UNITED
STATES
SECURITIES
AND EXCHANGE COMMISSION
WASHINGTON,
D.C. 20549
Form
10-K
For
the fiscal year ended: December 31, 2023
OR
For
the transition period from to
Commission
File Number 001-38306
ENSYSCE
BIOSCIENCES, INC.
(Exact
name of registrant as specified in its charter)
(Address of principal executive offices) (Zip Code)
(Registrant’s telephone number, including area code)
SECURITIES
REGISTERED PURSUANT TO SECTION 12(b) OF THE ACT:
Title of each class Trading Symbol(s) Name of each exchange on which registered
Common Stock, $0.0001 par value per share ENSC The Nasdaq Stock Market
Warrants, to purchase one share of Common Stock ENSCW OTC Pink Open Market
SECURITIES
REGISTERED PURSUANT TO SECTION 12(g) OF THE ACT: NONE
Indicate
by check mark if the registrant is a well-known seasoned issuer, as defined in Rule 405 of the Securities Act. Yes ☐ No ☒
Indicate
by check mark if the registrant is not required to file reports pursuant to Section 13 or 15(d) of the Exchange Act. Yes ☐ No ☒
Indicate
by check mark whether the registrant (1) has filed all reports required to be filed by Section 13 or 15(d) of the Securities Exchange
Act of 1934 during the preceding 12 months (or for such shorter period that the registrant was required to file such reports), and (2)
has been subject to such filing requirements for the past 90 days. Yes ☒ No ☐
Indicate
by check mark whether the registrant has submitted electronically every Interactive Data File required to be submitted pursuant to Rule
405 of Regulation S-T (§232.405 of this chapter) during the preceding 12 months (or for such shorter period that the registrant
was required to submit such files). Yes ☒ No ☐
Indicate
by check mark whether registrant is a large accelerated filer, an accelerated filer, a non-accelerated filer or a smaller reporting company,
or an emerging growth company. See definitions of “large accelerated filer”, “accelerated filer”, “smaller
reporting company”, and “emerging growth company” in Rule 12b-2 of the Exchange Act:
Large accelerated filer ☐ Accelerated filer ☐
Non-accelerated filer ☒ Smaller reporting company ☒
Emerging growth company ☐
If
an emerging growth company, indicate by checkmark if the registrant has elected not to use the extended transition period for complying
with any new or revised financial accounting standards provided pursuant to section 13(a) of the Exchange Act ☐
Indicate
by check mark whether the registrant has filed a report on and attestation to its management’s assessment of the effectiveness
of its internal control over financial reporting under Section 404(b) of the Sarbanes-Oxley Act (15 U.S.C. 7262(b)) by the registered
public accounting firm that prepared or issued its audit report. ☐
If
securities are registered pursuant to Section 12(b) of the Act, indicate by check mark whether the financial statements of the registrant
included in the fi ling reflect the correction of an error to previously issued financial statements. ☐
Indicate
by check mark whether any of those error corrections are restatements that required a recovery analysis of incentive-based compensation
received by any of the registrant’s executive officers during the relevant recovery period pursuant to §240.10D-1(b). ☐
Indicate
by check mark whether the registrant is a shell company (as defined in Rule 12b-2 of the Exchange Act). Yes ☐ No ☒
The
aggregate market value of the common stock held by non-affiliates of the registrant on June 30, 2023, the last business day of the registrant’s
most recently completed second fiscal quarter, was $4.6 million. The aggregate market value was computed by reference to the closing
price of the common stock on such date.
Registrant
had 7,329,172 shares of common stock outstanding as of March 8, 2024.
DOCUMENTS
INCORPORATED BY REFERENCE
None
ENSYSCE
BIOSCIENCES, INC.
INDEX
Risk Factor Summary 3
Glossary 5
Cautionary Note Regarding Forward-Looking Statements 8
PART I 9
Item 1. Business 9
Item 1A. Risk Factors 33
Item 1B. Unresolved Staff Comments 66
Item 1C. Cybersecurity 66
Item 2. Properties 66
Item 3. Legal Proceedings 67
Item 4. Mine Safety Disclosures 67
Item 7A. Quantitative and Qualitative Disclosures About Market Risk 84
Item 8. Financial Statements and Supplementary Data 84
Item 9A. Controls and Procedures 84
Item 9B. Other Information 85
Item 9C. Disclosure Regarding Foreign Jurisdictions that Prevent Inspections 85
PART III 86
Item 10. Directors, Executive Officers and Corporate Governance 86
Item 11. Executive Compensation 91
Item 14. Principal Accounting Fees and Services 99
Item 15. Exhibits and Financial Statement Schedules 100
Risk
Factor Summary
Below
is a summary of material factors that make an investment in our securities speculative or risky. Importantly, this summary does not address
all of the risks and uncertainties that we face. Additional discussion of the risks and uncertainties in this summary, as well as other
risks and uncertainties that we face, can be found under the section titled “Risk Factors” beginning on page 34 of
this Annual Report on Form 10-K. This summary is qualified in its entirety by that more complete discussion of such risks and uncertainties.
