What changed in this filing

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Item 1A. Risk Factors

2024-04-01 compared with 2023-03-22 · 294 added, 360 removed, 339 unchanged (66% of the section changed)

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in our efforts to identify or discover additional product candidates, which may materially and adversely impact our business.

Our success depends heavily

on the successful development of our product candidates, which may never occur.

Our product candidates, which are in early stages of development,

could be delayed, not advance into the clinic, or unexpectedly fail at any stage of development.

Our ability to identify, develop and

commercialize product candidates is dependent on extensive preclinical and other non-clinical tests in order to support an IND application

in the United States, or the equivalent with regulatory authorities in other jurisdictions.

These research programs to identify new product

candidates require substantial financial and human resources, are difficult to design and can take many years to complete.

Our success depends heavily on the successful development

of our product candidates, which may never occur.

Our product candidates, which are in early stages of development, could be delayed,

not advance into the clinic, or unexpectedly fail at any stage of development.

Our ability to identify, develop and commercialize product

candidates is dependent on extensive preclinical and other non-clinical tests in order to support an IND in the United States, or the

equivalent with regulatory authorities in other jurisdictions, if applicable.

These research programs to identify new product candidates

require substantial financial and human resources, are difficult to design and can take many years to complete.

We cannot be certain of the outcome of our research

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condition, and results of operations.

Further, the FDA, or equivalent foreign regulatory

authority, may not accept the results of our preclinical studies or clinical trials and may require us to complete additional studies

or impose stricter approval conditions than we expect, which could impact the value of a particular program, the approvability or commercialization

of the particular product candidate or product and our Company in general.

Because of these factors, it is difficult to predict the time

and cost of the development of our product candidates.

Any delay or failure in obtaining required approvals may prevent us from completing

our preclinical studies or clinical trials and could have a material adverse effect on our ability to initiate or commercialize any drug

candidate on a timely basis, or at all.

Additionally, preclinical studies and clinical trials are lengthy and expensive and if our cash

resources become limited we may not be able to commence, continue or complete such preclinical studies or clinical trials.

We are dependent on our collaboration partners

for the successful development of our adoptive cell therapy product candidates.

Further, the FDA may not accept the results of

our preclinical studies or clinical trials and may require us to complete additional studies or impose stricter approval conditions than

we expect, which could impact the value of a particular program, the approvability or commercialization of the particular product candidate

or product and our Company in general.

Because of these factors, it is difficult to predict the time and cost of the development of our

product candidates.

Any delay or failure in obtaining required approvals may prevent us from completing our preclinical studies or clinical

trials and could have a material adverse effect on our ability to initiate or commercialize drug or biologic candidate on a timely basis,

Additionally, preclinical studies and clinical trials are lengthy and expensive and if our cash resources become limited we

may not be able to commence, continue or complete such preclinical studies or clinical trials.

We are dependent on our collaboration partner

for the successful development of our adoptive cell therapy product candidate.

We are dependent on third parties that have direct

access to the patient or donor cells used in cell therapy and expect to depend on third-party collaborators to support the clinical development

of our ACT product candidates.

We have entered into a clinical collaboration development agreement with AgonOx, Inc.

for the clinical

development of our PH-762 product candidate in ACT and have entered into other research agreements with academic and industry collaborators,

each of which is terminable by the relevant party at any time, subject to applicable notice periods.

The success of our collaborations

depends upon the efforts of our collaboration partners, and their performance in achieving the development activities to the extent they

are responsible under our collaboration agreements.

Each of our partners may not be successful in performing these activities, including

completing the required preclinical studies and other information to be included in an IND application (or foreign equivalent), obtaining

approval to initiate clinical trials, conducting the necessary clinical trials and arranging for the manufacturing or contract research

organization (“ CRO ”) relationships and obtaining marketing authorization.

Our partners work with other companies, potentially

including some of our competitors, their corporate objectives may not align with ours, and they may change their strategic focus or pursue

alternative technologies.

If our collaborations are not successful or a partner terminates our collaboration agreement, our business,

financial condition, and results of operations could be materially and adversely affected.

access to the patient or donor cells used in cell therapy and expect to depend on our third-party collaborator to support the clinical

development of our ACT product candidate.

We have entered into a clinical co-development collaboration agreement with AgonOx, Inc.

conduct a Phase 1 clinical trial of the evaluation of PH-762 treated “double positive” tumor infiltrating lymphocytes in patients

with advanced melanoma and other advanced solid tumors.

The success of our collaboration depends upon the efforts of our collaboration

partner, and their performance in achieving the development activities to the extent they are responsible under our collaboration agreement.

Our partner may not be successful in performing these activities, including completing the required preclinical studies and other information

to be included in an IND application (or foreign equivalent), obtaining approval to initiate clinical trials, conducting the necessary

clinical trials and arranging for the manufacturing or contract research organization (“ CRO ”) relationships and obtaining

marketing authorization.

Our partner works with other companies, potentially including some of our competitors, their corporate objectives

may not align with ours, and they may change their strategic focus or pursue alternative technologies.

If our collaboration is not successful

or our partner terminates our collaboration agreement, our business, financial condition, and results of operations could be materially

and adversely affected.

Further, we may not be successful in negotiating

agreements with these collaborators or with future collaborators for the development and commercialization of our ACT product candidates

agreements with this collaborator or with future collaborators for the development and commercialization of our ACT product candidates

through collaborations such as joint development or licensing agreements.

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If we experience delays or difficulties in

identifying and enrolling subjects in clinical trials, it may lead to delays in generating clinical data and the receipt of necessary

identifying and enrolling patients in clinical trials, it may lead to delays in generating clinical data and the receipt of necessary

regulatory approvals.

Clinical trials of a new drug candidate require the

enrollment of a sufficient number of subjects, including subjects who are suffering from the disease or condition the drug candidate is

intended to treat and who meet other eligibility criteria.

