What changed in this filing

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Item 1. Business

2024-03-15 compared with 2023-03-30 · 227 added, 321 removed, 1097 unchanged (33% of the section changed)

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The TAAP platform is designed to seek to improve the care of patients with chronic pain while reducing the

human and economic costs associated with prescription opioid drug abuse.The MPAR™ platform when combined with our TAAP prodrugs

human and economic costs associated with prescription opioid drug abuse.

The MPAR® platform when combined with our TAAP prodrugs

is designed not only to seek to prevent abuse of prescription drugs but also to reduce overdose occurrences.

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July 2022 and a nasal human abuse potential (HAP) study was completed in October 2022.

A second oral HAP study has been initiated in

September 2022 and data is expected in early 2023.

MPAR™ technology is designed to limit the bioavailability of active opioid following co-ingestion of multiple doses, whether inadvertent

or intentional, through a combination of a TAAP prodrug with nafamostat.

Nafamostat is a small molecule that clinical studies have shown

to have a steep dose response curve and to be a highly potent trypsin inhibitor.

When combined with our TAAP prodrugs, our MPAR technology

is designed not to affect metabolism and the release of the active pharmaceutical ingredient.

However, if the MPAR combination product

is taken in larger quantities than intended, the excess nafamostat is designed to inhibit trypsin, thereby preventing metabolic activation

and averting a drug overdose.

We believe the potential benefits to society of an opioid that resists both oral and parenteral abuse are

considerable.

A Phase 1 study to explore the combination of PF614 and nafamostat, PF614-MPAR-101 was initiated in December of 2021, and

early data from the study reported in May 2022 demonstrated the combination product showed overdose protection, with a reduction in the

release of oxycodone over that of PF614 delivered alone.

A second oral HAP study was completed in March

Most recently, a study to evaluate efficacy was completed in December 2023.

MPAR ® technology is designed to limit the bioavailability of active opioid following co-ingestion of multiple doses, whether

inadvertent or intentional, through a combination of a TAAP prodrug with nafamostat.

Nafamostat is a small molecule that clinical studies

have shown to have a steep dose response curve and to be a highly potent trypsin inhibitor.

When combined with our TAAP prodrugs, our

MPAR ® technology is designed not to affect metabolism and the release of the active pharmaceutical ingredient.

if the MPAR ® combination product is taken in larger quantities than intended, the excess nafamostat is designed to inhibit

trypsin, thereby preventing metabolic activation and averting a drug overdose.

We believe the potential benefits to society of an opioid

that resists both oral and parenteral abuse are considerable.

A Phase 1 study to explore the combination of PF614 and nafamostat, PF614-MPAR-101

was initiated in December of 2021, and early data from the study reported in May 2022 demonstrated the combination product showed overdose

protection, with a reduction in the release of oxycodone over that of PF614 delivered alone.

A second part of this trial to confirm overdose

protection from PF614-MPAR 25 mg was completed in 2023 and data reported in May 2023.

PF614-MPAR was granted Breakthrough Therapy designation

by the FDA in January 2024.

pipeline has been developed over the course of 15 years of research and investment and includes three clinical-stage product candidates.

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(IR) tablets 40 mg (equivalent opioid doses) and placebo following intranasal administration.

In study 2, PF614-104 which is ongoing,

we are evaluating the oral abuse potential of intact PF614 at 3 different dose levels 50, 100 and 200 mg to IR oxycodone 40 mg and placebo.

The purpose of this study is to assess the pharmacokinetics (PK) and human abuse potential of oral PF614 and data is expected is 2023.

We believe PF614 has the potential to provide a safer alternative to the abuse deterrent formulated opioid products that are currently

commercially available.

In study 2, PF614-104, we evaluated the

oral abuse potential of intact PF614 at 3 different dose levels 50, 100 and 200 mg to IR oxycodone 40 mg and placebo.

The purpose of

this study is to assess the PK and human oral abuse potential of PF614.

An efficacy study, PF614-201 was conducted to evaluate 50 and

100 mg PF614 in 16 healthy male subjects for the time of onset of pain relief and the ability of PF614 to relieve pain.

The data will

be used to design our Phase 3 clinical trials.

We believe PF614 has the potential to provide a safer alternative to the abuse deterrent

formulated opioid products that are currently commercially available.

a combination product of PF614 and nafamostat has been designed to limit abuse potential by providing resistance to use through injection

or inhalation and to provide overdose protection against excessive oral ingestion.

Our IND application (150966) for PF614-MPAR™

received FDA allowance on April 27, 2021 following the release of a Full Clinical Hold from January 8, 2021.

We addressed deficiencies

from the initial IND submission, amended the protocol and submitted a response to the clinical hold letter on March 29, 2021.

a Phase 1 clinical trial, PF614-MPAR-101, to evaluate safety and PK in healthy subjects in December 2021.

Initial data from this trial

was reported in May of 2022.

The PF614-MPAR-101 overdose protection study examined PF614 administered orally alone or in combination

with the trypsin inhibitor nafamostat (MPAR) to healthy volunteers.

Our IND application (150966) for PF614-MPAR received

FDA allowance on April 27, 2021 following the release of a Full Clinical Hold from January 8, 2021.

We addressed deficiencies from the

initial IND submission, amended the protocol and submitted a response to the clinical hold letter on March 29, 2021.

We initiated a Phase

1 clinical trial, PF614-MPAR-101, to evaluate safety and PK in healthy subjects in December 2021.

