What changed in this filing

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Item 1. Business

2024-04-01 compared with 2023-03-22 · 187 added, 427 removed, 246 unchanged (71% of the section changed)

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“ we ,” “ our ” or the “ Company ”) is a clinical stage biotechnology company whose

proprietary INTASYL™ self-delivering RNAi technology platform is designed to make immune cells more effective in killing tumor

proprietary INTASYL™ self-delivering RNAi technology platform is designed to make immune cells more effective in killing tumor cells.

We are developing therapeutics that are designed to leverage INTASYL to precisely target specific proteins that reduce the body’s

ability to fight cancer, without the need for specialized formulations or drug delivery systems.

We are committed to discovering and

developing innovative cancer treatments for patients by creating new pathways toward a cancer-free future.

We are committed to discovering and developing

innovative cancer treatments for patients by creating new pathways toward a cancer-free future.

In 2023, the Company implemented a cost rationalization

program driven by its transition from discovery research to product development.

This resulted in a decision not to renew the lease for

office and laboratory space in Marlborough, Massachusetts, which will expire on March 31, 2024.

Beginning in April of 2024, we expect

to continue operations as a remote business with a small laboratory facility in Worcester, Massachusetts for 321 square feet of space

that commenced on March 1, 2024.

Additionally, we rationalized discovery research personnel resulting in headcount reduction by approximately

Expense reductions have been redirected to funding the Phase 1b clinical trial with PH-762 directed toward skin cancer.

INTASYL Platform

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cells, which protect the body from cancer cells and infections, to kill cancer cells.

Preclinical studies conducted by the Company have

demonstrated that direct-to-tumor application of PH-762 resulted in potent anti-tumoral effects and have shown that direct-to-tumor treatment

with PH-762 inhibits tumor growth in a dose dependent fashion in PD-1 responsive and refractory models.

Our preclinical studies have demonstrated that

direct-to-tumor application of PH-762 resulted in potent anti-tumoral effects and have shown that direct-to-tumor treatment with PH-762

inhibits tumor growth in a dose dependent fashion in PD-1 responsive and refractory models.

Importantly, direct-to-tumor administration

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antibody therapy.

PH-762 is currently being

evaluated in a Phase 1b dose escalation clinical trial in France that is expected to enroll up to 21 subjects with advanced melanoma.

PH-762 will be administered as a neoadjuvant monotherapy intratumorally once a week, for a total of four injections, across five escalating

Dosing will be followed by tumoral excision after an additional two weeks.

The primary study objectives are to evaluate the

safety and tolerability, and pharmacokinetics of PH-762;

to determine the potential immunologic and pathologic tumor responses;

determine the recommended dose for later clinical trials.

Safety data from the initial cohort of three subjects in the clinical trial

was evaluated by a Data Monitoring Committee in the first quarter of 2023.

The safety data review disclosed no dose-limiting toxicity,

and no drug-related severe or serious adverse events, and the Data Monitoring Committee recommended proceeding to the enrollment of the

subsequent dose cohort.

The next cohort is now open for enrollment of subjects.

In addition to the French

clinical trial, we expect to commence a U.S.

Phase 1b clinical trial with PH-762 in the second half of 2023.

trial is expected

to focus on the application of PH-762 to treat cutaneous squamous cell carcinoma (“ cSCC ”) and other selected cutaneous

malignancies.

Due to INTASYL’s ease

of administration, we have shown that our compounds can easily be incorporated into current ACT manufacturing processes.

In ACT, T cells

are usually taken from a patient's own blood or tumor tissue, grown in large numbers in a laboratory, and then given back to the patient

to help the immune system fight cancer.

By treating T cells with our INTASYL compounds while they are being grown in the laboratory, we

believe our INTASYL compounds can improve these immune cells to make them more effective in killing cancer.

PH-762 is currently being evaluated in a U.S.

Phase 1b dose-escalating clinical trial through the intratumoral injection of PH-762 for the treatment of patients with cutaneous squamous

cell carcinoma, melanoma and Merkel cell carcinoma.

The trial is designed to evaluate the safety and tolerability of neoadjuvant use of

intratumorally injected PH-762, assess the tumor response, and determine the dose or dose range for continued study of PH-762 and is expected

to enroll up to 30 patients.

In November 2023, we announced the dosing of the first patient and the trial is currently open for the continued

enrollment of patients.

Given our intention to focus our efforts and resources

clinical trial with PH-762, we have completed the winding down process for our first-in-human clinical trial for PH-762 in

France, which was limited to the treatment of patients with metastatic melanoma.

Safety data from the initial cohort of three patients

in the French clinical trial were evaluated by a data monitoring committee in the first quarter of 2023.

The safety data review disclosed

no dose-limiting toxicity, and no drug-related severe or serious adverse events.

Due to INTASYL’s

ease of administration, we have shown that our compounds can easily be incorporated into current ACT manufacturing processes.

T cells are usually taken from a patient's own blood or tumor tissue, grown in large numbers in a laboratory, and then given back to the

patient to help the immune system fight cancer.

By treating T cells with our INTASYL compounds while they are being grown in the laboratory,

we believe our INTASYL compounds can improve these immune cells to make them more effective in killing cancer.

Preclinical data generated

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targeting key regulators of the immune response to cancer, demonstrated that treating AgonOx’s “double positive” tumor

infiltrating lymphocyte (“ DP TIL ”) with PH-762 increased by two-fold their tumor killing activity.

