What changed in this filing

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Item 1. Business

2026-03-30 compared with 2025-03-10 · 151 added, 131 removed, 1119 unchanged (20% of the section changed)

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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).

page on our website, blog posts on our website, press releases, public conference calls, webcasts, and our X feed (@EnsysceBio).

information disclosed by the foregoing channels could be deemed to be material information.

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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,

Activated Abuse Protection, or the TAAP platform, and an overdose protection opioid prodrug technology - the Multi-Pill Abuse Resistant,

or the MPAR® platform.

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enrollment of subjects in December 2024 and is continuing enrollment.

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.

pipeline has been developed over the course of more than twenty years of research and investment and includes three clinical-stage product

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.

is our lead TAAP prodrug candidate under development for the treatment of acute or chronic pain.

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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.

used to design our Phase 3 clinical trial.

initiated our pivotal Phase 3 trial, PF614-301, examining the efficacy of PF614 in post-operative acute pain following abdominoplasty

in July 2025 and enrollment began in December 2025.

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

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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

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.

second three-part trial, PF614-MPAR-102, began in December 2024 to examine a 100 mg dose of PF614-MPAR.

Parts 1 and 2 of the trial have

been completed and Part 3 is currently ongoing.

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.

Abuse and Drug Overdose

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In 2021, the total number of opioid-related deaths rose to 109,600, whereas in 2022 that

number had declined to 81,806.

number declined to 81,806.

CDC data projects that almost 80,000 people die every year from opioid overdose, of which prescription opioids

factor into 12.4% of these deaths ( https://drugabusestatistics.org/opioid-epidemic/ ).

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

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Misuse or abuse of opioids is often done in one of the following manners:

Excessive Tablet Abuse .

Generally recognized as the most prevalent route of administration by abusers, an abuser orally ingests

more tablets (or capsules) than is recommended for pain relief.

Oral Excessive Tablet

Generally recognized as the most prevalent route of administration by abusers, an abuser orally ingests more tablets (or

capsules) than is recommended for pain relief.

Nasal snorting .

Crushed tablets are insufflated for absorption of the drug through the nasal tissues.

The opioid is physically or chemically removed from the dosage and injected into the vein using a syringe.

Manipulated Tablet Abuse .

Extended-release tablets or patches are crushed, chewed, or otherwise physically or chemically manipulated

to defeat an extended-release mechanism and provide an immediate-release of the opioid for oral ingestion.

is physically or chemically removed from the dosage and injected into the vein using a syringe.

Oral Manipulated Tablet

Extended-release tablets or patches are crushed, chewed, or otherwise physically or chemically manipulated to defeat an

extended-release mechanism and provide an immediate-release of the opioid for oral ingestion.

Poly-pharmacy .

Opioids are sometimes used in conjunction with alcohol, methamphetamine, benzodiazepines or other drugs to enhance the euphoria.

Users may accidentally introduce excessive quantities of drugs in their systems or combine drugs that may heighten the chance of

adverse effects of drugs.

are sometimes used in conjunction with alcohol, methamphetamine, benzodiazepines or other drugs to enhance the euphoria.

may accidentally introduce excessive quantities of drugs in their systems or combine drugs that may heighten the chance of adverse

effects of drugs.

Some patients may over-ingest drugs accidentally or with the express intent of suicide.

or prolonged use.

Chronic or prolonged

Chronic or prolonged use of opioids resulting in dependence is another form of misuse or abuse.

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

End of Phase 2 regulatory 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-2025.

Phase 3 Clinical Trial

pivotal PF614-301 trial is a multicenter, randomized, double-blind, placebo-controlled study evaluating the efficacy and safety of PF614

for the treatment of moderate to severe pain following abdominoplasty.

The study is designed to demonstrate PF614’s ability to provide

strong, consistent post-surgical pain relief while incorporating an innovative chemical mechanism intended to reduce the risk of abuse.

The trial will also evaluate PF614’s potential to provide a smoother, safer treatment of severe acute pain using twice daily dosing with

reduced highs and lows in blood drug concentration, an approach which is seen as beneficial by leaders in the field.

Enrollment in the

study began in December 2025.

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

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The study initiated in December

2024 and will continue through 2025.

2024 and is expected to be completed in 2026.