Initial data from this trial was reported

in May of 2022.

The PF614-MPAR-101 overdose protection study examined PF614 administered orally alone or in combination with the trypsin

inhibitor nafamostat (MPAR ® ) to healthy volunteers.

The initial data demonstrated the overdose protection of our MPAR ®

combination product, with reduced release of oxycodone from PF614 in a simulated overdose situation.

It also demonstrated the PF614 in

the systemic circulation (simulated injection) did not convert to oxycodone.

It also demonstrated the PF614

in the systemic circulation (simulated injection) did not convert to oxycodone.

We completed the clinical portion and reported data from

Part A of this study in December 2022.

The study will continue in 2023 to test the overdose protection of the selected formulation by

administering an escalating number of dose units to a group of healthy subjects.

Data is expected in the second half of 2023.

Part B of the study to test the overdose protection of the selected PF614-MPAR 25 mg formulation

by administering an escalating number of dose units to a group of healthy subjects completed enrollment in March 2023.

The PK data from

Part B successfully showed that PF614-MPAR ® 25 mg administered at a prescribed dose of one or two dose units (capsules)

provided oxycodone in an equivalent manner to PF614 without MPAR ® .

However, the simultaneous administration of 3 dose

units or greater of PF614-MPAR 25 mg, resulted in reduced oxycodone in the circulation, as compared to the unprotected PF614.

a highly significant difference between the oxycodone blood levels following delivery of PF614 200 mg versus 8 dose units of PF614-MPAR

25 mg (200 mg PF614 total) demonstrating the overdose protection produced by the MPAR ® technology.

This was reported in

PF614-MPAR was granted Breakthrough Therapy designation by the FDA in January 2024.

is being tested clinically in partnership with Quotient Sciences, using its integrated Translational Pharmaceutics® platform to search

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died each day from opioid-related overdoses.

Currently, that number has risen to approximately 188 deaths per day.

In 2021 the total number of opioid-related deaths rose to 109,600, with 45 people dying

each day from a prescription opioid overdose.

large increase in overall overdose deaths is now driven by use of synthetic opioids, in particular fentanyl, as prescription opioids

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processes needed for virus product, such as RNA replication or viral protein processing.

An inhaled form of nafamostat could be prescribed

for patients that have a more severe stage of the disease.

lead clinical program is an oral drug product of nafamostat for use against COVID-19 and other coronaviral infections.

The dosing and

positioning of oral nafamostat will be similar to antiviral drug oseltamivir phosphate, Tamiflu®.

Tamiflu® is a seasonal influenza

treatment that is taken in oral form within two days of influenza symptoms starting and applying a two-dosage daily schedule.

other coronavirus outbreaks, sales of Tamiflu® were $950 million in the US and $2.426 billion cumulative sales worldwide (2016-2020).

Sales of Paxlovid from Pfizer for COVID-19 totaled approximately $19 billion in 2022, an indication of the continuing unmet need for

treatments around the world.

World Health Organization estimates influenza epidemics result in approximately three to five million cases of severe illness and 290,000

to 650,000 deaths each year.

Nafamostat will be well positioned to generate revenue from several changing market conditions:

new virus strains of influenza and coronavirus create new outbreaks, there is a window of opportunity to grow or boost sales before

production of the appropriate vaccine is increased.

our antiviral in situations of waning immunity to vaccines, particularly in the elderly, and in immunocompromised patients;

influenza vaccines are approximately 45% effective since the 2010 influenza season.

are only four antiviral treatments for early symptoms of influenza for hospitalized patients that have severe, complicated, or progressive

illness, or who are at high risk for complications.

reality of unexpected and rapidly spreading influenza or coronavirus outbreaks causes healthcare systems to stockpile and replenish

first response antivirals.

a drug repurposing model and the Hatch Waxman Act, we believe that we will be able to receive eight to ten years of market exclusivity

in North America, European Union, and Japan.

See “— Intellectual Property ” for further detail.

Nafamostat delivered orally was evaluated in

a Phase 1 study for safety and tolerability with the anticipation of further evaluating an oral nafamostat drug product against COVID-19

in Phase 2 trials, however at this time the oral nafamostat program is not the company’s primary focus.

Technology Platform Solution

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been on opioid pain products and opioid use disorder products.

Our development pipeline of TAAP prodrugs is summarized in the table below.

Each prodrug is intended to be able to be combined with our MPAR™ technology for overdose protection.

Additionally, nafamostat,

which is an ingredient in our overdose protection combination products, is also being developed for infection and pulmonary lung diseases.

Besides our clinical candidates, we have a product portfolio of other TAAP and MPAR TM opioids that could potentially be developed

to build on this pipeline.

our clinical candidates, we have a product portfolio of other TAAP and MPAR TM opioids and amphetamines that could potentially

be developed to build on this pipeline.

Each prodrug is intended to be able to be combined with our MPAR®

technology for overdose protection.

Additionally, nafamostat, which is an ingredient in our overdose protection combination products,

may be developed for infection and pulmonary lung diseases.

Besides our clinical candidates, we have a product portfolio of other TAAP

and MPAR ® opioids and amphetamines that could potentially be developed to build on this pipeline.

is a chemically modified, extended-release oxycodone-derivative which releases clinically effective oxycodone only when exposed trypsin

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available, in a number of ways.

First, the abuse-resistance provided by PF614 is designed to be unaffected by simple physical manipulations

(e.g., extraction, chewing, and/or crushing).