Rates of subject enrollment are affected by many factors, and delays in subject

enrollment can result in increased costs and longer development times, which could materially and adversely impact our business and financial

We may experience slower than expected subject enrollment, including as a result of the coronavirus pandemic, in our current

or future clinical trials.

In addition, clinical trials for drug candidates that treat the same indications as our product candidates

may result in subjects who would otherwise be eligible for our clinical trials instead enrolling in clinical trials for other drug candidates.

Clinical trials of a new drug or biologic candidate

require the enrollment of a sufficient number of patients, including patients who are suffering from the disease or condition the drug

or biologic candidate is intended to treat and who meet other eligibility criteria.

Rates of patient enrollment are affected by many factors,

and delays in patient enrollment can result in increased costs and longer development times, which could materially and adversely impact

our business and financial condition.

We may experience slower than expected patient enrollment in our current or future clinical trials.

In addition, clinical trials for drug or biologic candidates that treat the same indications as our product candidates may result in patients

who would otherwise be eligible for our clinical trials instead enrolling in clinical trials for other drug or biologic candidates.

Topline data may not accurately reflect or

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of our product candidates may be materially impacted.

We depend upon third-party CROs, medical institutions,

clinical investigators, consultants and other third-parties to support and conduct our clinical trials and rely on these third-party CROs

for the execution of certain of our preclinical studies and expect to continue to do so.

Because we rely on these third-parties, we cannot

necessarily control the timing, quality of work or amount of resources that our contract partners will devote to these activities.

and our CROs are responsible for ensuring that our clinical trials are conducted in accordance with applicable regulations and protocols.

If we or our CROs fail to comply with these applicable regulations, the FDA, or equivalent foreign regulatory authority, may not accept

We rely upon third-party CROs, medical institutions,

collaborators, clinical investigators, consultants and other third-parties to support and conduct our clinical trials and we rely on these

third-party CROs for the execution of certain of our preclinical studies and expect to continue to do so.

Because we rely on these third-parties,

we cannot necessarily control the timing, quality of work or amount of resources that our contract partners will devote to these activities.

We, our collaborators, and our CROs are responsible for ensuring that our clinical trials are conducted in accordance with applicable

regulations and protocols.

If we, our collaborators, or our CROs fail to comply with these applicable regulations, the FDA may not accept

these data and may require us to complete additional preclinical studies and clinical trials, which could result in significant additional

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trials may need to be extended, delayed, terminated or repeated, and we may not be able to obtain regulatory approval in a timely fashion,

or at all, for the applicable drug candidate, or to commercialize such drug candidate being tested in such studies or trials.

France adopted the General Data Protection

Regulation, a data privacy regulation, and as we are conducting a clinical trial in France we are required to follow this law, which,

if violated, could subject us to significant fines.

The collection and use of personal health data and

other personal information in the European Union is governed by the provisions of the GDPR, which came into force in May 2018 and related

implementing laws in individual EU Member States.

The GDPR imposes a number of strict obligations and

restrictions on the ability to process (processing includes collection, analysis and transfer of) personal data of individuals within

the EU and in the EEA, including health data from clinical trials and adverse event reporting.

The GDPR also includes requirements relating

to the consent of the individuals to whom the personal data relates, the information provided to the individuals prior to processing their

personal data or personal health data, notification of data processing obligations to the national data protection authorities and the

security and confidentiality of the personal data.

EU Member States may also impose additional requirements in relation to health, genetic

and biometric data through their national implementing legislation.

Under the GDPR, personal data can only be transferred

within the EU Member States and the three additional EEA countries (Norway, Iceland and Liechtenstein) that have adopted a national law

implementing the GDPR.

Appropriate safeguards are required to enable cross-border transfers of personal data from the EU and EEA Member

States to a “third country” (a country outside the EU or EEA).

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 prohibits the transfer of personal data

to countries outside of the EU/EEA (including the United States) that are not considered by the EC to provide an adequate level of data

protection, except if the data controller meets very specific requirements such as the use of standard contractual clauses (“ SCC s”),

issued by the EC.

In this respect recent legal developments in Europe have created complexity and compliance uncertainty regarding

certain transfers of personal data from the EU/EEA.

For example, following the Schrems II decision of the Court of Justice of the EU on

July 16, 2020, in which the Court invalidated the Privacy Shield under which personal data could be transferred from the EU/EEA to United

States entities who had self-certified under the Privacy Shield scheme, there is uncertainty as to the general permissibility of international

data transfers under the GDPR.

The Court did not invalidate the then current SCCs, but ruled that data exporters relying on these SCCs

are required to verify, on a case-by-case basis, if the law of the third country ensures an adequate level of data protection that is

essentially equivalent to that guaranteed in the EU/EEA.

In light of the implications of this decision we may face difficulties regarding

the transfer of personal data from the EU/EEA to third countries, such as the United States.

However, on June 4, 2021 the EC issued a

new set of SCCs for data transfers from controllers or processors in the EU/EEA to controllers or processors established outside the EU/EEA.

These SCCs replace the old sets of SCCs that were adopted under the previous European Data Protection Directive 95/46.

Since September

27, 2021, it is no longer possible to conclude contracts incorporating these previous versions of the SCCs.

In addition, for contracts

concluded before September 27, 2021, it is still possible to rely on the previous SCCs until the end of an additional 15 months transitional

period (until December 27, 2022), provided that the processing operations which are the subject matter of the contract remain unchanged

and reliance on previous SCCs ensures that the transfer is subject to appropriate safeguards.

On November 11, 2021, the European Data

Protection Board adopted recommendations on such appropriate safeguards that supplement transfer mechanisms.