If we are unable to adequately address these and other risks we face, our business, results of operations, financial condition and prospects
may be harmed. You should consider carefully the risks and uncertainties described under the section titled “Risk Factors”
as part of your evaluation of an investment in our securities:
● We require substantial additional funding.
● Government grant awards may not be available to us in the future.
● Interim and preliminary data from our clinical trials may change.
● We may encounter difficulties enrolling patients in our clinical trials.
GLOSSARY
Definitions:
ADFs Abuse deterrent formulations
ADHD Attention deficit hyperactivity disorder
ANDA Abbreviated New Drug Application
API Active pharmaceutical ingredient
AUC Area under the concentration time curve
Board Board of directors of Ensysce, or a committee thereof, as applicable
CARA Comprehensive Addiction and Recovery Act
CDC Center for Disease Control
CDER Center for Drug Evaluation and Research
cGMP Current Good Manufacturing Practice
Cmax Maximum plasma concentration
CMC Chemistry, manufacturing, and controls
CMOs Contract manufacturing organizations
CNS Central nervous system
Company Ensysce Biosciences, Inc. and its consolidated subsidiaries
COVID-19 Novel coronavirus disease
Covistat A subsidiary renamed EBIR, Inc.
CROs Contract research organizations
CSA Controlled Substances Act
CSOS Controlled Substance Ordering System
DEA United States Drug Enforcement Agency
EMA European Medicines Agency
Ensysce Ensysce Biosciences Inc.
EPO European Patent Office
ETASU Elements to assure a products safe use
Exchange Act Securities Exchange Act of 1934, as amended
FDA United States Food and Drug Administration
FDC Act Federal Food, Drug and Cosmetic Act, as amended
GAAP Generally Accepted Accounting Principles in the United States of America
GCP Good Clinical Practices
GEM Global GEM Global Yield LLC SCS
GMP Good Manufacturing Practices
GYBL GEM Yield Bahamas Limited
HHS United States Department of Health and Human Services
IMPDs Investigational Medicinal Product Dossiers
IND Investigational New Drug
Investor Notes The 2021 Notes, 2022 Notes and 2023 Notes, collectively.
IRB Institutional Review Board
JOBS Act Jumpstart Our Business Startups Act of 2012
LACQ Leisure Acquisition Corp., a Delaware Corporation
MAD Multi-Ascending Dose
Nasdaq The Nasdaq Stock Market LLC
NCE New Chemical Entity
NDA New Drug Application
NEO Named Executive Officer
NIDA National Institute of Drug Abuse
NIH National Institutes of Health
NME New molecular entity
PCT Patent Cooperation Treaty
PDMA U.S. Prescription Drug Marketing Act
PK Pharmacokinetics
PTA Patent Term Adjustment
PTE Patent Term Extension
R&D Research and Development
Recro Recro Gainesville LLC
REMS Risk evaluation and mitigation strategy
SARS-CoV-2 Severe acute respiratory syndrome coronavirus 2
SAQ Signature Acquisition Corp., a wholly-owned subsidiary of Signature
SEC U.S. Securities and Exchange Commission
Securities Act Securities Act of 1933, as amended
Signature Signature Therapeutics Inc.
TAAP Trypsin Activated Abuse Protection
TEAEs Treatment-emergent adverse events
USPTO United States Patent and Trademark Office
CAUTIONARY
NOTE REGARDING FORWARD-LOOKING STATEMENTS
This
Annual Report on Form 10-K includes statements that express our opinions, expectations, beliefs, plans, objectives, assumptions, or projections
regarding future events or future results and therefore are, or may be deemed to be, “forward-looking statements.”