It also limits the bioavailability of active medication following co-ingestion of multiple

First, the abuse-resistance provided by PF614 is retained even when dissolved in water and is designed

to be unaffected by simple physical manipulations (e.g., extraction, chewing, and/or crushing).

It also limits the bioavailability of

active medication following co-ingestion of multiple doses.

ingestion, the release of oxycodone from PF614 proceeds via a two-step process comprised of (1) trypsin activation in the small intestine

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The single ascending dose study also compared the release of oxycodone from PF614 under both fasted and fed

conditions at the highest does of PF614 evaluated, 200 mg.

conditions at the highest dose of PF614 evaluated, 200 mg.

The pharmacokinetics of the prodrug fragments was also evaluated.

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subjects achieved steady state after repeated oral BID dosing of PF614 and OxyContin at all dose levels.

A total of 57 subject were included in the PK analyses.

The data for C max , AUC 0-t , and AUC 0-inf of

oxycodone post 100 mg PF614 versus 40 mg OxyContin dosing under fasted and fed conditions were completely contained within the standard

A total of 57 subjects were included in the PK analyses.

The data for C max , AUC 0-t , and AUC 0-inf

of oxycodone post 100 mg PF614 versus 40 mg OxyContin dosing under fasted and fed conditions were completely contained within the standard

bioequivalence limits of 80% to 125%.

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The results demonstrated that inhaled powdered PF614 had significantly lower drug liking than inhaled crushed IR

2022 we initiated two human abuse potential studies of PF614 to understand the tendency for drug abusers to like the effects achieved

from taking PF614 either orally or intranasally as compared to that of a comparator product such as crushed oxycodone.

The data from

these studies will be used to support our application for ‘Abuse Deterrent’ labeling for PF614.

The data from the intranasal

study was reported on October 31, 2022 and the data from the oral study is expected to be available in early 2023.

We intend to explore

pain indications to evaluate PF614 for efficacy and safety which we are seeking to initiate in 2023.

We are also planning to evaluate

nafamostat in COVID-19 subjects when delivered as an oral drug product.

The ability to undertake these studies will depend on additional

We have funded our operations to date primarily with proceeds from the sale of equity and borrowings under convertible promissory

notes and federal grants.

See “ —Convertible Promissory Notes ” and “ —Federal Grants ”

for additional information.

Oral Human Abuse Potential Clinical Trial

was a randomized, double-blind, placebo- and active-controlled, 5-way crossover study to evaluate the abuse potential and pharmacokinetics

of orally administered PF614, relative to oxycodone IR tablets and placebo, in non-dependent recreational opioid users conducted by DVCR,

study consisted of 4 phases:

Screening, Qualification, Treatment, and Follow-up.

Subjects were randomized to receive PF614 50, 100 and

200 mg, oxycodone 40 mg or placebo orally.

The primary objective of the study was to evaluate the abuse potential of PF614 relative to

oxycodone immediate-release (IR) tablets and placebo following oral administration in non-dependent recreational opioid users (n=28),

with the primary pharmacodynamic endpoint being the maximum effect (E max ) for Drug Liking (“ at this moment ”)

and “Take Drug Again” Emax (Secondary endpoint) measured up to 24 hours after dosing using a visual analogue scale (VAS).

The secondary objectives of the study were to evaluate the pharmacokinetic profile of PF614 relative to oxycodone IR tablets and to evaluate

the safety of PF614.

produced statistically lower effects than oxycodone, the lowest dose p<0.0001, and statistically significant overall “Drug Liking”

at both the low and the mid doses p<0.0001 and p=0.0025, respectively.

PF614 took a significantly lower median time to reach Emax

for “Drug Liking” than oxycodone at all three dose levels, which is highly important for reducing drug abuse.

Similar findings

were noted with a second endpoint “Take Drug Again”.

The secondary endpoint was met at both the low and mid dose of PF614

with highly significant values of p<0.001 and p=0.0038, respectively, and was numerically lower than comparator even at double the

dose, demonstrating that recreational users would be less motivated to abuse PF614 compared to immediate release oxycodone.

November 2022, we received written guidance from the FDA that an acute pain indication may be appropriate for PF614.

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acute pain indication may reduce the development timeline and be more cost-effective than initially pursuing a chronic pain indication

Time of Onset clinical study

was a randomized, double-blind, placebo-controlled study of PF614 50 and 100 mg to evaluate the onset of analgesia following administration

of a single oral dose of PF614 in healthy male subjects in an experimental pain model (cold pressor test [CPT]).

This study was initiated

in September of 2023 and enrolled 16 subjects.

The Treatment Phase consisted of 2 treatment periods;

PF614 50 mg or 100 mg versus placebo.

The CPT, pharmacodynamic (PD), and safety assessments were conducted prior to dosing and for six hours after each study drug administration.

This study was the first to successfully demonstrate the efficacy of PF614.

Data was reported December 2023, stating the time-of-onset

of pain relief from both doses of PF614 was identified, and PF614 did decrease the intensity of pain.