These recommendations aim

to assist data exporters with their duty to identify and implement appropriate supplementary measures where they are needed to ensure

an essentially equivalent level of protection to the personal data they transfer to third countries.

Failure to comply with the requirements of the

GDPR and the related national data protection laws of the EU Member States may result in significant monetary fines for noncompliance

of up to €20 million or 4% of the annual global revenues of the noncompliant company, whichever is greater, other administrative

penalties and a number of criminal offenses (punishable by uncapped fines) for organizations and in certain cases their directors and

officers as well as civil liability claims from individuals whose personal data was processed.

Data protection authorities from the different

EU Member States may still implement certain variations, enforce the GDPR and national data protection laws differently, and introduce

additional national regulations and guidelines, which adds to the complexity of processing personal data in the EU.

Guidance developed

at both EU level and at the national level in individual EU Member States concerning implementation and compliance practices are often

updated or otherwise revised.

Ensuring compliance with GDPR is time-intensive and may increase the cost of doing business, and failure

to comply with these laws may have a material impact on our operations and financial condition.

There is, moreover, a growing trend towards required

public disclosure of clinical trial data in the EU which adds to the complexity of obligations relating to processing health

data from clinical trials.

Such public disclosure obligations are provided in the new EU Clinical Trials Regulation, EMA disclosure initiatives

and voluntary commitments by industry.

Failing to comply with these obligations could lead to government enforcement actions and significant

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 GDPR, further adds to the complexity that we face

with regard to data protection regulation.

On June 28, 2021 the European Commission adopted

two adequacy decisions for the UK – one under the GDPR and the other for the Law Enforcement Directive.

data may now freely flow from the EU to the UK since the UK is deemed to have an adequate data protection level.

Additionally, following

the UK's withdrawal from the EU and the EEA, companies also have to comply with the UK’s data protection laws (including the UK

GDPR, which is based on the EU GDPR), the latter regime having the ability to separately fine up to the greater of £17.5 million

or 4% of global turnover.

The adequacy decisions include a ‘sunset clause’ which entails that the decisions will automatically

expire four years after their entry into force.

or at all, for the applicable drug or biologic candidate, or to commercialize such drug or biologic candidate being tested in such studies

A number of different factors could prevent

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Before obtaining regulatory approval for the sale

of any drug candidate, we must conduct extensive preclinical tests and successful clinical trials to demonstrate the safety and efficacy

of our product candidates in humans.

Before human clinical trials may commence, we must submit to the FDA an IND application, or foreign

An IND application involves the completion of preclinical studies and the submission of the results, together with proposed

clinical protocols, manufacturing information, analytical data and other data in the IND submission.

The FDA may require us to complete

additional preclinical studies or disagree with our clinical trial study design.

Also, animal models may not exist for some of the disease

areas we choose to develop our product candidates for.

As a result, our clinical trials may be delayed or we may be required to incur

more expense than we anticipated.

of any drug or biologic candidate, we must conduct extensive preclinical tests and successful clinical trials to demonstrate the safety

and efficacy of our product candidates in humans.

Before human clinical trials may commence, we must submit to the FDA an IND.

involves the completion of preclinical studies and the submission of the results, together with proposed clinical protocols, manufacturing

information, analytical data and other data in the IND submission.

The FDA may require us to complete additional preclinical studies or

disagree with our clinical trial study design.

Also, animal models may not exist for some of the disease areas we choose to develop our

product candidates for.

As a result, our clinical trials may be delayed or we may be required to incur more expense than we anticipated.

Clinical trials require the review and oversight

of IRBs, which approve and continually review clinical investigations and protect the rights and welfare of human subjects.

clinical trials can begin, we must also submit to the FDA a clinical protocol accompanied by the approval of the IRB at the institution(s)

participating in the clinical trial.

An inability or delay in obtaining IRB approval could prevent or delay the initiation and completion

of our clinical trials, and the FDA may decide not to consider any data or information derived from a clinical investigation not subject

to initial and continuing IRB review and approval.

of IRBs, which approve and continually review clinical investigations and protect the rights and welfare of patients.

Before our clinical

trials can begin, we must also submit to the FDA a clinical protocol accompanied by the approval of the IRB at the institution(s) participating

in the clinical trial.

An inability or delay in obtaining IRB approval could prevent or delay the initiation and completion of our clinical

trials, and the FDA may decide not to consider any data or information derived from a clinical investigation not subject to initial and

continuing IRB review and approval.

Preclinical studies and clinical trials are lengthy

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Historical failure rates are high due to a number of factors, such as safety and

efficacy of drug candidates.

We, our collaborators, the FDA, or an IRB may suspend clinical trials of a drug candidate at any time for

various reasons, including if we or they believe the subjects participating in such trials are being exposed to unacceptable health risks.

Among other reasons, adverse side effects of a drug candidate on subjects in a clinical trial could result in the FDA or other regulatory

authorities suspending or terminating the clinical trial and refusing to approve a particular drug candidate for any or all indications

We also are subject to numerous foreign regulatory

requirements governing the conduct of clinical trials, manufacturing and marketing authorization, pricing and third-party reimbursement.

The foreign regulatory approval process includes all of the risks associated with the FDA approval described above, as well as risks attributable

to the satisfaction of local regulations in foreign jurisdictions.

Approval by the FDA does not assure approval by regulatory authorities

outside of the United States.

efficacy of drug or biologic candidates.

We, our collaborators, the FDA, or an IRB may suspend clinical trials of a drug or biologic candidate

at any time for various reasons, including if we or they believe the patients participating in such trials are being exposed to unacceptable

health risks.