These forward-looking statements can generally be identified by the use of forward-looking terminology, including the terms “believes,”
“estimates,” “anticipates,” “expects,” “seeks,” “projects,”
“intends,” “plans,” “may,” “will,” or “should”
or, in each case, their negative or other variations or comparable terminology. These forward-looking statements include all matters
that are not historical facts. They appear in a number of places throughout this Annual Report on Form 10-K and include statements regarding
our intentions, beliefs or current expectations concerning, among other things, results of operations, financial condition, liquidity,
prospects, growth, strategies and the markets in which we operate. Such forward-looking statements are based on available current market
material and management’s expectations, beliefs and forecasts concerning future events impacting our company. Factors that may
impact such forward-looking statements include:
● our ability to continue as a going concern for the next twelve months;
● effects of competition;
● the loss of key members of our management team;
● changes in our regulatory environment;
● changes in our industry;
● the risk that our common stock will be delisted from Nasdaq;
● potential litigation associated with the Business Combination Transactions;
● other factors disclosed in this Annual Report on Form 10-K; and
● other factors beyond our control.
The
forward-looking statements contained in this Annual Report on Form 10-K are based on our current expectations and beliefs concerning
future developments and their potential effects on our company. There can be no assurance that future developments affecting us will
be those that we have anticipated. These forward-looking statements involve a number of risks, uncertainties (some of which are beyond
our control) or other assumptions that may cause actual results or performance to be materially different from those expressed or implied
by these forward-looking statements. These risks and uncertainties include, but are not limited to, those factors described under the
heading “Risk Factors”. Should one or more of these risks or uncertainties materialize, or should any of the assumptions
prove incorrect, actual results may vary in material respects from those projected in these forward-looking statements. We will not undertake
any obligation to update or revise any forward-looking statements, whether as a result of new information, future events or otherwise,
except as may be required under applicable securities laws.
References
in this Annual Report on Form 10-K to “we,” “our,” “us,” the “Company” or “Ensysce”
generally refer to Ensysce and its consolidated subsidiaries.
PART
I
Item
1. Business
Corporate
Information
We
were originally incorporated in the State of Delaware in April 2003 as PharmacoFore, Inc. and, in January 2012, we changed our name from
PharmacoFore, Inc. to Signature Therapeutics Inc. (“Signature”). On December 28, 2015, Signature, Signature Acquisition
Corp., a wholly-owned subsidiary of Signature (“SAQ”), and Ensysce Biosciences, Inc. (“EB”) entered
into an Agreement and Plan of Merger (“EB-ST Agreement”). Pursuant to the EB-ST Agreement, SAQ merged with and into
EB with EB surviving the merger as a wholly-owned subsidiary of Signature. As part of the transaction, Signature changed its name to
“Ensysce Biosciences, Inc.” (“Former Ensysce”) and changed EB’s name to EBI Operating Inc. On January
31, 2021, LACQ, Former Ensysce, and Merger Sub entered into the Merger Agreement. On June 30, 2021, pursuant to the Merger Agreement,
Merger Sub merged with and into Former Ensysce, with Former Ensysce surviving the transaction as a wholly-owned subsidiary of LACQ. As
part of the transaction, LACQ changed its name to “Ensysce Biosciences, Inc.” and Former Ensysce changed its name to EBI
OpCo, Inc.
The
mailing address of our principal executive office is 7946 Ivanhoe Avenue, Suite 201, La Jolla, California 92037. Our corporate telephone
number is (858) 263-4196. Our website address is www.ensysce.com. Information contained on our website, or connected thereto, does not
constitute part of, and is not incorporated by reference into, this Annual Report on Form 10-K.
Channels
for Disclosure of Information
Investors,
the media, and others should note that we announce material information to the public through filings with the SEC, the investor relations
page on our website, blog posts on our website, press releases, public conference calls, webcasts, and our twitter feed (@EnsysceBio).
The
information disclosed by the foregoing channels could be deemed to be material information. As such, we encourage investors, the media,
and others to follow the channels listed above and to review the information disclosed through such channels.
Any
updates to the list of disclosure channels through which we will announce information will be posted on the investor relations page on
our website.
Business
Overview
We
are a clinical stage pharmaceutical company seeking to develop innovative solutions for severe pain relief while reducing the potential
for opioid misuse, abuse, and overdose.
We
are currently developing product candidates designed to improve the safety of prescription drugs. Our primary focus has been on opioid
pain products and opioid use disorder products. Prescription opioid abuse presents major burdens to society, resulting in significant
costs, illnesses, and deaths, many of which we believe could be prevented through the use of our proprietary technologies. We believe
the intertwined issues of (1) the widespread abuse of prescription opioids and (2) the resultant reluctance of many prescribers to write
prescriptions for opioid analgesics have resulted in the persistent under-treatment of patients with moderate-to-severe pain. Our platforms
utilize a novel molecular delivery technology designed to deter prescription opioid abuse at the molecular level.