End of Phase 2 regulatory meeting request for PF614 IND 116794 was submitted on October 13, 2023, with a meeting was held on January

The meeting clarified the non-clinical and clinical Phase 3 study plans for the further development of PF614 which are expected

to initiate in mid-2024.

initiated a Phase 1 study that is evaluating PF614-MPAR in study entitled “A Single Dose, 2 Part Study to Evaluate the Pharmacokinetics

of Oxycodone, PF614, PFR06082, and nafamostat, when PF614 Solution is Co-Administered with nafamostat, as an Immediate Release Solution

and/or Extended Release (ER) Capsule Formulations in Healthy Subjects:” We are clinically testing MPAR in partnership with Quotient

Sciences, using its integrated Translational Pharmaceutics® platform to search for a PF614-MPAR formulation that allows conversion

of Oxycodone and PF614, when PF614 Solution is Co-Administered with nafamostat, as an Immediate Release Solution and/or Extended Release

(ER) Capsule Formulations in Healthy Subjects:” We are clinically testing MPAR ® in partnership with Quotient Sciences,

using its integrated Translational Pharmaceutics ® platform to search for a PF614-MPAR formulation that allows conversion

into oxycodone within the prescribed dose range but reduces conversion to oxycodone at higher than prescribed dose levels in an overdose

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more than the prescribed PF614-MPAR dose is taken.

Extended release prototype capsule formulations will be selected from a two-dimensional

design space describing formulation variables for release rate and dose.

Initial data was reported in May 2022 that demonstrated nafamostat

administer in combination with PF614 in a simulated overdose situation reduced the release of oxycodone from PF614 as designed.

the clinical portion of Part A of this study in December 2022 and expect to report final data from this portion of the study by the end

of December 2022.

The study will continue in 2023 to test the overdose protection of the selected formulation by administering an escalating

number of dose units to a group of healthy subjects.

Data is expected in the second half of 2023.

Phase 1 Clinical Trial

believe nafamostat has the potential to be effective in the treatment of patients with COVID-19 as it is an inhibitor of transmembrane

protease Serine 2 (TMPRSS2) the protease responsible for cleaving the spike protein of SARS-CoV-2.

While patients with COVID-19 typically

present with fever and a respiratory illness, some patients also report gastrointestinal symptoms, such as diarrhea, vomiting, and abdominal

Studies have identified the most recent strain of COVID-19 virus, SARS-CoV-2 RNA, in stool specimens of infected patients, and

its viral receptor angiotensin converting enzyme 2 was found to be highly expressed in gastrointestinal epithelial cells.

These suggest

that SARS-CoV-2 can actively infect and replicate in the gastrointestinal tract, and oral nafamostat which acts locally in the gut will

reduce the ability of the virus to replicate.

The purpose of our study was to evaluate the safety of oral nafamostat in healthy volunteers.

This was a three-part single ascending dose study (Part 1) examining safety and pharmacokinetics of single doses of 50, 100, and 200

mg nafamostat administered sequentially on three separate days to a single cohort of eight subjects.

The multiple ascending dose study

(Part 2) administered 100 mg nafamostat twice daily to four healthy subjects and evaluated safety and pharmacokinetic for five days.

A second cohort of four subjects received 200 mg nafamostat twice daily for five days and evaluated safety and pharmacokinetic.

group of six healthy subjects received 200 mg nafamostat the multiple fixed dose study (Part 3) to evaluate the safety and tolerability

of oral nafamostat solution administered three times daily.

Pharmacokinetic

was shown to have limited bioavailability at any dose level evaluated up to 200 mg.

were no drug-related adverse events reported for nafamostat delivered at 200 mg three times daily, therefore additional dose levels are

currently being examined for safety.

We concluded that 200 mg can be delivered three times daily which may provide local effects in the

gastrointestinal tract.

are planning to evaluate nafamostat in a Phase 2 clinical trial in COVID-19 subjects when delivered as an oral drug product.

200 mg capsules have been manufactured and are on stability evaluation.

Initial data was reported in May 2022 that demonstrated nafamostat administer in combination

with PF614 in a simulated overdose situation reduced the release of oxycodone from PF614 as designed.

We completed the clinical portion

of Part A of this study in December 2022, with the identification of an optimal drug product formulation.

A second, Part B was initiated

in January 2023 to test the overdose protection of the selected formulation by administering an escalating number of dose units to a

group of healthy subjects.

Enrollment was completed in March 2023.

B was a dose escalation study of PF614 25 mg alone, or increasing dose units of PF614-MPAR 25 mg (PF614 25 mg with 1 mg formulated nafamostat),

and enrolled 6 to 8 healthy subjects in each cohort.

PF614-MPAR 25 mg was delivered at 1, 2, 3, 5, and 8 doses simultaneously, with safety

and PK endpoints.

The plasma PK of oxycodone released from PF614 or PF614-MPAR was measured and compared to prior data where PF614 was

delivered up to 200 mg alone.

Additionally, the PK of parent PF614 and metabolic fragments were measured.

results of the study successfully demonstrated that up to 2 dose units of PF614-MPAR delivered oxycodone at the same level as was derived

from PF614 without MPAR ® .

At 3 units of PF614-MPAR the amount of oxycodone delivered was reduced compared to a 75 mg dose

At 8 dose units there was a significant decrease (p<0.00333) in the maximal oxycodone plasma concentration (Cmax) as compared

to that delivered from unprotected PF614 200 mg.

In addition, delivering 2 doses of PF614-MPAR sequentially, 12 hours apart did not affect

the release of oxycodone from the 2nd dose.

Data from this study was reported in May 2023.

was granted Breakthrough Therapy designation by the FDA in January 2024.