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

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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

Comprising Enzyme-Cleavable Ketone-Modified Opioid Prodrugs and Optional Inhibitors Thereof

Australia, Brazil, Canada, China, Europe, Hong Kong, Israel, India, Japan, Mexico, Russia

Comprising Enzyme-Cleavable Opioid Prodrugs and Inhibitors Thereof

Comprising Enzyme-Cleavable Oxycodone Prodrugs

Australia, Brazil, Canada, China, Europe, Hong Kong, Israel, India, Japan, Russia

Comprising Enzyme-Cleavable Prodrugs and Controlled Release Nafamostat and Methods of Use Thereof

Agent Prodrugs with Heterocyclic Linkers

Australia, Brazil, Canada, China, Europe, Hong Kong, Israel, India, Japan, Russia

Enzyme-Cleavable

Methadone Prodrugs and Methods of Use Thereof

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

Patents and Applications

of Treating Coronavirus Infections and COVID-19

Canada, Europe

formulations of Nafamostat

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

of Treating Respiratory Diseases with Mucostasis

France, Italy, United Kingdom

and MPAR Patents and Applications for Amphetamines

Comprising Enzyme-Cleavable Amphetamine Prodrugs and Inhibitors Thereof

Europe, Hong Kong

Natural or Projected

TAAP and MPAR Patents and Applications for Opioids

Compositions Comprising Enzyme-Cleavable

Ketone-Modified Opioid Prodrugs and Optional Inhibitors Thereof

U.S., Australia, Brazil, Canada,

China, Europe, Hong Kong, Israel, India, Japan, Mexico, Russia

Compositions Comprising Enzyme-Cleavable Opioid Prodrugs

and Inhibitors Thereof

Compositions Comprising Enzyme-Cleavable Oxycodone

U.S., Australia, Brazil, Canada, China, Europe, Hong

Kong, Israel, India, Japan, Russia

Compositions Comprising Enzyme-Cleavable Prodrugs and

Controlled Release Nafamostat and Methods of Use Thereof

U.S., PCT, Taiwan

Active Agent Prodrugs with Heterocyclic Linkers

U.S., Australia, Brazil, Canada, China, Europe, Hong

Kong, Israel, India, Japan, Russia

Enzyme-Cleavable Methadone Prodrugs and Methods of

U.S., PCT, Europe, Brazil, China, Japan, Korea, Canada,

Mexico, Australia, India, Israel

Nafamostat Patents and Applications

Methods of Treating Coronavirus Infections and COVID-19

U.S., Canada, Europe

Oral formulations of Nafamostat

U.S., PCT, Taiwan, Europe, Brazil, China, Japan, Korea,

Canada, Mexico, Australia, India, Israel

Methods of Treating Respiratory Diseases with Mucostasis

Germany, France, Italy, United Kingdom

TAAP and MPAR Patents and Applications for Amphetamines

Compositions Comprising Enzyme-Cleavable Amphetamine

Prodrugs and Inhibitors Thereof

Compositions Comprising Enzyme-Cleavable Amphetamine

Prodrugs and Inhibitors Thereof

U.S., Europe, Hong Kong

refers to patent applications filed in, and patents issued by, the European Patent Office (“ EPO ”), which can provide

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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

We also own issued United States and pending 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.

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and MPAR® Patents and Applications for Amphetamines

are the owner of one patent family that includes pending applications in the United States and numerous European foreign jurisdictions

relating to chemically modified amphetamines covalently linked to a gastrointestinal enzyme-cleavable moiety, pharmaceutical compositions

containing the modified amphetamines, pharmaceutical compositions containing the modified amphetamines and a gastrointestinal enzyme

inhibitor and methods of using the same to treat a subject.

While we own this patent family, we have not updated the records in the various

patent offices to reflect our ownership of this patent family.

Failure to update such ownership may result in an innocent purchaser potentially

acquiring rights in such patents that are adverse to our interests.

In addition, we own pending 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 subject.

We have not obtained assignments from all of the inventors

of these applications to date, which could negatively impact our ability to pursue or enforce this application.

If issued, these patent

applications would expire between 2031 and 2040, subject to any applicable patent term adjustment or extension that might be available

in a jurisdiction.

are the owner of two patent families that include issued and pending applications in the United States and numerous European foreign

jurisdictions relating to chemically modified amphetamines covalently linked to a gastrointestinal enzyme-cleavable moiety, pharmaceutical

compositions containing the modified amphetamines, pharmaceutical compositions containing the modified amphetamines and a gastrointestinal

enzyme inhibitor and methods of using the same to treat a subject.

While we own these patent families, we have not updated the records

in the various patent offices to reflect our ownership of this patent family.

Failure to update such ownership may result in an innocent

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

In addition, we own pending 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 subject.