Our
current development pipeline includes two new drug platforms - an abuse-resistant opioid prodrug technology – the Trypsin
Activated Abuse Protection, or the TAAP platform, and an over-dose protection opioid prodrug technology - the Multi-Pill Abuse Resistant,
or the MPAR® platform. 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
is designed not only to seek to prevent abuse of prescription drugs but also to reduce overdose occurrences. Each prodrug is intended
to be able to be combined with our MPAR® technology for overdose protection. Additionally, nafamostat di-mesylate (“nafamostat”),
which is an ingredient in our overdose protection combination products, is also being developed for the intended purpose of treating
infection and pulmonary lung diseases.
The
technology under the TAAP platform when applied to opioid drugs is designed to release clinically effective opioid drugs only when exposed
to specific physiological conditions (i.e., when the drug is ingested and exposed to the digestive enzyme trypsin). Our lead product
candidate, PF614, is a TAAP oxycodone prodrug that is a biologically inactive compound which can be metabolized in the body to produce
a drug with demonstrable features aimed at resisting both oral and non-oral modes of prescription drug abuse. This approach differs from
current formulation-based strategies such as OxyContin OP which uses Intac® Technology (crush-resistant polymers) and Extampza®ER
which uses DETERxTM (insoluble fatty acid salts in polymers), in a number of ways. First, the TAAP technology seeks to remove the
ability of a user to abuse PF614 intravenously or intranasally based on preclinical studies that show PF614 does not readily convert
into oxycodone in the blood stream and trypsin is not present in the nasal passage, and, accordingly, PF614 would not convert to oxycodone
in the nose. Furthermore, the chemically modified and abuse-resistance TAAP opioid drug is unaffected by simple physical manipulations
designed to extract abusable amounts of opioid, such as through kitchen chemistry. Our portfolio of TAAP product candidates is based
on a differentiated understanding of chemical reactivity and metabolism, as well as the key pillars of our unique approach which focuses
on: (1) enzyme mediated metabolic activation localized in the gastrointestinal track; (2) rearrangement chemistry to achieve pharmacokinetic
release of active drug products; and (3) preclinical and clinical data that set forth the metabolic and chemical activation profile for
each of our clinical candidates.
Utilizing
this approach, we filed an Investigational New Drug application, or IND (116794), and commenced a Phase 1 clinical trial for PF614, which
was completed in February 2018. The clinical data from the Phase 1 trial demonstrated that oxycodone released from PF614 as chemically-designed,
and that it was absorbed following oral administration of the TAAP PF614, resulting in blood levels that matched the same release profile
as the extended release oxycodone product, OxyContin OP. A second multi-ascending dose study with a bioequivalent arm was completed in
July 2022 and a nasal human abuse potential (HAP) study was completed in October 2022. A second oral HAP study was completed in March
2023. Most recently, a study to evaluate efficacy was completed in December 2023.
The
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 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.
Our
pipeline has been developed over the course of 15 years of research and investment and includes three clinical-stage product candidates.
While our principal focus and lead product candidates are geared towards combating abuse and overdose of opioid drugs, we have, over
the years of research and development, discovered and recognized qualities and unique features of certain product candidates that may
be useful in addressing other treatments. For example, we discovered the ability of nafamostat in inhibiting the action of enzymes associated
with the COVID-19 infection, and, as such, have devoted efforts to develop an oral and inhalation drug product of nafamostat, for use
against coronaviral infections and other pulmonary diseases such as cystic fibrosis.