Among other reasons, adverse side effects of a drug or biologic candidate on patients in a clinical trial could result in

the FDA suspending or terminating the clinical trial and refusing to approve a particular drug or biologic candidate for any or all indications

An additional number of factors could affect the

timing, cost or outcome of our drug development efforts, including the following:

Delays in filing or acceptance of initial drug applications for our product candidates;

Delays in filing or acceptance of INDs, NDAs, or BLA for our product candidates;

Difficulty in securing centers to conduct clinical trials;

Conditions imposed on us by the FDA or comparable foreign authorities regarding the scope or design of our clinical trials;

Conditions imposed on us by the FDA regarding the scope or design of our clinical trials;

Problems in engaging IRBs to oversee trials or problems in obtaining or maintaining IRB approval of studies;

Difficulty in enrolling subjects in conformity with required protocols or projected timelines;

Difficulty in enrolling patients in conformity with required protocols or projected timelines;

Third-party contractors failing to comply with regulatory requirements or to meet their contractual obligations to us in a timely manner;

Our drug candidates having unexpected and different chemical and pharmacological properties in humans than in laboratory testing and interacting with human biological systems in unforeseen, ineffective or harmful ways;

The need to suspend or terminate clinical trials if the participants are being exposed to unacceptable health risks;

Our drug or biologic candidates having unexpected and different chemical and pharmacological properties in humans than in laboratory testing and interacting with human biological systems in unforeseen, ineffective or harmful ways;

The need to suspend or terminate clinical trials, for example, if the participants are being exposed to unacceptable health risks;

Insufficient or inadequate supply or quality of our product candidates or other necessary materials necessary to conduct our clinical trials;

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Negative or inconclusive results from our clinical trials or the clinical trials of others for similar product candidates or inability to generate statistically significant data confirming the efficacy of the product being tested;

Changes in the FDA’s requirements for testing during the course of that testing;

The impact from the ongoing coronavirus pandemic;

Changes in the FDA’s requirements or expectations for testing during the course of that testing;

Reallocation of our limited financial and other resources to other clinical programs;

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Any delay or failure in obtaining required approvals may prevent us from completing our preclinical

studies or clinical trials and could have a material adverse effect on our ability to initiate or commercialize any drug candidate on

a timely basis, or at all.

Additionally, preclinical studies and clinical trials are lengthy and expensive and if our cash resources become

limited we may not be able to commence, continue or complete our clinical trials, which could have a material impact on our business,

studies or clinical trials and could have a material adverse effect on our ability to initiate or commercialize any drug or biologic candidate

on a timely basis, or at all.

Additionally, preclinical studies and clinical trials are lengthy and expensive and if our cash resources

become limited we may not be able to commence, continue or complete our clinical trials, which could have a material impact on our business,

financial condition, and results of operations.

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The biotechnology and pharmaceutical industries

have intense competition and contain a high degree of risk and there are many other companies actively engaged in the discovery, development

are intensely competitive, contain a high degree of risk and there are many other companies actively engaged in the discovery, development

and commercialization of products that may compete with our product candidates.

We face a number of competitors that have substantially

greater experience and greater research and development capabilities, staffing, financial, manufacturing, marketing, technical and other

resources than us, and we may not be able to successfully compete with them.

These companies include large and small pharmaceutical and

biotechnology companies, academic institutions, government agencies and other private and public research organizations.

Many of our competitors have substantially greater experience

and greater research and development capabilities, staffing, financial, manufacturing, marketing, technical and other resources than us,

and we may not be able to successfully compete with them.

These companies include large and small pharmaceutical and biotechnology companies,

academic institutions, government agencies and other private and public research organizations.

In addition, even if we are successful in developing

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A number of our competitors have already commenced clinical testing

of product candidates and may be more advanced than we are in the process of developing products.

If we are not first to market or are

unable to demonstrate superiority, on a cost-effective basis or otherwise, any products for which we are able to obtain approval may not

be successful.

Our competitors also compete with us in acquiring

technologies complementary to our INTASYL technology.

We may face competition with respect to product efficacy and safety, ease of use

and adaptability to modes of administration, acceptance by physicians, timing and scope of regulatory approvals, reimbursement coverage,

price and patent position, including dominant patent positions of others.

If we are not able to successfully obtain regulatory approval

or commercialize our product candidates, we may not be able to establish market share and generate revenues from our technology.

of product candidates and may be more advanced than we are in the process of developing such product candidates.

If we are not first to

market or are unable to demonstrate superiority, on a cost-effective basis or otherwise, any products for which we are able to obtain

approval may not be successful.

We also face competition acquiring technologies

complementary to our INTASYL technology.

Further, we may face competition with respect to product efficacy and safety, ease of use and

adaptability to modes of administration, acceptance by physicians, timing and scope of regulatory approvals, reimbursement coverage, price

and patent position, including dominant patent positions of others.

If we are not able to successfully obtain regulatory approval or commercialize

our product candidates, we may not be able to establish market share and generate revenues from our technology.

If we fail to attract, hire and retain qualified

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While we have entered

into an employment agreement with our Chief Executive Officer, they could leave at any time, in addition to our other employees, who are

into an employment agreement with our Chief Executive Officer, he could leave at any time, in addition to our other employees, who are

all “at will” employees.

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may not be able to recruit and retain the personnel we need.

The loss of the services of any key research, product development, regulatory

and technical personnel, or our inability to hire new personnel with the requisite skills, could restrict our ability to develop our product

The loss of the services of any key personnel, or our inability to hire new

personnel with the requisite skills, could restrict our ability to develop our product candidates.

We are subject to potential liabilities from

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or others who come into contact with our product candidates or approved products.

We will seek to obtain clinical trial insurance for

clinical trials that we conduct, as well as liability insurance for any products that we market.

However, there is no assurance that we

will be able to obtain insurance in the amounts we seek, or at all.

We anticipate that licensees who develop our products will carry liability

insurance covering the clinical testing of our product candidates and the marketing of those product candidates, if approved.

no assurance, however, that any insurance maintained by us or our licensees will prove adequate in the event of a claim against us.

we cannot successfully defend against product liability claims, we could incur substantial liabilities.