A Type D meeting request to discuss the non-clinical program

for PF614-MPAR was submitted in 2023 and responses to questions were received in February 2024.

life sciences industry is characterized by rapidly advancing technologies, intense competition, and a strong emphasis on proprietary

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There are only four commercially available (in the United States) opioid drugs for chronic pain relief that have an abuse-deterrent label.

These drugs are MorphaBond™ ER, marketed by Daiichi Sankyo, OxyContin® ER and Hysingla® ER, both of which are marketed

by Purdue Pharma, LP, and Collegium Pharmaceutical, Inc.’s XTampza®ER.

However, obtaining an abuse-deterrent label involves

a lengthy and complicated process with no certainty of success.

We believe abuse-deterrent opioids represent a therapeutic option to

maximize pain relief in patients for whom opioid analgesia is indicated, while reducing the risks of abuse and diversion.

These drugs are MorphaBond™ ER, marketed by Daiichi Sankyo, OxyContin ® ER and Hysingla ® ER, both

of which are marketed by Purdue Pharma, LP, and Collegium Pharmaceutical, Inc.’s XTampza ® ER.

However, obtaining

an abuse-deterrent label involves a lengthy and complicated process with no certainty of success.

We believe abuse-deterrent opioids

represent a therapeutic option to maximize pain relief in patients for whom opioid analgesia is indicated, while reducing the risks of

abuse and diversion.

number of other companies including, but not limited to, Pfizer Inc., Daiichi Sankyo, Endo Health Solutions, Nektar Therapeutics, Teva

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with various delivery technologies, but these products do not have abuse-deterrent claims on their labels.

Vertex has recently announced

a non-opioid pain product that inhibits NaV1.8 and has entered Phase 3 development.

do not believe there are other companies developing products that have an overdose mechanism similar to our MPAR ® technology.

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A table of the key patent families and their natural or projected expiry dates is presented below.

or Projected Expiry Date

and MPAR Patents and Applications for Opioids

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Methadone Prodrugs and Methods of Use Thereof

PCT, Europe, Brazil, China, Japan, Korea, Canada, Mexico, Australia, India, Israel

Patents and Applications

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formulations of Nafamostat

PCT, Taiwan, Europe, Brazil, China, Japan, Korea, Canada, Mexico, Australia, India, Israel

of Treating Respiratory Diseases with Mucostasis

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compositions containing these modified opioids and a gastrointestinal enzyme inhibitor, and methods of using the same to treat pain.

Three of these patent families are directed to ketone containing opioids and cover PF614 and PF614-MPAR™ and certain methadone

TAAP product candidates that are still in the discovery phase.

These three families contain issued patents in the United States and certain

foreign jurisdictions, including Australia, Brazil, Canada, China, Europe, India, Japan, and Russia and expire between 2030 and 2032,

subject to any applicable patent term extension that might be available in a jurisdiction.

We also own pending United States, Patent

Cooperation Treaty (PCT), and Taiwan applications directed to oral formulations of PF614-MPAR™, which if pursued and issued would

expire in 2042, subject to any potential patent term adjustment or extension that may be available in a jurisdiction.

We also own one

patent family that includes granted patents in the United States, as well as granted patents and pending patent applications in numerous

foreign jurisdictions, including Australia, Brazil, Canada, China, Europe, India, Japan, and Russia, relating to chemically modified

ketone-containing agents, such as oxycodone, methadone, and hydromorphone, covalently linked using specific linkers to a gastrointestinal

enzyme-cleavable moiety, pharmaceutical compositions containing these modified ketone-containing agents, pharmaceutical compositions

containing these modified ketone-containing agents and a gastrointestinal enzyme inhibitor, and methods of using the same to treat pain,

would cover certain methadone TAAP product candidates that are still in discovery phase and expire in 2032.

While we own these patent

families, we have not updated records in the various patent offices to reflect our ownership of these patent families.

Failure to update

such ownership may result in an innocent purchaser potentially acquiring rights in such patents that are adverse to our interests.

as noted above, we have not obtained assignments for certain patent applications relating to abuse-resistant amphetamines.

Three of these patent families are directed to ketone containing opioids and cover PF614 and PF614-MPAR and certain methadone TAAP product

candidates that are still in the discovery phase.

These three families contain issued patents in the United States and certain foreign

jurisdictions, including Australia, Brazil, Canada, China, Europe, India, Japan, and Russia and expire between 2030 and 2032, subject

to any applicable patent term extension that might be available in a jurisdiction.

We also own pending United States, Patent Cooperation

Treaty (PCT), and Taiwan applications directed to oral formulations of PF614-MPAR, which if pursued and issued would expire in 2042,

subject to any potential patent term adjustment or extension that may be available in a jurisdiction.

We also own one patent family that

includes granted patents in the United States, as well as granted patents and pending patent applications in numerous foreign jurisdictions,

including Australia, Brazil, Canada, China, Europe, India, Japan, and Russia, relating to chemically modified ketone-containing agents,

such as oxycodone, methadone, and hydromorphone, covalently linked using specific linkers to a gastrointestinal enzyme-cleavable moiety,

pharmaceutical compositions containing these modified ketone-containing agents, pharmaceutical compositions containing these modified

ketone-containing agents and a gastrointestinal enzyme inhibitor, and methods of using the same to treat pain, would cover certain methadone

TAAP product candidates that are still in discovery phase and expire in 2032.

While we own these patent families, we have not updated

records in the various patent offices to reflect our ownership of these patent families.

Failure to update such ownership may result

in an innocent purchaser potentially acquiring rights in such patents that are adverse to our interests.