In March 2021, we entered

into a clinical co-development collaboration agreement (the “ Clinical Co-Development Agreement ”) with AgonOx to conduct

a Phase 1 clinical trial using DP TIL and PH-762.

Under the Clinical Co-Development Agreement, we paid AgonOx $0.3 million as an upfront

payment in December 2022 and have agreed to provide up to $4 million in total financial support to AgonOx to conduct a Phase 1 clinical

trial of PH-762 treated DP TIL.

Phio is also eligible to receive certain future development milestones and low single-digit sales-based

royalty payments from AgonOx’s licensing of its DP TIL technology.

PH-762 treated DP TILs are

expected to be evaluated in a Phase 1 clinical trial in the United States with up to 18 subjects with advanced melanoma and other advanced

solid tumors.

The primary study objectives are to evaluate the safety and to study the potential for enhanced therapeutic benefit from

the administration of PH-762 treated DP TILs.

Enrollment of subjects is expected to commence in the second quarter of 2023.

PH-762’s use in ACT

is not limited to TILs.

We have presented preclinical data showing that PH-762 significantly enhanced the antitumor efficacy of HER2-targeted

chimeric antigen receptor (“ CAR ”) T cells (“ HER2CART ”) in solid tumors.

Analysis of the PH-762 treated

HER2CART cells isolated from the tumors suggest that PH-762 enhances CAR-T cell function through multiple mechanisms including enhanced

efficiency, degranulation and promotion of memory/stem populations.

infiltrating lymphocytes (“ DP TIL ”) with PH-762 increased their tumor killing activity by two-fold.

In February 2021, we entered into a clinical co-development

collaboration agreement (the “ Clinical Co-Development Agreement ”) with AgonOx to develop a T cell-based therapy using

PH-762 and AgonOx’s DP TIL.

Under the Clinical Co-Development Agreement, we agreed to reimburse AgonOx up to $4 million in expenses

incurred to conduct a Phase 1 clinical trial of PH-762 treated DP TIL in patients with advanced melanoma and other advanced solid tumors.

As of December 31, 2023, there was approximately $2.8 million of remaining costs not yet incurred under the Clinical Co-Development Agreement.

We are also eligible to receive certain future development milestones and low single-digit sales-based royalty payments from AgonOx’s

licensing of its DP TIL technology.

PH-762 treated DP TIL are being evaluated in a

Phase 1 clinical trial in the U.S.

with up to 18 patients with advanced melanoma and other advanced solid tumors by AgonOx.

trial objectives are to evaluate the safety and to study the potential for enhanced therapeutic benefit from the administration of PH-762

treated DP TIL.

We announced the first patient was dosed in August 2023 and the trial is open for the continued enrollment of patients.

PH-894 is an INTASYL compound that is designed

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results in T cell activation, and suppression of BRD4 in tumor cells results in tumors becoming more sensitive to being killed by T cells.

Preclinical studies conducted have demonstrated that

PH-894 resulted in a strong, concentration dependent and durable silencing of BRD4 in T cells and in various cancer cells.

PH-762, preclinical studies have also shown that direct-to-tumor application of PH-894 resulted in potent and statistically significant

anti-tumoral effects and demonstrated a systemic anti-tumor response.

These preclinical data indicate that PH-894 can reprogram T cells

and other cells in the tumor microenvironment to provide enhanced immunotherapeutic activity.

The Company has completed the investigational

new drug (“ IND ”)-enabling studies and is in the process of finalizing the study reports required for an IND submission

As a result of the reprioritization to advance the Company’s clinical trial with PH-762 in the U.S., the Company has

elected to defer the IND submission for PH-894.

Phio has also demonstrated in preclinical studies

that PH-894 has been shown to improve T cell function and persistence by differentiating T cells into a more active state (stem-cell like

memory phenotype).

Preclinical data indicates that silencing BRD4 with PH-894 may be used to improve the characteristics of CAR-T cell

products during the cell manufacturing process.

These data demonstrate that PH-894 could enhance the activity of CAR-T cells by improving

the quality of the final CAR-T cell product by overcoming immunosuppression, reversing exhaustion, and preserving the characteristics

associated with cell persistence.

Other Compounds in Discovery

PH-804 is an INTASYL compound that is designed to target

TIGIT, a protein that inhibits the activity of Natural Killer (“ NK ”) cells.

Preclinical studies conducted have demonstrated

that NK cells treated with PH-804 displayed increased activation and enhanced the ability of NK cells to kill cancer cells.

PH-109 is an INTASYL compound that is designed to suppress

the connective tissue growth factor (“ CTGF ”) protein, a protein that regulates a number of cellular functions and is

associated with poor prognosis in breast cancer.

In a preclinical study, mice were treated with either the drug doxorubicin, a chemotherapeutic

which has a high toxicity profile, or with PH-109.

In this study, PH-109 reduced tumor growth and reduced metastatic lung lesions, with

no evidence of toxicity as compared to the toxicity profile of doxorubicin.

Phio has developed an INTASYL compound that is designed

to target CTLA-4, a protein that inhibits the ability of T cells to kill tumor cells.

The CTLA-4 targeting INTASYL compound demonstrated

dose-associated anti-tumor efficacy in two preclinical tumor models.

Delivering CTLA-4 by intratumoral injection may avoid or minimize

the severe systemic adverse events associated with current CTLA-4 therapeutics.

We are also investigating the use of INTASYL to

target multiple genes in a single formulation.

Unlike other combination approaches, we believe the INTASYL platform can target multiple

protein drug targets in a specific therapeutic dose, enhancing potency while maintaining a favorable tolerability and safety profile.