PF614
PF614
is our lead TAAP prodrug candidate under development for the treatment of acute or chronic pain. PF614 is a delayed release TAAP prodrug
designed to release oxycodone under certain specific physiological circumstances when taken orally. PF164 was evaluated for safety and
pharmacokinetic release of oxycodone in a Phase 1 single ascending dose clinical trial in 64 healthy subjects. The trial showed that
PF614 was well tolerated with no serious adverse events. The study also showed pharmacokinetics had a maximum blood concentration of
oxycodone at 4 to 6 hours after swallowing PF614, demonstrating its delayed release profile. A second Phase 1b multi-ascending dose study
(MAD) was initiated in 2021 to evaluate PF614 delivered to healthy subjects twice daily for 4.5 days. This study evaluated both safety
and PK, with a second part to evaluate the bioequivalence (BE) of PF614 versus OxyContin. Final data from this trial was reported in
July 2022. The MAD study demonstrated both the safety of PF614 showing it was well tolerated at doses up to 200 mg, which was comparable
to 80 mg of OxyContin both delivered twice daily. The BE study arm followed the successful completion of the multi-ascending twice-daily
dosing study of PF614 and compared the release of oxycodone from PF614 versus OxyContin® administered to subjects in both fasted
and fed states. It was concluded that 100 mg PF614 was bioequivalent to 40 mg OxyContin under both fasted and fed conditions. This data
is critical to understand future prescribing criteria for PF614 as an agent bioequivalent to OxyContin and therefore may be developed
through the 505(b)(2) regulatory path as defined by the FDA. The intranasal (IN) and oral human abuse potential of PF614 was assessed
in two different studies. In study 1, PF614-103, we evaluated the abuse potential of PF614 100 mg relative to crushed oxycodone immediate-release
(IR) tablets 40 mg (equivalent opioid doses) and placebo following intranasal administration. 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.
PF614-MPAR
PF614-MPAR,
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. 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. We completed the clinical portion and reported data from
Part A of this study in December 2022. 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. There was
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
May of 2023. PF614-MPAR was granted Breakthrough Therapy designation by the FDA in January 2024.
MPAR
is being tested clinically 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 scenario.
Nafamostat
Nafamostat
is an enzyme inhibitor (protease inhibitor) used in our combination overdose protection technology, MPAR®. Due to its ability to
inhibit the action of enzymes associated with the COVID-19 infection, we are also developing an oral drug product of nafamostat, for
use against coronaviral infections and other pulmonary diseases such as cystic fibrosis. An IND was submitted (149877) for the evaluation
of oral nafamostat in coronaviral infections. A Phase 1 trial to evaluate safety and PK was completed in 2021.
Market
Opportunity
Drug
Abuse and Drug Overdose
Opioid
pain medications are essential for improving the care and outcomes of a majority of Americans who live with chronic pain. An NIH study,
updated September 2018, reported that 25.3 million adults suffered from pain every day for the preceding three months and almost 40 million
adults experience severe levels of pain, which is linked to worse health status. High impact chronic pain affects over 10 million Americans
and is characterized by extended periods of suffering which impair life quality to a severe degree. Prescription opioids drugs, such
as morphine, hydromorphone, hydrocodone, and oxycodone, have a long history of use for the management of severe and chronic pain. Prescriptions
for opioid medications in 2021 totaled 153 million, with $4.2 billion in market size in the United States.
The
CDC recently provided recommendations for clinicians who provide pain care, defining acute pain (duration less than 1 month), subacute
pain (duration of 1–3 months), or chronic pain (duration of 3 months or more), not including sickle cell disease related pain management,
cancer pain treatment, palliative care, and end-of life care. These guidelines are based on the indications, acute and chronic
pain, that we intend to explore for our TAAP and MPAR® opioid products including PF614.
Opioids
are offered in a variety of dosages including immediate-release tablets (or capsules), extended-release tablets (or capsules), patches,
and other dose forms. Oxycodone is one of the most effective pain killers available today. This drug helps the patient to overcome pain
and focus on his or her work. Opioids have a risk of dependence and, when used improperly, a common side effect of high doses of opioids
like oxycodone can be euphoria, or a “high.” As a result of these side effects, opioids have become amongst the most misused
or abused prescription drugs in the United States. Opioid abuse was declared a public-health emergency in 2017 when more than 91 people
died each day from opioid-related overdoses. In 2021 the total number of opioid-related deaths rose to 109,600, with 45 people dying
each day from a prescription opioid overdose.
The
large increase in overall overdose deaths is now driven by use of synthetic opioids, in particular fentanyl, as prescription opioids
have become harder to obtain. From 2017 to 2018 the prescription opioid-involved death rates decreased by 13.5% showing that attention
to the problem had beneficial effect. However, 2.1 million people reported having opioid use disorder (“Opioid Use Disorder”)
in 2019. Based on information from the CDC, the most common drugs involved in prescription opioid overdose deaths include Methadone,
Oxycodone (such as OxyContin®), and Hydrocodone (such as Vicodin®). The CDC indicates that improving opioid prescribing, treatment
of opioid use disorder, and prevention of opioid use disorder would help to improve the opioid crisis. Misuse or abuse of opioids is
often done in one of the following manners:
Amphetamines
like Adderall are manufactured in pill form and are intended for oral ingestion. As of Q4 2022, seventy-five percent of Adderall prescriptions
are prescribed to the 10.5 million adults, age 22 or older, that are diagnosed with attention deficit hyperactivity disorder, or ADHD.