Even if claims asserted against

us are unsuccessful, they may divert management’s attention from our operations and we may have to incur substantial costs to defend

We have, and will seek to obtain, clinical trial insurance

for current and any future clinical trials that we conduct, as well as liability insurance for any products that we market.

However, there

is no assurance that we will be able to obtain insurance in the amounts we seek, or at all.

We anticipate that licensees who develop our

products will carry liability insurance covering the clinical testing of our product candidates and the marketing of those product candidates,

There is no assurance, however, that any insurance maintained by us or our licensees will prove adequate in the event of

a claim against us.

If we cannot successfully defend against product liability claims, we could incur substantial liabilities.

claims asserted against us are unsuccessful, they may divert management’s attention from our operations and we may have to incur

substantial costs to defend such claims.

Any of these outcomes could materially impact our business and financial condition.

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supply source for the required materials to manufacture our compounds.

Further, we have limited current good manufacturing practice (“ cGMP ”)

manufacturing capabilities and limited experience in scale-up of clinical supply as our internal capabilities are limited to small-scale

production of research material.

Accordingly, we are dependent upon third-party suppliers and contract manufacturers to obtain supplies

and manufacture our product candidates and we will need to either develop, contract for, or otherwise arrange for the necessary manufacturers

for these supplies.

There are a limited number of manufacturers that make

oligonucleotides and we currently contract with multiple manufacturers for the supply of our product candidates to reduce the risk of

supply interruption or availability.

However, there is no assurance that our supply of our product candidates will not be limited, interrupted,

of satisfactory quality or be available at acceptable prices.

For example, constraints on the supply chain and availability of resources

due to the ongoing coronavirus pandemic have resulted in delays and shortages at manufacturing facilities.

While we have engaged with

multiple manufacturers for the supply of our product candidates in order to mitigate the impact of the loss or delay of any one manufacturer,

there can be no assurance that our efforts will be successful.

If for any reason we are unable to obtain the clinical supply of our product

candidates from our current manufacturers, we would have to seek to contract with another major manufacturer.

If we or any of these manufacturers

are unable or unwilling to increase its manufacturing capacity or if we are unable to establish alternative arrangements on a timely basis

or on acceptable terms, the development and commercialization of such an approved product may be delayed or there may be a shortage in

Any inability to manufacture our product candidates or future approved drugs in sufficient quantities when needed would seriously

harm our business.

Approval of any of our product candidates will not

occur unless the manufacturing facilities are in compliance with the FDA’s cGMP regulations, or a foreign equivalent’s regulations,

in order to ensure that drug products are safe and that they consistently meet applicable requirements and specifications.

These requirements

are enforced by the FDA and other regulatory authorities through periodic inspections of the manufacturing facilities and can result in

enforcement action, such as warning letters, fines and suspension of production if they are found to not be in compliance with the regulations.

If our suppliers or manufacturers do not comply with the FDA or foreign regulations for our product candidates, we may experience delays

in timing or supply, be forced to manufacture our product candidates ourselves or seek to contract with another supplier or manufacturer.

If we are required to switch suppliers or manufacturers, we will be required to verify that the new supplier or manufacturer maintains

facilities and processes in line with cGMP regulations, which may result in delays, additional expenses, and may have a material adverse

effect on our ability to complete the development of our product candidates.

Further, we have limited cGMP manufacturing capabilities and limited

experience scaling up of clinical supply as our internal capabilities are limited to small-scale production of research material.

we are dependent upon third-party suppliers and contract manufacturers to obtain supplies and manufacture our product candidates and we

will need to either develop, contract for, or otherwise arrange for the necessary manufacturers for these supplies.

There are a limited number of manufacturers that

make oligonucleotides and we currently contract with multiple manufacturers for the supply of our product candidates to reduce the risk

of supply interruption or availability.

However, there is no assurance that our supply of our product candidates will not be limited,

interrupted, of satisfactory quality or be available at acceptable prices.

For example, constraints on the supply chain and availability

of resources have resulted in delays and shortages at manufacturing facilities.

While we have engaged with multiple manufacturers for

the supply of our product candidates in order to mitigate the impact of the loss or delay of any one manufacturer, there can be no assurance

that our efforts will be successful.

If for any reason we are unable to obtain the clinical supply of our product candidates from our

current manufacturers, we would have to seek to contract with another major manufacturer.

If we or any of these manufacturers are unable

or unwilling to increase its manufacturing capacity or if we are unable to establish alternative arrangements on a timely basis or on

acceptable terms, the development and commercialization of such an approved product may be delayed or there may be a shortage in supply.

Any inability to manufacture our product candidates or future approved drugs in sufficient quantities when needed would seriously harm

our business.

Approval of any of our product candidates will

not occur unless the manufacturing facilities are in compliance with the FDA’s cGMP regulations in order to ensure that drug products

are safe and that they consistently meet applicable requirements and specifications.

These requirements are enforced by the FDA through

periodic inspections of the manufacturing facilities and can result in enforcement action, such as warning letters, fines and suspension

of production if they are found to not be in compliance with the regulations.

If our suppliers or manufacturers do not comply with the

FDA regulations for our product candidates, we may experience delays in timing or supply, be forced to manufacture our product candidates

ourselves or seek to contract with another supplier or manufacturer.

If we are required to switch suppliers or manufacturers, we will

be required to verify that the new supplier or manufacturer maintains facilities and processes in line with cGMP regulations, which may

result in delays, additional expenses, and may have a material adverse effect on our ability to complete the development of our product

Unstable market and economic conditions,

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in a period of economic uncertainty and capital markets disruption, which has been significantly impacted by domestic and global monetary

and fiscal policy, geopolitical instability, an ongoing military conflict between Russia and Ukraine, and historically high domestic and

global inflation.