Preclinical data has shown that combining PH-762 and PH-894 in a single formulation elicited complete cure of tumors in a liver cancer

model and outperformed the efficacy of the small molecule and antibody control treatments toward the same targets.

In addition, local

INTASYL therapy was shown to induce a systemic anti-tumor response with the clearance of distant untreated tumors.

We believe that these

data demonstrate that the use of INTASYL to target multiple genes may provide a durable and systemic anti-tumor immune response that can

combat tumor growth.

that PH-894 resulted in a strong, concentration dependent and durable silencing of BRD4 in T cells and in various cancer cells.

to PH-762, preclinical studies have also shown that direct-to-tumor application of PH-894 resulted in potent and statistically significant

anti-tumoral effects against distant untreated tumors, indicative of a systemic anti-tumor response.

These preclinical data indicate that

PH-894 can reprogram T cells and other cells in the tumor microenvironment to provide enhanced immunotherapeutic activity.

We have completed

the investigational new drug application (“ IND ”)-enabling studies and are in the process of continuing to finalize

the study reports required for an IND submission with PH-894.

As a result of the reprioritization to advance our clinical trial with PH-762

in the U.S., we have elected to defer the IND submission for PH-894.

Synergies With Other Therapies

Preclinical studies with our INTASYL compounds

in combination with antibodies resulted in enhanced potency in vivo.

The combination of INTASYL with antibodies may also increase the

number of addressable drug targets.

Unlike other antibody combination approaches, INTASYL can target multiple protein drug targets in

a specific therapeutic dose, thereby enhancing potency while maintain a favorable tolerability and safety profile.

We have demonstrated preclinical efficacy with

INTASYL in ACT applications.

In preclinical studies, INTASYL was shown to enhance the activity of ACT therapies, including with tumor

infiltrating lymphocytes and natural killer cells.

As demonstrated in these preclinical studies, INTASYL is easily incorporated into current

ACT manufacturing processes.

Intellectual Property

INTASYL compounds have a single-stranded phosphorothioate

region, a short duplex region, and contain a variety of nuclease-stabilizing and lipophilic chemical modifications that we believe combines

region, a short duplex region, and contain a variety of nuclease-stabilizing and lipophilic chemical modifications that we believe combine

the beneficial properties of both conventional RNAi and antisense technologies.

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and patent applications under licenses with third parties, which require us to pay royalties, milestone payments, or both.

of patent protection for biotechnology products and processes, including ours, remains uncertain, both in the United States and in other

important markets, because the scope of protection depends on decisions of patent offices, courts and lawmakers in these countries.

is no certainty that our existing patents or others, if obtained, will afford us substantial protection or commercial benefit.

there is no assurance that our pending patent applications or patent applications licensed from third parties will ultimately be granted

as patents or that those patents that have been issued or are issued in the future will stand if they are challenged in court.

of patent protection for biotechnology products and processes, including ours, remains uncertain, both in the U.S.

and in other important

markets, because the scope of protection depends on decisions of patent offices, courts and lawmakers in these countries.

certainty that our existing patents or others, if obtained, will afford us substantial protection or commercial benefit.

Similarly, there

is no assurance that our pending patent applications or patent applications licensed from third parties will ultimately be granted as

patents or that those patents that have been issued or are issued in the future will stand if they are challenged in court.

our license agreements on an ongoing basis and may from time to time terminate licenses to technology that we do not intend to employ

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Other Markets

Our portfolio includes 119 issued patents, 87 of which

cover our INTASYL platform.

Our portfolio includes 81 issued patents, 73 of

which cover our INTASYL platform.

There are 13 patent families broadly covering both the composition and methods of use of our self-delivering

platform technology and uses of our INTASYL compounds targeting immune checkpoint, cellular differentiation and metabolism targets for

ex vivo cell-based cancer immunotherapies.

These patents are scheduled to expire between 2029 and 2040.

Furthermore, there are

47 patent applications, encompassing what we believe to be important new RNAi compounds and their use as therapeutics, chemical modifications

of RNAi compounds that improve the compounds’ suitability for therapeutic uses (including delivery) and compounds directed to specific

targets ( i.e.

INTASYL platform technology and uses of our INTASYL compounds targeting immune checkpoint, cellular differentiation and metabolism targets

for ex vivo cell-based cancer immunotherapies.

The INTASYL platform patents are scheduled to expire between 2029 and 2038.

Furthermore, there are 40 patent applications,

encompassing what we believe to be important new RNAi compounds and their use as therapeutics, chemical modifications of RNAi compounds

that improve the compounds’ suitability for therapeutic uses (including delivery) and compounds directed to specific targets ( i.e.

that address specific disease states).

The patents and any patents that may issue from these pending patent applications

will, if issued, be set to expire between 2022 and 2040, not including any patent term extensions that may be afforded under the Federal

Food, Drug, and Cosmetic Act (“ FFDCA ”) (and the equivalent provisions in foreign jurisdictions) for any delays incurred

during the regulatory approval process relating to human drug products (or processes for making or using human drug products).

The patents that may issue from these pending patent applications will, if issued, be set to expire

between 2029 and 2042, not including any patent term extensions that may be afforded under the Federal Food, Drug, and Cosmetic Act (“ FFDCA ”)

(and the equivalent provisions in foreign jurisdictions) for any delays incurred during the regulatory approval process relating to human

drug products (or processes for making or using human drug products).

Key Intellectual Property License Agreements

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our intellectual property portfolio and unique intellectual property position.