ADHD is the most common neurodevelopment disorder in children. Five million adults misuse stimulant medication annually, by using alternative
consumption methods to achieve a more intense high faster; snorting or injecting are most-common methods of abuse. Both of these methods
involve crushing pills.
We
believe that having prescription drug products available that have a reduced potential for abuse by crushing and injecting, snorting,
and chewing could provide an even greater reduction of prescription opioid related deaths in the abuse of opioids or amphetamines.
Nafamostat
Nafamostat’s
market opportunity is multifaceted. The oral form could be used alone or in combination with other antiviral drugs that target separate
processes needed for virus product, such as RNA replication or viral protein processing. 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.
Our
Technology Platform Solution
TAAP
Prescription Drugs
The
technology under the TAAP platform utilizes a novel technology designed to deter prescription drug abuse at the molecular level. The
molecular delivery system is designed to release clinically effective drugs only when exposed to specific physiological conditions (i.e.,
when the drug is ingested and exposed to the digestive enzyme trypsin). Our TAAP prodrugs delivery system demonstrates a number
of features aimed at resisting both oral and non-oral modes of abuse. This platform’s approach differs from current formulation-based
strategies (abuse deterrent formulations, or ADFs) in a number of ways. First, the abuse-resistance provided by TAAP is designed to be
unaffected by simple physical manipulations (e.g., crushing and extraction and/or chewing of the dose form provided to patients). We
believe the potential benefits to society of applying TAAP to opioids and amphetamines providing medication that resists both oral and
parenteral abuse are considerable.
MPAR®
Prescription Drugs
MPAR®
combination therapy, involves co-formulating TAAP prodrugs with a trypsin inhibitor, nafamostat, which, when administered at prescribed
dose levels, are intended to have no effect on the conversion of the prodrug to the active ingredient thus allowing normal drug plasma
exposure levels. However, if the drug were taken in greater than prescribed quantities, the trypsin inhibitor would also be present at
higher levels, inhibiting the first step in the activation process, preventing the conversion of the prodrug to the active ingredient
thus limiting the potential to an overdose from the medication.
Our
Development Programs
We
are currently developing product candidates designed to improve the safety and performance of prescription drugs. Our primary focus has
been on opioid pain products and opioid use disorder products. 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.
Clinical
agents
PF614
PF614
is a chemically modified, extended-release oxycodone-derivative which releases clinically effective oxycodone only when exposed trypsin
in the gut (i.e., when the drug is ingested). This approach differs from formulation-based strategies which are currently commercially
available, in a number of ways. 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.
Following
ingestion, the release of oxycodone from PF614 proceeds via a two-step process comprised of (1) trypsin activation in the small intestine
and (2) a subsequent intramolecular cyclization release reaction. This reaction releases oxycodone with concomitant formation of a cyclic
urea metabolite. The time-course of oxycodone release from PF614 is a function of the kinetics of (i) the trypsin hydrolysis and (ii)
the cyclization-release reaction. In the Phase 1 study of PF614, the time to maximal blood concentration of oxycodone (Tmax)
was five to six hours for the release of oxycodone and this time cannot be modified by crushing, chewing, or physically manipulating
the drug product. Oxycodone safety, metabolism, and pharmacokinetics have been well studied.
PF614-101
Phase 1 Clinical Trial
PF614
(IND 116796) has been evaluated in a Phase 1 clinical study for safety and pharmacokinetics of oxycodone release in 64 healthy subjects
in seven different closing cohorts from November 2016 to January 2018. This study was conducted for us by PRA Health Sciences –
Early Development Services Lenexa, Kansas, principal investigator, Daniel Dickerson, M.D., Ph.D. to evaluate the safety and pharmacokinetics
of PF614, as well as the pharmacokinetics of oxycodone at doses sufficient to characterize the extent to which plasma oxycodone is produced
and maintained following oral ingestion of PF614 and was compared to the oxycodone released from extended release oxycodone from OxyContin
OP. Subjects were randomized to receive a single dose of PF614 (dose of 15, 25, 50, 100, and 200 mg with 6 subjects per dosing group)
or OxyContin OP (dose of 10, 20, 50, and 80 mg with 2 subjects per dosing group). New subjects were recruited for each cohort. Cohort
1 compared subjects receiving PF614 and OxyContin OP with and without naltrexone blockade. Naltrexone is an opioid blocker to prevent
opioids from attaching to the opioid receptors, preventing the effect of the opioid medication such as pain relief, feeling of euphoria
or respiratory depression. The single ascending dose study also compared the release of oxycodone from PF614 under both fasted and fed
conditions at the highest dose of PF614 evaluated, 200 mg. The pharmacokinetics of the prodrug fragments was also evaluated. In addition,
this study instructed as to the “conversion efficiency” of the PF614 prodrug to oxycodone, with respect to OxyContin.