In particular, the conflict in Ukraine has exacerbated market disruptions, including significant volatility in commodity

prices, as well as supply chain interruptions, and has contributed to record inflation globally.

Federal Reserve and other central

banks may be unable to contain inflation through more restrictive monetary policy and inflation may increase or continue for a prolonged

period of time.

Inflationary factors, such as increases in the cost of clinical supplies, interest rates, overhead costs and transportation

costs may adversely affect our operating results.

We continue to monitor these events and the potential impact on our business.

we do not believe that inflation has had a material impact on our financial position or results of operations to date, we may be adversely

affected in the future due to domestic and global monetary and fiscal policy, supply chain constraints, consequences associated with the

coronavirus pandemic and the ongoing conflict between Russia and Ukraine, and such factors may lead to increases in the cost of manufacturing

and fiscal policy, geopolitical instability, ongoing military conflicts, and high domestic and global inflation.

Federal Reserve

and other central banks may be unable to contain inflation through more restrictive monetary policy and inflation may increase or continue

for a prolonged period of time.

Inflationary factors, such as increases in the cost of clinical supplies, interest rates, overhead costs

and transportation costs may adversely affect our operating results.

We continue to monitor these events and the potential impact on our

Although we do not believe that inflation has had a material impact on our financial position or results of operations to date,

we may be adversely affected in the future due to domestic and global monetary and fiscal policy, supply chain constraints, consequences

associated with the coronavirus pandemic and the ongoing military conflicts, and such factors may lead to increases in the cost of manufacturing

our product candidates and delays in initiating studies.

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availability, declines in consumer confidence, declines in economic growth, uncertainty about economic stability and increased inflation.

There can be no assurance that further deterioration

in credit and financial markets and confidence in economic conditions will not occur.

There can be no assurance that deterioration in

credit and financial markets and confidence in economic conditions will not occur.

Our general business strategy may be adversely affected

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If the current

equity and credit markets deteriorate, or do not improve, it may make any necessary debt or equity financing more difficult, more costly,

equity and credit markets deteriorate, or do not improve, it may make any necessary debt or equity financings more difficult, more costly,

and more dilutive.

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economic times, which could directly affect our ability to attain our operating goals.

Natural disasters, epidemic or pandemic disease

outbreaks, trade wars, political unrest or other events could disrupt our business or operations or those of our development partners,

manufacturers, regulators or other third parties with whom we conduct business now or in the future.

A wide variety of events beyond our control, including

natural disasters, epidemic or pandemic disease outbreaks (such as the coronavirus pandemic), trade wars, political unrest or other events

could disrupt our business or operations or those of our manufacturers, regulatory authorities, or other third parties with whom we conduct

These events may cause businesses and government agencies to be shut down, supply chains to be interrupted, slowed, or rendered

inoperable, and individuals to become ill, quarantined, or otherwise unable to work and/or travel due to health reasons or governmental

restrictions.

These limitations could negatively affect our business operations and continuity, and could negatively impact our development

timelines and ability to timely perform basic business functions, including preparing and filing financial reports.

If our operations

or those of third parties with whom we have business are impaired or curtailed as a result of these events, the development and commercialization

of our products and product candidates could be impaired or halted, which could have a material adverse impact on our business.

Our business and operations would suffer

in the event of computer system failures, cyberattacks or a deficiency in our cybersecurity.

Despite the implementation of security measures,

our internal computer systems and those of our third-party contractors and collaborators are vulnerable to damage from computer viruses,

unauthorized access, natural disasters, terrorism, war and telecommunication and electrical failures, cyberattacks or cyber-intrusions

over the Internet, attachments to emails, persons inside our organization, or persons with access to systems inside our organization.

The risk of a security breach or disruption, particularly through cyber-attacks or cyber intrusion, including by computer hackers, foreign

governments, and cyber terrorists, has generally increased as the number, intensity and sophistication of attempted attacks and intrusions

from around the world have increased.

Such an event could cause interruption of our operations.

As part of our business, we and our third-party

contractors and collaborators maintain large amounts of confidential information, including non-public personal information on patients

and our employees.

Breaches in security could result in the loss or misuse of this information, which could, in turn, result in potential

regulatory actions or litigation, including material claims for damages, interruption to our operations, damage to our reputation or otherwise

have a material adverse effect on our business, financial condition and operating results.

We expect to have appropriate information security

policies and systems in place in order to prevent unauthorized use or disclosure of confidential information, including non-public personal

information, but there can be no assurance that such use or disclosure will not occur.

Risks Relating to Our Intellectual Property

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To acquire new technologies, licenses or products.

We are dependent on obtaining funding from third parties,

such as proceeds from the issuance of debt, sale of equity or strategic opportunities, in order to maintain our operations.

assure you that additional financing will be available to us on acceptable terms, or at all.

If we cannot, or are limited in the ability

to, issue equity, incur debt or enter into strategic collaborations, we may be unable to fund the discovery and development of our product

candidates or improve our technology.

If we fail to obtain additional funding when needed, we may ultimately be unable to continue to

develop and potentially commercialize our product candidates, and we may be forced to scale back or terminate our operations or seek to

merge with or be acquired by another company.

We are dependent on obtaining funding from third

parties, such as proceeds from the issuance of debt, sale of equity or strategic opportunities, in order to maintain our operations.

cannot assure you that additional financing will be available to us on acceptable terms, or at all.

If we cannot, or are limited in the

ability to, issue equity, incur debt or enter into strategic collaborations, we may be unable to fund the discovery and development of

our product candidates or improve our technology.

If we fail to obtain additional funding when needed, we may ultimately be unable to

continue to develop and potentially commercialize our product candidates, and we may be forced to scale back or terminate our operations

or seek to merge with or be acquired by another company.