Advanced RNA Technologies, LLC (“ Advirna ”).

In September 2011, the Company entered into an agreement with Advirna, pursuant to which Advirna assigned to us its existing patent and

technology rights related to the INTASYL technology in exchange for an annual maintenance fee, a one-time milestone payment upon the future

issuance of the first patent with valid claims covering the assigned patent and technology rights and the issuance of shares of common

stock of the Company equal to 5% of the Company’s fully-diluted shares outstanding at the time of issuance.

In 2012, we issued shares

of common stock of the Company to Advirna equal to 5% of our fully-diluted shares outstanding at the time of issuance and paid $350,000

In September 2011, the Company entered into an

agreement with Advanced RNA Technologies, LLC (“ Advirna ”), pursuant to which Advirna assigned to us its existing patent

and technology rights related to the INTASYL technology in exchange for an annual maintenance fee, a one-time milestone payment upon the

future issuance of the first patent with valid claims covering the assigned patent and technology rights and the issuance of shares of

common stock of the Company equal to 5% of the Company’s fully-diluted shares outstanding at the time of issuance.

In 2012, we issued

shares of common stock of the Company to Advirna equal to 5% of our fully-diluted shares outstanding at the time of issuance and paid

$350,000 to Advirna upon the issuance of the first patent in 2014.

Additionally, we also pay to Advirna an annual maintenance fee of $100,000 and

are required to pay low single-digit royalties on any licensing revenue received by us with respect to future licensing of the assigned

Additionally, we also pay to Advirna an annual maintenance fee of $100,000

and are required to pay low single-digit royalties on any licensing revenue received by us with respect to future licensing of the assigned

Advirna patent and technology rights.

To date, any royalties owed to Advirna under the agreement have been minimal.

To date, any royalties owed to Advirna under the Advirna agreement have been minimal.

Our rights under the Advirna agreement will expire

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(i) the expiration of the last-to-expire of the “patent rights” (as defined therein) included in the

agreement or (ii) the abandonment of the last-to-be abandoned of such patents, unless earlier terminated in accordance with the provisions

of the agreement.

Further, the Company also granted back to Advirna a license under the assigned patent and technology rights for fields

of use outside human therapeutics.

Advirna agreement or (ii) the abandonment of the last-to-be abandoned of such patents, unless earlier terminated in accordance with

the provisions of the Advirna agreement.

Further, the Company also granted back to Advirna a license under the assigned patent and technology

rights for fields of use outside human therapeutics.

Manufacturing and

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to produce our product candidates in accordance with regulatory requirements.

We currently rely on and contract

with third parties for the manufacture of drug substances and drug products for use in our preclinical studies and clinical trials in

accordance with regulatory requirements.

We intend that we will continue to rely on and contract with third parties to manufacture our

product candidates in the future.

We currently rely on and contract with third parties

for the manufacture of drug substances and drug products for use in our preclinical studies and clinical trials in accordance with regulatory

requirements.

We expect that we will continue to rely on and contract with third parties to manufacture our product candidates in the

The biotechnology and pharmaceutical industries,

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data, together with proposed clinical protocols, manufacturing information, analytical data and other information submitted to the FDA

in an IND application, must become effective before human clinical trials may commence.

Preclinical studies generally involve FDA regulated

laboratory evaluation of product characteristics and animal studies to assess the efficacy and safety of the product candidate.

through an IND, must become effective before human clinical trials may commence.

Preclinical studies generally involve evaluation of product

characteristics and animal studies to assess the efficacy and safety of the product candidate.

Many of these studies must be conducted

in accordance with the FDA’s current Good Laboratory Practices, the Animal Welfare Act, and other applicable regulations.

After the IND becomes effective, a company may

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case of a biologic, a biologics license application (“ BLA ”).

The amount of time taken by the FDA for approval of

an NDA or BLA will depend upon a number of factors, including whether the product candidate has received priority review, the quality

of the submission and studies presented, the potential contribution that the compound will make in improving the treatment of the disease

in question and the workload of the FDA’s staff.

The FDA may, in some cases, confer upon an investigational

product the status of a fast track product.

A fast track product is defined as a new drug or biologic intended for the treatment of a

serious or life-threatening condition that demonstrates the potential to address unmet medical needs for this condition.

The FDA can base

approval of an NDA or BLA for a fast track product utilizing a surrogate endpoint, or on another endpoint that is reasonably likely to

predict clinical benefit.

If a preliminary review of clinical data suggests that a fast track product may be effective, the FDA may initiate

review of entire sections of a marketing application for a fast track product before the sponsor completes the application.

The amount of time taken by the FDA to approve

a NDA or BLA will depend upon a number of factors, including whether the product candidate has received priority review, the quality of

the submission and studies presented, the potential contribution that the compound will make in improving the treatment of the disease

in question and agency resources.

The FDA maintains several programs to facilitate

and expedite the development and review of applications that are intended for the treatment of a serious or life-threatening disease or

condition that meet certain other criteria, including Fast Track Designation, Breakthrough Designation, Priority Review, and the Accelerated

Approval pathway.

We anticipate that our products will be manufactured

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Act, the Toxic Substance Control Act and the Resource Conservation and Recovery Act and other applicable environmental statutes.

approval, the FDA periodically inspects drug and biologic manufacturing facilities to ensure continued compliance with the cGMP.

Our manufacturers

will have to continue to comply with those requirements.

Failure to comply with these requirements subjects the manufacturer to possible

legal or regulatory action, such as suspension of manufacturing or recall or seizure of product.