Pharmacokinetic
Analyses
The
shape of the plasma concentration versus time curve of oxycodone was similar following administration of OxyContin OP (oxycodone extended
release) and PF614. The efficiency of conversion for PF614 to oxycodone was determined to be approximately 86%. A PF614 dose of 50 mg
yields oxycodone exposure comparable to a 20.01 mg dose of OxyContin, indicating a potency ratio of 0.40. This data has allowed us to
match doses of PF614 to those of commercially available OxyContin OP.
Safety
A
total of 64 subjects were included in this study, of which 23 (35.9%) experienced 47 treatment-emergent adverse events, or TEAEs. The
majority of TEAEs were either gastrointestinal disorders or nervous system disorders with no deaths, serious adverse events, or severe
TEAEs. Additionally, there were no discontinuations due to study drug-related adverse events. Over half of TEAEs were study drug related,
but they were mostly mild in severity. The three TEAEs that were moderate in severity were nephrolithiasis, or kidney stones, nausea,
and vomiting, with the nausea and vomiting being study drug related. Comparing safety data across cohorts, the data indicated that dose,
naltrexone, and fed/fasted state had no clinically relevant effect on the safety profile of PF614. PF614 was generally well tolerated
at doses up to 200 mg in healthy subjects.
PF614-102
Phase 1b Clinical Trial
A
Phase 1b study was conducted by ICON (formerly PRA Health Sciences) with Dr. M Johnston as Principal investigator. This was a 2-part
study comprised of a MAD study (Part A) and a comparative bioavailability/bioequivalence and food effect study (Part B) in healthy subjects.
Part A treated a total of 24 subjects and utilized a randomized, open-label, MAD design with up to 3 separate dose groups of 8 subjects
per group. Within each dose group, subjects were randomized to receive either PF614 (n=6) or OxyContin (n=2). Subjects received repeated
BID doses, planned to be administered every 12 hours (q12h) over a 5-day period, for a total of 9 doses. PF614 doses were 50 mg, 100
mg, and 200 mg, which were expected to be approximately equivalent to the 20 mg, 40 mg, and 80 mg OxyContin doses, for Dose Groups 1,
2, and 3, respectively. Serial PK sampling was performed for the first day/first dose (Day 1) and for the last day/last dose (Day 5).
Only trough PK samples were taken within 30 minutes prior to the morning dose on Days 2, 3, and 4. Safety assessments, including regular
assessments of adverse events (AEs), vital signs (pulse rate, blood pressure, respiratory rate, and oxygen saturation [SpO2]),
clinical laboratory tests, 12-lead electrocardiograms (ECGs), and cardiac telemetry were monitored throughout the study. Subjects were
monitored for hypotension, hypopnea, apnea, and oxygen desaturation.
Part
B treated a total of 60 subjects and utilized an open-label, single-dose, randomized, 4-way crossover design. Subjects were randomized
to receive each of the following single oral doses of study drugs in a Williams design crossover manner (1 at each treatment period):
●
Treatment A: 100 mg PF614, administered under fasted conditions (hereafter referred to as 100 mg PF614, fasted)
●
Treatment B: 100 mg PF614, administered under fed conditions (high-fat breakfast) (hereafter referred to as 100 mg PF614, fed)
●
Treatment C: 40 mg OxyContin, administered under fasted conditions (hereafter referred to as 40 mg OxyContin, fasted)
●
Treatment D: 40 mg OxyContin, administered under fed conditions (high-fat breakfast) (hereafter referred to as 40 mg OxyContin, fed)
Each
treatment was separated by a washout interval of 5 days. Serial PK sampling was performed after each study drug administration up to
120 hours postdose. Safety including regular assessments of AEs, vital signs (pulse rate, blood pressure, respiratory rate, and SpO2
), clinical laboratory tests, and 12-lead ECGs were monitored. Subjects were monitored for hypotension, hypopnea, apnea, and oxygen
desaturation.
