, restrictions on promoting products for uses or in-patient populations that are not described in the product’s approved labeling, limitations on industry-sponsored scientific and educational activities and requirements for promotional activities involving the internet.

FDA regulations require that products be manufactured in specific approved facilities and in accordance with cGMPs.

8 unchanged sentences

The Drug Supply Chain Security Act, or the DSCSA, was enacted with the aim of building an electronic system to identify and trace certain prescription drugs distributed in the United States, including most biological products.

The DSCSA mandates phased-in and resource-intensive obligations for pharmaceutical manufacturers, wholesale distributors, and dispensers over a 10‐year period that is expected to culminate in November 2023.

From time to time, new legislation and regulations may be implemented that could significantly change the statutory provisions governing the approval, manufacturing and marketing of products regulated by the FDA.

It is impossible to predict whether further

legislative or regulatory changes will be enacted, or FDA regulations, guidance or interpretations changed or what the impact of such changes, if any, may be.

It is impossible to predict whether further legislative or regulatory changes will be enacted, or FDA regulations, guidance or interpretations changed or what the impact of such changes, if any, may be.

Regulation Outside of the United States

1 unchanged sentence

Whether or not we obtain FDA approval for a product, we must obtain approval by the comparable regulatory authorities of countries outside of the United States before we can commence clinical trials in such countries and approval of the regulators of such countries or economic areas, such as the European Union, before we may market products in those countries or areas.

It also is not yet clear how the United Kingdom’s recent withdrawal from the European Union will affect the approval of medicinal products in the United Kingdom.

The approval process and requirements governing the conduct of clinical trials, product licensing, pricing and reimbursement vary greatly from place to place, and the time may be longer or shorter than that required for FDA approval.

3 unchanged sentences

The decentralized procedure provides for recognition by European Union national authorities of a first assessment performed by one of the member states.

and the remaining being the “Concerned Member States.”

The Reference Member State must prepare and send drafts of an assessment report, summary of product characteristics and the labeling and package leaflet within 120 days after receipt of a valid marketing authorization application to the Concerned Member States, which must decide within 90 days whether to recognize approval.

Under this procedure, an identical application for marketing authorization is submitted simultaneously to the national authorities of several European Union member states, one of them being chosen as the “Reference Member State,” and the remaining being the “Concerned Member States.” The Reference Member State must prepare and send drafts of an assessment report, summary of product characteristics and the labeling and package leaflet within 120 days after receipt of a valid marketing authorization application to the Concerned Member States, which must decide within 90 days whether to recognize approval.

If any Concerned Member State does not recognize the marketing authorization on the grounds of potential serious risk to public health, the disputed points are eventually referred to the European Commission, whose decision is binding on all member states.

9 unchanged sentences

Payment rates may vary according to the use of the product and the clinical setting in which it is used, may be based on payments allowed for lower cost products that are already reimbursed and may be incorporated into existing payments for other services.

Net prices for products may be reduced by mandatory discounts or rebates required by third-party payors and by any future relaxation of laws that presently restrict imports of products from countries where they may be sold at lower prices than in the United States.

Net prices for products may

be reduced by mandatory discounts or rebates required by third-party payors and by any future relaxation of laws that presently restrict imports of products from countries where they may be sold at lower prices than in the United States.

In the U.S., third-party payors often rely upon Medicare coverage policy and payment limitations in setting their own reimbursement policies, but they also have their own methods and approval process apart from Medicare coverage and reimbursement determinations.

Accordingly, one third-party payor’s determination to provide coverage for a product does not assure that other payors will also provide coverage for the product.

Additionally, the containment of healthcare costs has become a priority of federal and state governments and the prices of therapeutics have been a focus in this effort.

12 unchanged sentences

In the United States and some foreign jurisdictions, there have been, and continue to be, several legislative and regulatory changes and proposed changes regarding the healthcare system that could prevent or delay marketing approval of product and therapeutic candidates, restrict or regulate post-approval activities, and affect the ability to profitably sell product and therapeutic candidates that obtain marketing approval.

The FDA’s and other regulatory authorities’

policies may change, and additional government regulations may be enacted that could prevent, limit, or delay regulatory approval of our product and therapeutic candidates.

For example, in the United States, the system for FDA to collect and expend user fees paid by manufacturers of drugs, biologics, and medical devices must be reauthorized by statute every five years, and since 1992, each reauthorization legislation has included, to greater or lesser degrees, various other changes to the FDA’s regulatory systems and procedures.

The current legislative authority for FDA user fees expires in September 2022, and by that time, new legislation will be required for FDA to continue collecting prescription drug user fees in future fiscal years.

The expected 2022 reauthorization may include new legal provisions that could significantly impact our business in ways that cannot be predicted at this time.