Furthermore, as noted above,

we have not obtained assignments for certain patent applications relating to abuse-resistant amphetamines.

believe that one patent covering PF614 will be eligible for up to five years of patent term extension in the United States and intend

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United States and European patent applications directed to pharmaceutical compositions containing chemically modified amphetamines covalently

linked to a gastrointestinal enzyme-cleavable moiety and a trypsin inhibitor and methods of using the same to treat a subjects.

linked to a gastrointestinal enzyme-cleavable moiety and a trypsin inhibitor and methods of using the same to treat a subject.

not obtained assignments from all of the inventors of these applications to date, which could negatively impact our ability to pursue

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they progress through clinical development.

We received registration of our trademark for MPAR on May 16, 2023.

we rely upon trade secrets, know-how, continuing technological innovation, and potential in-licensing opportunities to develop and maintain

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Our drug substance and drug products are manufactured for us by contract manufacturing organizations, or CMOs, to our specifications.

Any manufacturing problem or the loss of a CMO could be disruptive to our operations and result in lost sales.

lead product candidate, PF614, is small molecule opioid prodrug.

Any manufacturing problem or the loss of a CMO could be disruptive to our operations.

lead product candidate, PF614, is a small molecule opioid prodrug.

As such, it is a controlled substance, regulated by the Drug Enforcement

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manufacture of PF614, PF614-MPAR and nafamostat.

We currently have sufficient supplies of PF614 and nafamostat on hand for our

current clinical trial needs.

Any reliance on suppliers may involve several risks, including a potential inability to obtain critical

materials and reduced control over production costs, delivery schedules, reliability, and quality.

We currently have sufficient supplies of PF614 and nafamostat on hand for our current

clinical trial needs.

Any reliance on suppliers may involve several risks, including a potential inability to obtain critical materials

and reduced control over production costs, delivery schedules, reliability, and quality.

LLC manufactures PF614 and other clinical trial materials under cGMP conditions and provides stability studies with respect to our PF614

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levels or prices ” for more information.

manufactures PF614 and other clinical trial drug products under cGMP conditions and provides stability studies with respect to our PF614

clinical trials.

Recro (now Societal CDMO) has completed the manufacture of PF614 50 and 100 mg capsules that have been used in clinical

studies PF614-102, PF614-103 and PF614-104.We expect to enter into additional related agreements with Societal CDMO as we manufacture

CDMO manufactures PF614 and other clinical trial drug products under cGMP conditions and provides stability studies with respect to our

PF614 clinical trials.

Societal has completed the manufacture of PF614 50 and 100 mg capsules that have been used in clinical studies

PF614-102, PF614-103, PF614-104 and PF614-201.

We expect to enter into additional related agreements with Societal CDMO as we manufacture

future batches of PF614.

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have received funding under federal grant award programs through governmental agencies, such as the NIH and NIDA.

For fiscal year 2021,

we received an aggregate of approximately $3.5 million in federal grant funds, approximately $2.6 million from the NIH related to the

Phase 1 clinical trial for PF614 MPAR™ and approximately $0.9 million from NIDA under our five-year award to undertake the preclinical

development of our opioid use disorder-MPAR TM technology.

For the fiscal year ended December 31, 2022, we received federal

grants totaling $2.5 million, $2.0 million from NIH related to the Phase 1 clinical trial for PF614 MPAR™ and $0.5 million from

NIDA for preclinical development of our opioid use disorder-MPAR TM technology.

Current remaining funding under the two approved

grants totals $4.6 million, covering the period through August 31, 2023.

We may apply for additional grant funding from these or similar

governmental agencies in the future.

For the year ended

December 31, 2023, we received federal grant funding totaling $2.2 million, $1.3 million from NIH related to the Phase 1 clinical trial

for PF614-MPAR and $0.9 million from NIDA for preclinical development of our opioid use disorder-MPAR ® technology.

remaining funding under approved grants totaled $2.2 million as of December 31, 2023, covering the period through August 2024.

apply for additional grant funding from these or similar governmental agencies in the future.

to the GEM Agreement, we are entitled to draw down up to $60 million of gross proceeds (“ Aggregate Limit ”) from GEM

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common stock in an amount equal to 2% of the Aggregate Limit or $1.2 million to be paid in two tranches.

The commitment fee for the first

tranche, which is equal to 67% of the commitment fee, or $800,000, was paid in shares in July 2022 and the commitment fee for the second

tranche, which is equal to the remaining 33% of the commitment fee, or $400,000, was paid in shares in January 2023.

The commitment fees have been

paid in full.

Additionally,

we issued a warrant with a 36-month term at the closing of the Merger granting GYBL the right to purchase 4,608 shares of our common

stock (an amount equal to 4% of the total number of our common stock outstanding as of the closing date of the Merger (subject to adjustments

described below), calculated on a fully diluted basis), at a strike price per share equal to, after several downward adjustments, $0.7512

as of January 12, 2023.

Any failure by us to timely transfer the shares under the warrant pursuant to GYBL’s exercise will entitle

GYBL to compensation in addition to other remedies.

The number of shares underlying the warrant as well as the strike price is subject

to adjustments for recapitalizations, reorganizations, change of control, stock split, stock dividend and reverse stock splits.

price is subject to adjustment for issuances of additional common shares at a price per share less than the strike price.

stock at a strike price per share equal to $1.5675, after several downward adjustments to the strike price.