Adverse patient experiences with the

product must be reported to the FDA and could result in the imposition of marketing restrictions through labeling changes or market removal.

Product approvals may be withdrawn if compliance with regulatory requirements is not maintained or if problems concerning safety or efficacy

of the product occur following approval.

approval, the FDA and certain state agencies periodically inspects drug and biologic manufacturing facilities to ensure continued compliance

with the cGMP.

Our manufacturers will have to continue to comply with those requirements.

Failure to comply with these requirements subjects

the manufacturer to possible legal or regulatory action, such as suspension of manufacturing or recall or seizure of product.

patient experiences with the product must be reported to the FDA and could result in the imposition of marketing restrictions through

labeling changes or market removal.

Product approvals may be withdrawn if compliance with regulatory requirements is not maintained or

if problems concerning safety or efficacy of the product occur following approval.

The labeling, advertising, promotion, marketing

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activities involving the internet, and direct-to-consumer advertising.

We also will be subject to a variety of federal, state and local

We also will be subject to state and local requirements governing

the manufacturing and distribution of pharmaceutical products.

In addition, we will be subject to a variety of federal, state and local

regulations relating to the use, handling, storage and disposal of hazardous materials, including chemicals and radioactive and biological

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effect on us.

We will also be subject to a variety of regulations

governing clinical trials and sales of our products outside the United States.

In the future, we may also be subject to a variety

of regulations governing clinical trials and sales of our products outside the U.S.

Whether or not FDA approval has been obtained, approval

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In the European Union, Canada and Australia, regulatory requirements and approval

processes are similar, in principle, to those in the United States.

Review and Approval of Drugs in the European Union Including France

In order to market any pharmaceutical product outside

of the United States, a company must also comply with numerous and varying regulatory requirements of other countries and jurisdictions

governing, among other things, research and development, testing, manufacturing, quality control, safety, efficacy, clinical trials, marketing

authorization, packaging, storage, record keeping, reporting, export and import, advertising and other promotional practices involving

pharmaceutical products, as well as commercial sales, distribution and post-approval monitoring and reporting of our products.

or not it obtains FDA approval for a pharmaceutical product, the company would need to obtain the necessary approvals by the comparable

foreign regulatory authorities before it can commence clinical trials or marketing of the pharmaceutical product in those countries or

jurisdictions.

The approval process ultimately varies between countries and jurisdictions and can involve additional product testing and

additional administrative review periods.

The time required to obtain approval in other countries and jurisdictions might differ from

and be longer and far more difficult than that required to obtain FDA approval.

Regulatory approval in one country or jurisdiction does

not ensure regulatory approval in another, but a failure or delay in obtaining regulatory approval in one country or jurisdiction may

negatively impact the regulatory process in others.

The United Kingdom (“ UK ”) formally

left the European Union (“ EU ”) on January 31, 2020 and the transition period, during which EU laws continued to apply

to the UK, expired on December 31, 2020.

This means EU laws now only apply to the UK in respect of Northern Ireland as laid out in the

Protocol on Ireland and Northern Ireland.

Following the end of the transition period, the EU and the UK concluded a trade and cooperation

agreement (“ TCA ”), which applied provisionally from January 1, 2021 and entered into force on May 1, 2021.

The TCA includes provisions affecting the life

sciences sector (including on customs and tariffs) but areas for further discussion between the EU and the UK remain.

In addition, there

are some specific provisions concerning pharmaceuticals.

These include the mutual recognition of Good Manufacturing Practice (“ GMP ”)

and issued GMP documents.

The TCA does not, however, contain wholesale mutual recognition of UK and EU pharmaceutical regulations and

product standards.

Since January 1, 2021, the EU laws which have been

transposed into UK law through secondary legislation continue to be applicable in the UK as “retained EU law”.

no general power to amend these regulations, the UK government has enacted the Medicines and Medical Devices Act 2021.

The purpose of

the act is to enable the existing regulatory frameworks in relation to human medicines, clinical trials of human medicines, veterinary

medicines and medical devices to be updated.

The powers under the act may only be exercised in relation to specified matters and must

safeguard public health.

Specified provisions of the Medicines and Medical Devices

Act 2021 entered into force on February 11, 2021.

The remaining provisions came into effect within two months of February 11, 2021 or

will otherwise come into effect as stipulated in subsequent statutory instruments.

The Medicines and Medical Devices Act 2021 supplements

the UK Medical Devices Regulations 2002 (the “ UK Regulations ”), which are based on the EU Medical Devices Directive

as amended to reflect the UK’s post-Brexit regulatory regime.

Notably, the UK Regulations do not include any of the revisions that

have been made by the EU Medical Devices Regulation (EU) 2017/745, which, since May 26, 2021, now applies in all EU Member States.

The UK’s Medicines and Healthcare products Regulatory

Agency conducted a comprehensive consultation between September and November 2021 on proposals to develop a new UK regime for medical

devices in the UK.

The proposals include more closely aligning definitions for medical devices and in vitro medical devices with internationally

recognized definitions and changing the classification of medical devices according to levels or risk.

The proposals are intended to improve

patient and public safety and increase the appeal of the UK market.

The new regime is planned to come into force on July 1, 2023, which

will align with the date from which the UK is due to stop accepting CE marked medical devices and require UKCA (UK Conformity Assessed)

It is envisaged that, in Northern Ireland, the amended regime could run in parallel with any existing or future EU rules in accordance

with the Protocol on Ireland and Northern Ireland.