The FDA’s and other regulatory authorities’ policies may change, and additional government regulations may be enacted that could prevent, limit, or delay regulatory approval of our product and therapeutic candidates.

The current legislative authority for FDA user fees expired in September 2022, new legislation will be required for FDA to continue collecting prescription drug user fees in future fiscal years.

The reauthorization may include new legal provisions that could significantly impact our business in ways that cannot be predicted at this time.

If we are slow or unable to adapt to changes in existing requirements or the adoption of new requirements or policies, or if we are not able to maintain regulatory compliance, we may lose any marketing approval that we otherwise may have obtained and we may not achieve or sustain profitability, which would adversely affect our business, prospects, financial condition and results of operations.

7 unchanged sentences

These changes include aggregate reductions to Medicare payments to providers of up to 2% per fiscal year pursuant to the Budget Control Act of 2011, which began in 2013 and will remain in effect through 2030 unless additional Congressional action is taken.

The Coronavirus Aid, Relief, and Economic Security Act, or the CARES Act, which was signed into law on March 27, 2020, and was designed to provide financial support and resources to individuals and businesses affected by the COVID-19 pandemic, suspended the 2% Medicare sequester from May 1, 2020 through December 31, 2020, and extended the sequester by one year, through 2030, in order to offset the added expense of the 2020 cancellation.

The Coronavirus Aid, Relief, and Economic Security Act, or the CARES Act, which was signed into law on March 27, 2020, and was designed to provide financial support and resources to individuals and businesses effected by the COVID-19 pandemic, suspended the 2% Medicare sequester from May 1, 2020 through December 31, 2020, and extended the sequester by one year, through 2030, in order to offset the added expense of the 2020 cancellation.

Additionally, on December 20, 2019, the Further Consolidated Appropriations Act for 2020 became law (P.L.

116-94), which includes a piece of bipartisan legislation called the Creating and Restoring Equal Access to Equivalent Samples Act of 2019 or the “CREATES Act.”

The CREATES Act aims to address the concern articulated by both the FDA and others in the industry that some brand manufacturers have improperly restricted the distribution of their products, including by invoking the existence of a REMS for certain products, to deny generic and biosimilar product developers access to samples of brand products.

116-94), which includes a piece of bipartisan legislation called the Creating and Restoring Equal Access to Equivalent Samples Act of 2019 or the “CREATES Act.” The CREATES Act aims to address the concern articulated by both the FDA and others in the industry that some brand manufacturers have improperly restricted the distribution of their products, including by invoking the existence of a REMS for certain products, to deny generic and biosimilar product developers access to samples of brand products.

Because generic and biosimilar product developers need samples to conduct certain comparative testing required by the FDA, some have attributed the inability to timely obtain samples as a cause of delay in the entry of generic and biosimilar products.

Whether and how generic and biosimilar product developments will use this new pathway, as well as the likely outcome of any legal challenges to provisions of the CREATES Act, remain highly uncertain and its potential effects on our future commercial products are unknown.

To remedy this concern, the CREATES Act establishes a private cause of action that permits a generic or biosimilar product developer to sue the brand manufacturer to compel it to furnish the necessary samples on “commercially reasonable, market-based terms.” Whether and how generic and biosimilar product developments will use this new pathway, as well as the likely outcome of any legal challenges to provisions of the CREATES Act, remain highly uncertain and its potential effects on our future commercial products are unknown.

Moreover, there has been heightened governmental scrutiny over the manner in which manufacturers set prices for their marketed products, which has resulted in several Congressional inquiries and proposed and enacted federal and state legislation designed to, among other things, bring more transparency to product pricing, review the relationship between pricing and manufacturer patient programs, and reform government program reimbursement methodologies for drug products.

14 unchanged sentences

• The federal civil and criminal false claims laws, including the civil False Claims Act, and civil monetary penalty laws, prohibit, among other things, knowingly presenting or causing the presentation of a false, fictitious or fraudulent claim for payment to the U.S.

government, knowingly making, using, or causing to be made or used a false record or statement material to a false or fraudulent claim to the U.S.

government, knowingly making, using, or causing to be made or used a false record or statement

material to a false or fraudulent claim to the U.S.

government, or from knowingly making a false statement to avoid, decrease or conceal an obligation to pay money to the U.S.

5 unchanged sentences

• HIPAA, as amended by the Health Information Technology for Economic and Clinical Health Act, or HITECH, and their respective implementing regulations impose specified requirements relating to the privacy, security and transmission of individually identifiable health information.