Any failure by us to timely

transfer the shares under the warrant pursuant to GYBL’s exercise will entitle GYBL to compensation in addition to other remedies.

The number of shares underlying the warrant as well as the strike price is subject to adjustments for recapitalizations, reorganizations,

change of control, stock split, stock dividend and reverse stock splits.

The strike price is subject to adjustment for issuances of additional

common shares at a price per share less than the strike price.

GEM Agreement contains certain negative covenants restricting us from securing an equity line similar to the financing provided under

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have not raised any capital pursuant to the GEM facility and we may not raise any capital pursuant to it prior to its expiration.

pursuant to the terms of our recent financings may also affect our ability to use the GEM Facility.

the United States, pharmaceutical products are subject to extensive regulation by the FDA, and those pharmaceutical products that are

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to the evaluation of an application designated for priority review to facilitate the review.

Therapy Designation

Breakthrough Therapy designation is designed to expedite the development and review of drugs that are intended to treat a serious condition

where preliminary clinical evidence indicates that the drug may demonstrate substantial improvement over available therapies.

intent of Breakthrough Therapy designation is to develop evidence needed to support approval as efficiently as possible.

The designation

provides all the features of Fast Track designation including accelerated approval and priority review along with intensive guidance

involving FDA senior managers on an efficient drug development program.

of Clinical Trial Information

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of whether such extensions should be granted, and if granted, the length of such extensions.

also believe that (1) PF614 and nafamostat will be eligible for a five-year NCE regulatory exclusivity, and (2) PF614-MPAR™ will

be eligible for a three-year clinical investigation, or CI, regulatory exclusivity, under the Hatch-Waxman Act, during which time no

ANDA can be approved.

also believe that (1) PF614 and nafamostat will be eligible for a five-year NCE regulatory exclusivity, and (2) PF614-MPAR will be eligible

for a three-year clinical investigation, or CI, regulatory exclusivity, under the Hatch-Waxman Act, during which time no ANDA can be

the Hatch-Waxman Act, patents covering the product such as patents claiming the approved composition of matter, approved methods of use,

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duration of initial opioid prescription and conducting follow-up, and 4) assessing risk and addressing potential harms of opioid

Drug Safety Communication:

In April 2023, the FDA issued a communication that in the ongoing effort to address the nation’s

opioid crisis, it was making several updates to the prescribing information of opioid pain medicines to provide additional guidance

on their use.

The changes include label updates addressing addiction, abuse and misuse as well as life-threatening respiratory depression,

accidental ingestion, risks from concomitant use with other CNS depressants, neonatal withdrawal and opioid analgesic risk evaluation

and mitigation strategy.

Warnings and Safety Labeling:

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directed at reducing the potential for oversupply of opioids to reduce the potential for misuse and diversion.

Capital Resources

of December 31, 2022, we had seven full-time employees and five consultants.

principal executive office is located at 7946 Ivanhoe Ave., Suite 201 in La Jolla, California, where we lease a total of 850 square feet

of office space that we use for our administrative activities.

All development activities are undertaken at contract research organizations.

The lease expires in October 2024.

We believe that our current arrangements will be sufficient to meet our needs for the foreseeable

future, and that, should it be needed, suitable space will be available to accommodate our administrative activities.

Capital Resources (Employees)

have seven full-time employees, one part-time employee and one consultant.

Of these, five have a Ph.D.

and two have an M.B.A.

time to time, we also retain independent contractors to support our organization.

None of our employees are represented by a labor union

or covered by collective bargaining agreements, and we believe our relationship with our employees is good.

Identification

of Our Executive Officers

Company’s Executive Officers and their age and position are below.

Lynn Kirkpatrick, Ph.D

Chief Executive Officer and Class III Director

Commercial Officer

Humphrey, CPA

Financial Officer, Secretary and Treasurer

Jeffrey Millard, Ph.D.

Operating Officer

Linda Pestano, Ph.D.

Development Officer

William Schmidt, Ph.D.

Medical Officer

presented as of December 31, 2022

Lynn Kirkpatrick, Ph.D.

has served as our Chief Executive Officer since January 2009.

Kirkpatrick has spent over 30 years

in drug discovery and development, has initiated the clinical development of four novel drug candidates and now strives to bring highly

novel and safe pain therapies to commercialization.

She received a Doctor of Philosophy (“ Ph.D.

”) degree in Medicinal

and Biomedicinal Chemistry at the University of Saskatchewan, completed a Post-Doctoral Fellowship at the Yale University School of Medicine,

and became a tenured full professor in the Department of Chemistry at the University of Regina.

She co-founded ProlX Pharmaceuticals,

(“ ProlX ”) an oncology discovery company, becoming Chief Executive Officer and successfully bringing three small

molecules from discovery into clinical development, two of these her own discoveries from academia.

ProlX was acquired by Biomira Inc.,

Kirkpatrick became the Chief Scientific Officer of the merged company to focus on the development of oncology products and vaccines.

In 2009, she co-founded PHusis Therapeutics, developing targeted small molecule precision medicines for oncology.

At the same time, she

became our Chief Executive Officer.

Kirkpatrick has published extensively in the area of targeted drug discovery, abuse deterrent

pain products and holds numerous patents for novel drugs and modalities.

We believe Dr.

Kirkpatrick is qualified to serve on our Board

because of her extensive executive experience in our industry and her service as our Chief Executive Officer.

Birkett has served as our Chief Commercial Officer since October 2018.