Drug Development Process

The conduct of clinical trials is currently governed

by the EU Clinical Trials Directive 2001/20/EC (the “ Clinical Trials Directive ”), and will be gradually replaced by

the EU Clinical Trials Regulation (EU) No.

536/2014 (“ CTR ”).

The CTR introduces a complete overhaul of the existing

regulation of clinical trials for medicinal products in the EU.

It entered into force on January 31, 2022.

Under the current regime, which will expire after

a transition period of one or three years, respectively, as outlined below in more detail, before a clinical trial can be initiated, it

must be approved in each EU Member State in which the clinical trial is to be conducted.

The approval must be obtained from two separate

the National Competent Authority (“ NCA ”) and one or more Ethics Committees.

The NCA of the EU Member States

in which the clinical trial will be conducted must authorize the conduct of the trial, and the independent Ethics Committee must grant

a positive opinion in relation to the conduct of the clinical trial in the relevant EU Member State before the commencement of the trial.

Any substantial changes to the trial protocol or other information submitted with the clinical trial applications must be submitted to

or approved by the relevant NCA and Ethics Committees.

Under the current regime all suspected unexpected serious adverse reactions to

the investigated drug that occur during the clinical trial must be reported to the NCA and to the Ethics Committees of the EU Member State

where they occur.

A more unified procedure applies under the new

CTR, which came into force on January 31, 2022.

A sponsor is able to submit a single application for approval of a clinical trial through

a centralized EU clinical trials portal.

One national regulatory authority (the reporting EU Member State proposed by the applicant) takes

the lead in validating and evaluating the application, and will consult and coordinate with the other concerned Member States.

If an application

is rejected, it may be amended and resubmitted through the EU clinical trials portal.

If an approval is issued, the sponsor may start

the clinical trial in all concerned Member States.

However, a concerned EU Member State may in limited circumstances declare an “opt-out”

from an approval and prevent the clinical trial from being conducted in such Member State.

The CTR also aims to streamline and simplify

the rules on safety reporting, and introduces enhanced transparency requirements such as mandatory submission of a summary of the clinical

trial results to the EU Database (“ CTIS ”).

While Member States will work in CTIS immediately after the system has gone

live, the CTR provides for two transition periods for sponsors:

For one year, until January 31, 2023, clinical trial sponsors can still

choose whether to submit an initial clinical trial application in line with the current system (Clinical Trials Directive) or via CTIS.

From January 31, 2023, submission of initial clinical trial applications via CTIS becomes mandatory, and by January 31, 2025, all ongoing

trials approved under the current Clinical Trials Directive will be governed by the new Regulation and have to be transitioned to CTIS.

Under both the current regime and the new CTR,

national laws, regulations, and the applicable Good Clinical Practice and Good Laboratory Practice standards must also be respected during

the conduct of the trials, including the International Council for Harmonization of Technical Requirements for Pharmaceuticals for Human

Use guidelines on Good Clinical Practice (“ GCP ”) and the ethical principles that have their origin in the Declaration

Marketing Authorization Procedures

In the EU and in Iceland, Norway and Liechtenstein

(together, the European Economic Area or “ EEA ”), after completion of all required clinical testing, pharmaceutical

products may only be placed on the market after obtaining a Marketing Authorization (“ MA ”).

To obtain a MA of a drug

under EU regulatory systems, an applicant can submit a Marketing Authorization Application (“ MAA ”) through, amongst

others, a centralized or decentralized procedure.

The centralized procedure provides for the grant

of a single MA by the European Commission (“ EC ”) that is valid for all EU Member States and, after respective national

implementing decisions, in the three additional EEA Member States.

The centralized procedure is compulsory for specific medicinal products,

including for medicines developed by means of certain biotechnological processes, products designated as orphan medicinal products, advanced

therapy medicinal products (“ ATMP ”) and medicinal products with a new active substance indicated for the treatment

of certain diseases (AIDS, cancer, neurodegenerative disorders, diabetes, auto-immune and viral diseases).

For medicinal products containing a new active

substance not yet authorized in the EEA before May 20, 2004 and indicated for the treatment of other diseases, medicinal products that

constitute significant therapeutic, scientific or technical innovations or for which the grant of a MA through the centralized procedure

would be in the interest of public health at EU level, an applicant may voluntarily submit an application for a marketing authorization

through the centralized procedure.

Under the centralized procedure, the Committee

for Medicinal Products for Human Use (“ CHMP ”), established at the European Medicines Agency (“ EMA ”),

is responsible for conducting the initial assessment of a drug.

The CHMP is also responsible for several post-authorization and maintenance

activities, such as the assessment of modifications or extensions to an existing marketing authorization.

Under the centralized procedure,

the timeframe for the evaluation of a MAA by the EMA’s CHMP is, in principle, 210 days from receipt of a valid MAA.

However, this

timeline excludes clock stops, when additional written or oral information is to be provided by the applicant in response to questions

asked by the CHMP, so the overall process typically takes a year or more, unless the application is eligible for an accelerated assessment.

Accelerated assessment might be granted by the CHMP in exceptional cases when a medicinal product is of major interest from the point

of view of public health and in particular from the viewpoint of therapeutic innovation.

On request, the CHMP can reduce the time frame

to 150 days if the applicant provides sufficient justification for an accelerated assessment.

The CHMP will provide a positive opinion

regarding the application only if it meets certain quality, safety and efficacy requirements.

However, the EC has final authority for

granting the MA within 67 days after receipt of the CHMP opinion.