We have a history

of net losses, and we expect to continue to incur net losses for the foreseeable future and may not achieve or maintain profitability.

We have generated significant

losses to date, have not generated any product revenue and may not generate product revenue in the foreseeable future, or ever.

to incur significant operating losses as we advance our product candidates through drug development and the regulatory process.

to achieve profitability, if ever, will depend on, among other things, us or our collaborators, obtaining regulatory approvals and successfully

commercializing our drug candidates.

Even if we are able to successfully commercialize our drug candidates, we may not be able to achieve

or sustain profitability, which could have a material adverse effect on our business, financial condition and results of operations.

We have generated significant losses to date, have

not generated any product revenue and may not generate product revenue in the foreseeable future, or ever.

We expect to incur significant

operating losses as we advance our product candidates through drug development and the regulatory process.

Our ability to achieve profitability,

if ever, will depend on, among other things, us or our collaborators, obtaining regulatory approvals and successfully commercializing

our drug or biologic candidates.

Even if we are able to successfully commercialize our drug or biologic candidates, we may not be able

to achieve or sustain profitability, which could have a material adverse effect on our business, financial condition and results of operations.

Future financing may be obtained through,

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to become profitable.

Changes in our operating plans, our existing and

anticipated working capital needs, the acceleration or modification of our expansion plans, increased expenses, potential acquisitions

or other events will all affect our ability to continue as a going concern.

The Company has limited cash resources, has reported recurring

losses from operations since inception and has not yet received product revenues.

These factors raise substantial doubt regarding the

Company’s ability to continue as a going concern, and the Company’s current cash resources may not provide sufficient capital

to fund operations for at least the next 12 months from the date of the release of these financial statements.

The continuation of the

Company as a going concern depends upon the Company’s ability to raise additional capital through an equity offering, debt offering

or strategic opportunity to fund its operations.

There can be no assurance that the Company will be successful in accomplishing these

plans in order to continue as a going concern.

Any such inability to continue as a going concern may result in our common stockholders

losing their entire investment.

Changes in our operating plans, our existing and anticipated

working capital needs, the acceleration or modification of our expansion plans, increased expenses, potential acquisitions or other events

will all affect our ability to continue as a going concern.

We have limited cash resources, have reported recurring losses from operations

since inception, negative operating cashflows and have not yet received product revenues.

These factors raise substantial doubt regarding

our ability to continue as a going concern, and the Company’s current cash resources may not provide sufficient capital to fund

operations for at least the next 12 months from the date of the release of the consolidated financial statements included elsewhere in

this Annual Report.

The continuation of the Company as a going concern depends upon our ability to raise additional capital through equity

offerings, debt offerings and/or strategic opportunities to fund our operations.

There can be no assurance that we will be successful

in accomplishing these plans in order to continue as a going concern.

Any such inability to continue as a going concern may result in

our common stockholders losing their entire investment.

There is no guarantee that we will become profitable or secure additional financing.

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net operating loss carryforwards and other tax benefits may be limited.

We have historically

incurred net losses and may never achieve or sustain profitability.

Under the Internal Revenue Code of 1986, as amended (the

“ Code ”), a corporation is generally allowed a deduction for net operating losses carried forward from a prior

taxable year.

Under that provision, we can carryforward our net operating losses to offset our future taxable income, if any, until

such net operating losses are used or expire.

Net operating losses incurred in tax years beginning after December 31, 2017 may be

carried forward indefinitely, but are limited to offset up to 80% of future taxable income.

Certain of our net operating loss

carryforwards predating December 31, 2017 could expire unused before offsetting potential future income tax liabilities.

We have historically incurred

net losses and may never achieve or sustain profitability.

Under the Internal Revenue Code of 1986, as amended (the “ Code ”),

a corporation is generally allowed a deduction for net operating losses carried forward from a prior taxable year.

Under that provision,

we can carryforward our net operating losses to offset our future taxable income, if any, until such net operating losses are used or

Net operating losses incurred in tax years beginning after December 31, 2017 may be carried forward indefinitely, but are limited

to offset up to 80% of future taxable income.

Certain of our net operating loss carryforwards predating December 31, 2017 could expire

unused before offsetting potential future income tax liabilities.

Additionally, an ownership

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loss or tax credit carryforwards before utilization.

During 2021, the Company completed

an assessment of the available net operating loss and tax credit carryforwards under Section 382 and 383 and determined that the Company

underwent multiple ownership changes during the period from 2012 to 2021.

As a result, our net operating losses and tax credit carryforwards

are subject to substantial annual limitations under Section 382 and 383 due to these ownership changes.

The Company has adjusted its net

operating loss and tax credit carryforwards to address the impact of the ownership changes.

The Company assesses the need to conduct an

ownership change analysis to determine whether any changes occurred in ownership that would limit net operating loss or tax credit carryforwards

on an annual basis.

We may experience ownership changes in the future as a result of subsequent shifts in our stock ownership, some of

which may be outside of our control.

If an ownership change occurs and our ability to use our net operating loss and tax credit carryforwards

is materially limited, it could harm our future operating results by effectively increasing our future tax obligations.

We have completed multiple assessments of the

available net operating loss and tax credit carryforwards under Sections 382 and 383 of the Code through the year ended December 31,

2023 and determined that we underwent multiple ownership changes during the period from inception to 2023.

As a result, our net operating

losses and tax credit carryforwards are subject to substantial annual limitations under Sections 382 and 383 of the Code due to these

ownership changes.

The Company has adjusted its net operating loss and tax credit carryforwards to address the impact of the ownership

We assess the need to conduct an ownership change analysis to determine whether any changes occurred in ownership that would

limit net operating loss or tax credit carryforwards on an annual basis.