He has over 30 years of experience in the Pharmaceutical

and Biotechnology area.

He started his career as a biochemist at the Royal Victoria Infirmary in Newcastle-upon-Tyne, England.

moved into the pharmaceutical industry, where he focused on pain/addiction and neuroscience throughout his career.

He has developed and

launched several groundbreaking therapies, including Nicorette (POM) and (OTC), Lexapro and several other psychiatry agents with Lundbeck.

Birkett assisted on the launch of Prozac and Humatrope (human growth hormone) with Eli Lilly.

He assisted in moving Seroquel from

Phase 2 to global market leader with multi-billion dollar sales and he also participated in the launch of Zomig for migraines, which

became a European market leader.

He worked for most of his pharmaceutical career at AstraZeneca plc in both the United Kingdom and the

United States, where he held many roles including overseeing the global oncology division.

When the AstraZeneca merger took place, Mr.

Birkett ran the merger process outside the United States across all markets, and ran a corporate change program to streamline research

and development involving 67,000 staff.

Since leaving AstraZeneca, Mr.

Birkett has held multiple roles in biotech companies as senior

officer or as a consultant.

He is co-founder of a novel drug delivery company and has consulted for IPSOS, a large global research and

consulting firm.

He also served as president for North America/Canada of INDIVIOR, a large company producing addiction treatment drugs.

Birkett joined us in 2018 and is focused on building a world class commercial team.

Birkett attended Henley Business College

in London and INSEAD Business School in France where he studied general management and a global leadership.

Humphrey, CPA has served as our Chief Financial Officer since February 2021.

Prior to joining the Company, Mr.

Humphrey was most

recently Chief Financial Officer of Senomyx, Inc.

(“Senomyx”), a publicly held biotechnology company focused on taste science.

In his previous employment, he guided public company financial reporting, including Forms 10-K, 10-Q, 8-K, S-3, S-8, proxy statements

and SOX internal controls compliance, and acted as primary liaison with the audit committee and external auditors.

Humphrey advised

Senomyx’s board of directors, as part of core executive management team, in a $75 million acquisition by Firmenich SA, a private

Swiss multinational flavor and fragrance company.

Previously, he held finance and accounting leadership positions and consulted at numerous

life sciences companies, including ActivX Biosciences, Aurora Biosciences and Gensia.

Humphrey started his career as an accountant

at Price Waterhouse.

He holds a Bachelor of Science with Honors in Accountancy from the University of Illinois at Urbana-Champaign and

is a Certified Public Accountant in California.

Jeffrey Millard, Ph.D.

has served as our Chief Operating Officer since January 2019.

Millard has both academic and industrial

experience in chemistry and pharmaceutical sciences covering all aspects of chemistry, manufacturing, and controls, or CMC.

involved in both start-up biotech as well as small and mid-sized public biopharmaceutical companies.

Millard has been directly responsible

for research and development activities and writing of more than seven IND submissions and Investigational Medicinal Product Dossiers,

He has directed the CMC efforts from discovery and in-licensing through commercial launch activities.

His experience covers

the application programming interface, or API, lifecycle (from synthetic route scouting, process chemistry, analytical chemistry development

and validation, cGMP production and release of API, to QbD and process validation), and drug product development through manufacture.

Millard received a Bachelor of Arts from Rice University and a Ph.D.

in Pharmaceutical Sciences from the University of Arizona.

Linda Pestano joined Ensysce in October 2021, as Chief Development Officer.

Pestano has worked throughout her career to guide

the development of novel therapeutics to improve patient outcomes and quality of life.

She has 20 years of experience developing vaccines,

drugs and novel biologics for a diverse range of indications.

She has been instrumental in guiding new therapies, including small molecules,

nucleic acids, and biologicals through development into clinical trials.

Pestano’s expertise spans lead development, pre-clinical

and translational studies, and interacting with multiple regulatory agencies.

Pestano received her PhD from Tufts University and

undertook a Post-Doctoral Fellowship with Dana Farber Cancer Institute at the Harvard Medical School in Boston.

Schmidt, Ph.D ., has served as our Chief Medical Officer since January 2016.

He is also the Head of NorthStar Consulting,

the Parliamentarian and a former president of the Eastern Pain Association, the largest regional affiliate of the American Pain Society.

He has over 25 years of pharmaceutical industry experience with a special emphasis on the discovery and development of novel analgesic

and narcotic antagonist drugs.

He was previously Vice President of Clinical Development for CrystalGenomics (Seoul, South Korea) and

its United States subsidiary, CG Pharmaceuticals (Emeryville, CA);

Senior Vice President of Development at Limerick BioPharma;

Vice President,

Clinical Research, for Renovis, Inc.;

and Vice President, Scientific Affairs and acting Vice President, Clinical Research and Development,

at Adolor Corporation.

At Adolor Corporation, Dr.

Schmidt was a key member of the team leading to the clinical development, NDA filing,

and FDA approval of Entereg® (alvimopan), a peripherally acting opioid antagonist.

Currently Dr.

Schmidt serves as an expert on

pain medicine pharmaceutical development with pharmaceutical and biotech companies throughout North America, Europe, Asia, Latin America,

and Australia.

Schmidt received a Bachelor of Arts degree from the University of California Berkeley and his Ph.D.

University of

California-San Francisco.

From time to time, we also retain

independent contractors to support our organization.

None of our employees is represented by a labor union or covered by collective bargaining

agreements, and we believe our relationship with our employees is good.

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