Pharmacokinetics
Part
A: The shape of the plasma concentration versus time curve of oxycodone was similar following administration of PF614 and OxyContin (oxycodone
extended release). Oxycodone plasma exposure (Tmax, Cmax,ss and AUCtau) were assessed and PF614 showed
similar trends as OxyContin following administration of multiple oral BID doses. Due to the small sample number for OxyContin some PK
parameters could not be calculated. Trough concentrations of oxycodone were generally similar from Day 2 through Day 4, suggesting that
subjects achieved steady state after repeated oral BID dosing of PF614 and OxyContin at all dose levels.
Part
B: A total of 57 subjects were included in the PK analyses. The data for Cmax, AUC0-t, and AUC0-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%. Therefore, it was concluded that 100 mg PF614 was bioequivalent to 40 mg OxyContin under both fasted
and fed conditions.
Safety
PF614
was generally safe and well-tolerated following oral administration of 50 mg, 100 mg, or 200 mg PF614 BID for 5 days. There was no apparent
difference in the safety profile of single oral doses of 100 mg PF614 when administered in the fasted or fed state or between PF614 and
OxyContin when administered in the fasted and fed state. PF614 was generally safe and well-tolerated following single and multiple oral
doses under naltrexone blockade.
PF614-103
Intranasal Human Abuse Potential Clinical Trial
PF614-103
was a randomized, double-blind, placebo- and active-controlled, 3-way crossover study to evaluate the abuse potential and pharmacokinetics
of intranasally administered PF614, relative to crushed oxycodone IR tablets and placebo, in non-dependent recreational opioid users
conducted by Lotus Clinical Trials LLC through Ohio Clinical Trials, Inc with Principal investigator, Dr. G. Apseloff.
The
study consisted of 4 phases: Screening, Qualification, Treatment, and Follow-up. Subjects were randomized to receive PF614 100mg or crushed
oxycodone 40 mg intranasally. The primary objective of the study was to evaluate the abuse potential of PF614 relative to crushed oxycodone
immediate-release (IR) tablets and placebo following intranasal administration in non-dependent recreational opioid users (n=26), with
the primary pharmacodynamic endpoint being the maximum effect (Emax) for Drug Liking (“at this moment”)
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 crushed oxycodone IR tablets following intranasal administration, to evaluate the safety
of PF614 following intranasal administration.
In
the study, PF614 powder produced a statistically significant lower peak “drug liking” (Emax) when compared with intranasal
crushed IR oxycodone (p = 0.0133) using the full modified completer population in a 3-period crossover of PF614 vs. crushed oxycodone
and placebo. Furthermore, in a first period analysis of initial impressions of each drug, a statistically significant difference was
noted between PF614 (n=8) and crushed IR oxycodone (n=10) (p = 0.0175), even with this smaller cohort of subjects.
Statistically
significant differences in peak effects (Emax) between PF614 and crushed IR oxycodone intranasal were also demonstrated for the secondary
endpoint of “take drug again,” also using a first period analysis (p < 0.0001).
The
intranasal HAP study was designed to test if known recreational drug users “liked” the product and is critical for
labeling claims for new drugs in this class. The primary measure in this study, “drug liking,” is recommended by the
FDA in their Guidance on “Assessment of Abuse Potential of Drugs.” This measure is known to correlate with a drug’s
potential for abuse. The results demonstrated that inhaled powdered PF614 had significantly lower drug liking than inhaled crushed IR
oxycodone.
PF614-104
Oral Human Abuse Potential Clinical Trial
PF614-104
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,
Kansas.
The
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 (Emax) 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.
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.
In
November 2022, we received written guidance from the FDA that an acute pain indication may be appropriate for PF614. The FDA guidance,
while not binding, states that our proposed clinical development approach of conducting at least two adequate and well-controlled clinical
trials in two different pain models comparing PF614 to a placebo and to another immediate release (IR) opioid, such as IR oxycodone,
appears reasonable to support a new drug application for PF614 for an acute pain indication. The FDA guidance also provides additional
guidance with respect to the non-clinical studies and clinical trials planned by us. The clinical development pathway of PF614 for an
acute pain indication may reduce the development timeline and be more cost-effective than initially pursuing a chronic pain indication
for PF614.
PF614-201
Time of Onset clinical study
PF614-201
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.
Next
Steps
An
End of Phase 2 regulatory meeting request for PF614 IND 116794 was submitted on October 13, 2023, with a meeting was held on January
30, 2024. 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.
PF614-MPAR