We may experience ownership changes in the future as a result

of subsequent shifts in our stock ownership, some of which may be outside of our control.

If an ownership change occurs and our ability

to use our net operating loss and tax credit carryforwards is materially limited, it could harm our future operating results by effectively

increasing our future tax obligations.

Risks Relating to Our Securities

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Announcements regarding clinical trial results or development announcements concerning our competitors product candidates;

Regulatory or legal developments in the United States and other countries;

Regulatory or legal developments in the United States;

The recruitment or departure of key personnel;

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To acquire new technologies, licenses or products;

Natural disasters and calamities, including the coronavirus pandemic;

General economic, industry and market conditions.

The stock markets, in general, and the markets for

drug delivery and pharmaceutical company stocks, in particular, have experienced extreme volatility, that has often been unrelated to

the operating performance of particular companies.

These broad market fluctuations may adversely affect the trading price of our common

stock and could result in the loss of all or part of your investment.

In addition, the limited trading volume of our stock may contribute

to its volatility.

Moreover, if we are unable to trade above $1.00 for a certain period of time, or fulfill the other continued listing

standards, The Nasdaq Stock Market may delist our common stock.

Delisting our common stock from Nasdaq would adversely affect our trading

volume and would likely negatively impact our trading price.

The stock markets, in general, and the markets

for drug delivery and pharmaceutical company stocks, in particular, have experienced extreme volatility, that has often been unrelated

to the operating performance of these particular companies.

These broad market fluctuations may adversely affect the trading price of

our common stock and could result in the loss of all or part of your investment.

In addition, the limited trading volume of our stock

may contribute to its volatility.

Moreover, if we are unable to trade above $1.00 for a certain period of time, or fulfill the other continued

listing standards, The Nasdaq Stock Market (“ Nasdaq ”) may delist our common stock.

Delisting our common stock from

Nasdaq would adversely affect our trading volume and would likely negatively impact our trading price.

We may not be able to regain compliance with

the continued listing requirements of The Nasdaq Capital Market.

On January 24, 2024, we received notice (the “ Notification

Letter ”) from Nasdaq notifying us that we are not in compliance with the minimum bid price requirements set forth in Nasdaq

Listing Rule 5550(a)(2) for continued listing on The Nasdaq Capital Market.

Nasdaq Listing Rule 5550(a)(2) requires listed securities

to maintain a minimum bid price of $1.00 per share, and Listing Rule 5810(c)(3)(A) provides that a failure to meet the minimum bid price

requirement exists if the deficiency continues for a period of 30 consecutive business days.

Based on the closing bid price of our common

stock for the 30 consecutive business days prior to the date of the Notification Letter, we no longer meet the minimum bid price requirement.

The Notification Letter does not impact our listing

on The Nasdaq Capital Market at this time.

The Notification Letter states that we have 180 calendar days, or until July 22, 2024, to regain

To regain compliance, the bid price of our common stock must have a closing bid price of at least $1.00 per share for a minimum

of 10 consecutive business days at any time prior to July 22, 2024.

In the event that we do not regain compliance by July 22, 2024, we

may be eligible for additional time to reach compliance with the minimum bid price requirement.

However, if we fail to regain compliance

with the minimum bid price listing requirement or fail to maintain compliance with all other applicable continued listing requirements

and Nasdaq determines to delist our common stock, the delisting could adversely impact us by, among other things, reducing the liquidity

and market price of our common stock;

reducing the number of investors willing to hold or acquire our common stock;

limiting our ability

to issue additional securities in the future;

and limiting our ability to fund our operations.

Our Board of Directors has the authority

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We are authorized to issue up to 10,000,000 shares

of preferred stock in one or more series and as of the year ended December 31, 2022 had one share of Series D Preferred Stock outstanding,

which was subsequently redeemed in full in January 2023 and is no longer outstanding.

Our Board of Directors (the “ Board ”)

may determine the terms of future preferred stock offerings without further action by our stockholders.

The issuance of our preferred

stock could affect the rights of existing stockholders or reduce the value of our outstanding preferred stock or common stock.

In particular,

rights granted to holders of certain series of preferred stock may include voting rights, preferences as to dividends and liquidation,

conversion and redemption rights and restrictions on our ability to merge with or sell our assets to a third party.

of preferred stock in one or more series.

Our Board of Directors (the “ Board ”) may determine the terms of future preferred

stock offerings without further action by our stockholders.

The issuance of our preferred stock could affect the rights of existing stockholders

or reduce the value of our outstanding preferred stock or common stock.

In particular, rights granted to holders of certain series of

preferred stock may include voting rights, preferences as to dividends and liquidation, conversion and redemption rights and restrictions

on our ability to merge with or sell our assets to a third party.

We may acquire other businesses or form joint

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Establish advance notice requirements for nominations for election to our Board or for proposing matters that can be acted upon by stockholders at stockholder meetings.

Although we believe these provisions collectively provide

for an opportunity to receive higher bids by requiring potential acquirers to negotiate with our Board, they would apply even if the offer

may be considered beneficial by some stockholders.

In addition, these provisions may frustrate or prevent any attempts by our stockholders

to replace or remove our current management team by making it more difficult for stockholders to replace members of our Board, which is

responsible for appointing the members of our management.

Although we believe these provisions collectively

provide for an opportunity to receive higher bids by requiring potential acquirers to negotiate with our Board, they would apply even

if the offer may be considered beneficial by some stockholders.

In addition, these provisions may frustrate or prevent any attempts by

our stockholders to replace or remove our current management team by making it more difficult for stockholders to replace members of our

Board, which is responsible for appointing the members of our management.

Moreover, because we are incorporated in Delaware,

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in which the person acquired in excess of 15% of our outstanding voting stock, unless the merger or combination is approved in a prescribed

UNRESOLVED STAFF COMMENTS

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 1A. Risk Factors