Among other things, HITECH makes HIPAA’s privacy and security standards directly applicable to “business associates,”

defined as independent contractors or agents of covered entities, which include certain healthcare providers, health plans, and healthcare clearinghouses, that create, receive, maintain or transmit protected 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;

Among other things, HITECH makes HIPAA’s privacy and security standards directly applicable to “business associates,” defined as independent contractors or agents of covered entities, which include certain healthcare providers, health plans, and healthcare clearinghouses, that create, receive, maintain or transmit protected health information in connection with providing a service for or on behalf of a covered entity.

• Analogous state laws and regulations, such as state anti-kickback and false claims laws which may apply to sales or marketing arrangements and claims involving healthcare items or services reimbursed by non-governmental third-party payors, including private insurers;

state laws which require pharmaceutical companies to comply with the pharmaceutical industry’s voluntary compliance guidelines and the relevant compliance guidance promulgated by the federal government in addition to requiring drug and therapeutic biologics manufacturers to report information related to payments to physicians and other healthcare providers or marketing expenditures and pricing information;

state and local laws which require the registration of pharmaceutical sales representatives;

7 unchanged sentences

We currently employ internal resources to manage our manufacturing relationships with these third parties.

Manufacturers of our products are required to comply with applicable FDA manufacturing requirements contained in the FDA’s current good manufacturing practices, or cGMP, regulations.

cGMP regulations require, among other things, quality control and quality assurance as well as corresponding maintenance of records and documentation.

Manufacturers of our products are required to comply with applicable FDA manufacturing requirements contained in the FDA’s current good manufacturing practices, or cGMP, regulations.

cGMP regulations require, among other things, quality control and

quality assurance as well as corresponding maintenance of records and documentation.

Pharmaceutical product manufacturers and other entities involved in the manufacture and distribution of approved pharmaceutical products 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 cGMP and other laws.

Accordingly, manufacturers must continue to expend time, money, and effort in the area of production and quality control to maintain cGMP compliance.

Discovery of problems with a product after

approval may result in restrictions on a product, manufacturer or holder of an approved NDA, including withdrawal of the product from the market.

Discovery of problems with a product after approval may result in restrictions on a product, manufacturer or holder of an approved NDA, including withdrawal of the product from the market.

In addition, changes to the manufacturing process generally require prior FDA approval before being implemented.

5 unchanged sentences

We believe that we maintain a satisfactory working relationship with our employees, and we have not experienced any significant labor disputes or any difficulty in recruiting staff for our operations.

None of our employees is represented by a labor union.

None of our employees are represented by a labor union.

Human Capital Resources

7 unchanged sentences

Our Corporate Information

We were incorporated in Delaware in August 2018, and we have operations in Chicago, Illinois, with some of our team members setup virtually and working remotely in California, Nevada and Florida, among others.

Our principal executive office is located at 444 West Lake Street, Suite 1700, Chicago, IL 60606, and our phone number is (312) 416-8592.

5 unchanged sentences

Implications of Being an Emerging Growth Company

We are an “emerging growth company,”

as defined in Section 2(a) of the Securities Act of 1933, as amended (the “Securities Act”), as modified by the Jumpstart Our Business Startups Act of 2012, or the JOBS Act.

We are an “emerging growth company,” as defined in Section 2(a) of the Securities Act of 1933, as amended (the “Securities Act”), as modified by the Jumpstart Our Business Startups Act of 2012, or the JOBS Act.

As such, we are eligible to take advantage of certain exemptions from various reporting requirements that are applicable to other public companies that are not emerging growth companies including, but not limited to:

3 unchanged sentences

If some investors find our common stock less attractive as a result of these exemptions, there may be a less active trading market for our common stock and the price of our common stock may be more volatile.

In addition, Section 107 of the JOBS Act also provides that an emerging growth company can take advantage of the extended transition period provided in Section 7(a)(2)(B) of the Securities Act of 1933 (the “Securities Act”) for complying with new or revised

accounting standards.

In other words, an emerging growth company can delay the adoption of certain accounting standards until those standards would otherwise apply to private companies.

3 unchanged sentences

Implications of Being a Smaller Reporting Company

Additionally, we are a “smaller reporting company”

as defined in Rule 10(f)(1) of Regulation S-K.

Additionally, we are a “smaller reporting company” as defined in Rule 10(f)(1) of Regulation S-K.

Smaller reporting companies may take advantage of certain reduced disclosure obligations, including, among other things, providing only two years of audited financial statements.

We will remain a smaller reporting company until the last day of the fiscal year in which (1) the market value of our common stock held by non-affiliates equals or exceeds $250 million as of the end of that year’s second fiscal quarter, or (2) our annual revenues equaled or exceeded $100 million during such completed fiscal year and the market value of our common stock held by non-affiliates equals or exceeds $700 million as of the end of that year’s second fiscal quarter.

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