The decentralized procedure permits companies to

file identical MA applications for a medicinal product to the competent authorities in various EU Member States simultaneously if such

medicinal product has not received marketing approval in any EU Member State before.

This procedure is available for pharmaceutical products

not falling within the mandatory scope of the centralized procedure.

The competent

authority of a single EU Member State, known as the reference EU Member State, is appointed to review the application and provide an assessment

Under this procedure, an applicant submits an application based on identical dossiers and related materials, including a draft

summary of product characteristics, and draft labeling and package leaflet, to the reference EU Member State and concerned EU Member States.

The reference EU Member State prepares a draft assessment report and drafts of the related materials within 120 days after receipt of

a valid application.

Subsequently, each concerned EU Member State must decide whether to approve the assessment report and related materials.

If an EU Member State cannot approve the assessment report and related materials on the grounds of potential serious risk to public health,

the disputed points are subject to a dispute resolution mechanism and may eventually be referred to the EC, whose decision is binding

for all EU Member States.

All new MAAs must include a Risk Management Plan

(“ RMP ”), describing the risk management system that the company will put in place and documenting measures to prevent

or minimize the risks associated with the product.

The regulatory authorities may also impose specific obligations as a condition of

RMPs and Periodic Safety Update Reports are routinely available to third parties requesting access, subject to limited

Marketing Authorizations have an initial duration

of five years.

After these five years, the authorization may subsequently be renewed on the basis of a reevaluation of the risk-benefit

Once renewed, the MA is valid for an unlimited period unless the EC or the national competent authority decides, on justified

grounds relating to pharmacovigilance, to proceed with only one additional five-year renewal.

Applications for renewal must be made to

the EMA at least nine months before the five-year period expires.

Data and Market Exclusivity in the European

As in the United States, it may be possible to

obtain a period of market and/or data exclusivity in the EU that would have the effect of postponing the entry into the marketplace of

a competitor’s generic, hybrid or biosimilar product (even if the pharmaceutical product has already received a MA) and prohibiting

another applicant from relying on the MA holder’s pharmacological, toxicological and clinical data in support of another MA for

the purposes of submitting an application, obtaining MA or placing the product on the market.

New medicinal products authorized in the European

Union, qualify for eight years of data exclusivity upon marketing authorization and an additional two years of market exclusivity.

overall ten-year period of market exclusivity can be extended to a maximum of eleven years if, during the first eight years of those ten

years, the marketing authorization holder obtains an authorization for one or more new therapeutic indications which, during the scientific

evaluation prior to their authorization, are held to bring a significant clinical benefit in comparison with existing therapies.

The data exclusivity period prevents generic or

biosimilar applicants from relying on the preclinical and clinical trial data contained in the dossier of the reference medicinal product

when applying for a generic or biosimilar marketing authorization in the EU during a period of eight years from the date on which the

reference product was first authorized in the EU.

The market exclusivity period prevents a successful generic or biosimilar applicant

from commercializing its product in the EU until 10 years have elapsed from the initial authorization of the reference product in the

Post-approval Regulation

Similar to the United States, both marketing authorization

holders and manufacturers of pharmaceutical products are subject to comprehensive regulatory oversight by the EMA, the EC and/or the competent

regulatory authorities of the EU Member States.

The holder of an EU marketing authorization for

a pharmaceutical product must also comply with EU pharmacovigilance legislation and its related regulations and guidelines, which entail

many requirements for conducting pharmacovigilance, or the assessment and monitoring of the safety of pharmaceutical products.

Failure by us or by any of our third-party partners,

including suppliers, manufacturers and distributors to comply with EU laws and the EU Member State laws implementing Directive 2001/83/EC

on pharmaceutical products for human use and other core legislation relating to pharmaceutical products, and other EU Member State laws

that apply to the conduct of clinical trials, manufacturing approval, marketing authorization of pharmaceutical products and marketing

of such products, both before and after grant of marketing authorization, manufacturing of pharmaceutical products, statutory health insurance,

bribery and anti-corruption or with other applicable regulatory requirements may result in administrative, civil or criminal penalties.

These penalties could include delays or refusal to authorize the conduct of clinical trials or to grant marketing authorization, product

withdrawals and recalls, product seizures, suspension, withdrawal or variation of the marketing authorization, total or partial suspension

of production, distribution, manufacturing or clinical trials, operating restrictions, injunctions, suspension of licenses, fines and

criminal penalties.

European Union Data Laws

processes are similar, in principle, to those in the U.S.

European Union Data Laws For Review and Approval of Drugs in the

European Union Including France

The collection and use of personal health data

and other personal information in the EU is governed by the provisions of the General Data Protection Regulation (“ GDPR ”),

which came into force in May 2018, and related implementing laws in individual EU Member States.

In addition, following the UK’s

formal departure from the EU on January 31, 2020 and the end of the transition period on December 31, 2020, the United Kingdom has become

a “third country” for the purposes of EU data protection law.

A “third country” is a country other than the EU

Member States and the three additional European Economic Area countries (Norway, Iceland and Liechtenstein) that have adopted a national

law implementing the GDPR.

However, the TCA includes a provision, whereby the transfer of personal data from the EU to the UK will not

be considered as a transfer to a “third country” for a period of four months starting from the entry into force of the TCA.

This period will be extended by two further months, unless the EU or the UK objects.

Under the GDPR, personal data can only be transferred

to third countries in compliance with specific conditions for cross-border data transfers.

Appropriate safeguards are required to enable

transfers of personal data from the EU Member States.

This status has a number of significant practical consequences, in particular for

international data transfers, competent supervisory authorities and enforcement of the GDPR.

The GDPR increased responsibility and liability

in relation to personal data that we process.

and other personal information in the European Union (“ EU ”) is governed by the provisions of the General Data Protection

Regulation (“ GDPR ”), which came into force in May 2018, and related implementing laws in individual EU Member States.

In addition, following the United Kingdom’s (“ UK ”) formal departure from the EU on January 31, 2020 and the end

of the transition period on December 31, 2020, the UK has become a “third country” for the purposes of EU data protection

A “third country” is a country other than the EU Member States and the three additional European Economic Area countries

(Norway, Iceland and Liechtenstein) that have adopted a national law implementing the GDPR.

However, the trade and cooperation agreement

(“ TCA ”) entered into between the EU and UK following the end of the transition period includes a provision, whereby

the transfer of personal data from the EU to the UK will not be considered as a transfer to a “third country” for a period

of four months starting from the entry into force of the TCA.

This period will be extended by two further months, unless the EU or the

Under the GDPR, personal data can only be transferred to third countries in compliance with specific conditions for cross-border

data transfers.

Appropriate safeguards are required to enable transfers of personal data from the EU Member States.

This status has a

number of significant practical consequences, in particular for international data transfers, competent supervisory authorities and enforcement

The GDPR increased responsibility and liability in relation to personal data that we process.

The GDPR imposes a number of strict obligations

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penalties against us, harm to our reputation, and adversely impact our business and operating results.

The uncertainty regarding the interplay

between different regulatory frameworks, such as the Clinical Trials Regulation and the General Data Protection Regulation, further adds

to the complexity that we face with regard to data protection regulation.

New Legislation and Regulations

From time to time, legislation is drafted, introduced

and passed in the EU, its Member States and other states of Europe that could significantly change the statutory provisions governing

the testing, approval, manufacturing, marketing, coverage and reimbursement of pharmaceutical products.

In addition to new legislation,

pharmaceutical regulations and policies are often revised or interpreted by the EMA and national agencies in ways that may significantly

affect our business and our products.

The uncertainty regarding the

interplay between different regulatory frameworks, such as the Clinical Trials Regulation and the General Data Protection Regulation,

further adds to the complexity that we face with regard to data protection regulation.

Environmental Compliance

Our research and development activities involve the

controlled use of potentially harmful biological materials as well as hazardous materials, chemicals and various radioactive compounds.

Our research and development activities involve

the controlled use of potentially harmful biological materials as well as hazardous materials, chemicals and various radioactive compounds.

We are subject to federal, state and local laws and regulations governing the use, storage, handling and disposal of these materials and

8 unchanged sentences

Human Capital Management

As of December 31, 2022, we had nine full-time

As of December 31, 2023, we had eight full-time

employees and one part-time employee at our facility in Marlborough, Massachusetts.

1 unchanged sentence

or covered by a collective bargaining agreement, nor have we experienced any work stoppages.

We expect to add additional employees in fiscal year

2023 to increase our expertise and resources available in our clinical development and administrative areas.

We continually evaluate our

business needs and weigh the use of in-house expertise and capacity with outsourced expertise and capacity.

We currently outsource substantially

all preclinical and clinical trial work to third party contract research organizations and drug manufacturing contractors.

Our ability to identify, attract,

retain and integrate additional qualified key personnel is also critical to our success and the competition for skilled research, product

development, regulatory and technical personnel is intense.

To attract qualified applicants, we offer a total rewards package consisting

of base salary and cash target bonus, a comprehensive benefit package and equity compensation for every employee.

Bonus opportunity and

equity compensation increase as a percentage of total compensation based on level of responsibility.

Actual bonus payouts are based

on performance.

We continually evaluate our business needs and

weigh the use of in-house expertise and capacity with outsourced expertise and capacity.

We currently outsource substantially all preclinical

and clinical trial work to third party contract research organizations and drug manufacturing contractors.

Our ability to identify,

attract, retain and integrate additional qualified key personnel is also critical to our success and the competition for skilled research,

product development, regulatory and technical personnel is intense.

To attract qualified applicants, we offer a total rewards package

consisting of base salary and cash target bonus, a comprehensive benefit package and equity compensation for every employee.

Bonus opportunity

and equity compensation increase as a percentage of total compensation based on level of responsibility.

Actual bonus payouts are

based on performance.

A majority of Phio’s

4 unchanged sentences

a 1-for-12 reverse stock split of the Company’s outstanding common stock.

The reverse stock split did not reduce the number of authorized

shares of the Company’s common or preferred stock.

All share and per share amounts have been adjusted to give effect to the reverse

The reverse stock split did not reduce the number of

authorized shares of the Company’s common or preferred stock.

All share and per share amounts have been adjusted to give effect

to the reverse stock split.

We were incorporated in the state of Delaware in

11 unchanged sentences

on our website the charters of our audit, compensation, nominating and governance committees, as well as our corporate code of ethics

The SEC maintains an internet site that contains reports,

proxy and information statements, and other information regarding Phio and other issuers that file electronically with the SEC.

website address is http://www.sec.gov .

The contents of this website, and our website, are not incorporated by reference into this

report and should not be considered to be part of this report.

The SEC maintains an internet site that contains

reports, proxy and information statements, and other information regarding Phio and other issuers that file electronically with the SEC.

The SEC’s website address is http://www.sec.gov .

The contents of this website, and our website, are not incorporated by reference

into this report and should not be considered to be part of this report.

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