We have not obtained

assignments from all of the inventors of these applications to date, which could negatively impact our ability to pursue or enforce this

If issued, these patent applications would expire between 2031 and 2040, subject to any applicable patent term adjustment

or extension that might be available in a jurisdiction.

and Trade Secrets

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For the year ended

December 31, 2024, we received federal grant funding totaling $5.2 million consisting of $3.1 million from NIH related to the Phase 1

clinical trial for PF614-MPAR and $2.1 million from NIDA for preclinical development of our opioid use disorder-MPAR ®

Current remaining funding under the PF614-MPAR grant totaled $1.6 million as of December 31, 2024, covering the period through

The PF614-MPAR grant includes a remaining $9.0 million of approved funding through May 2027.

December 31, 2025, we received federal grant funding totaling $4.8 million from NIH related to the Phase 1 clinical trial for PF614-MPAR.

Current remaining funding under the PF614-MPAR grant totaled $2.1 million as of December 31, 2025, covering the period through May 2026.

The PF614-MPAR grant also includes $5.3 million of pending funding from June 2026 through May 2027.

We may apply for additional grant

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actions to address the opioid abuse epidemic include:

In April 2015, the FDA adopted final guidance regarding studies and clinical trials that should be conducted to demonstrate

that a given formulation has abuse-deterrent properties, how those studies and clinical trials will be evaluated, and what product

labeling claims may be approved based on the results of those studies and clinical trials.

The guidance describes four categories

of abuse-deterrence studies and clinical trials:

Categories 1, 2, and 3 consist of pre-marketing studies and clinical trials designed

to evaluate a product candidate’s potentially abuse-deterrent properties under controlled conditions, while Category 4, post-marketing

clinical trials and studies, assesses the real-world impact of abuse-deterrent formulations.

The final guidance also provides examples

of product label claims that may be made based on the results of the corresponding studies and clinical trials.

Opioids Action Plan:

In February 2016, the FDA released an action plan to address the opioid abuse epidemic and reassess the FDA’s

approach to opioid medications.

FDA guidance:

2015, the FDA adopted final guidance regarding studies and clinical trials that should be conducted to demonstrate that a given formulation

has abuse-deterrent properties, how those studies and clinical trials will be evaluated, and what product labeling claims may be

approved based on the results of those studies and clinical trials.

The guidance describes four categories of abuse-deterrence studies

and clinical trials:

Categories 1, 2, and 3 consist of pre-marketing studies and clinical trials designed to evaluate a product candidate’s

potentially abuse-deterrent properties under controlled conditions, while Category 4, post-marketing clinical trials and studies,

assesses the real-world impact of abuse-deterrent formulations.

The final guidance also provides examples of product label claims

that may be made based on the results of the corresponding studies and clinical trials.

FDA Opioids Action Plan:

In February 2016, the FDA released an action plan to address the opioid abuse epidemic and reassess the FDA’s approach to opioid

The FDA’s plan is part of a broader initiative led by the U.S.

Department of Health and Human

Services (“ HHS ”), to address opioid-related overdose, death, and dependence.

Prescribing Guidelines:

In November 2022, the CDC released a new Guideline for Prescribing Opioids for Pain to update their 2016

The new guidance includes recommendations for managing acute (duration of <1 month), subacute (duration of 1–3

months), and chronic (duration of >3 months) pain.

Department of Health and Human Services (“ HHS ”),

to address opioid-related overdose, death, and dependence.

CDC Prescribing Guidelines:

In November 2022, the CDC released a new Guideline for Prescribing Opioids for Pain to update their 2016 Guidelines.

The new guidance

includes recommendations for managing acute (duration of <1 month), subacute (duration of 1–3 months), and chronic (duration

of >3 months) pain.

The guideline addresses the following four areas:

1) determining whether or

not to initiate opioids for pain, 2) selecting opioids and determining opioid dosages, 3) deciding duration of initial opioid prescription

and conducting follow-up, and 4) assessing risk and addressing potential harms of opioid use.

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:

In March 2016, the FDA announced required enhanced warnings for immediate-release opioid pain medications

related to risks of misuse, abuse, addiction, overdose, and death.

Subsequently, there have been several class-wide labeling changes,

including the addition of boxed warnings relating to serious risks of using certain opioids medications along with benzodiazepines

and other central nervous system depressants, including alcohol (Decembers 2016);

and additional information relating to the new

class-wide REMS (Septembers 2018).

of the Comprehensive Addiction and Recovery Act (“ CARA ”):

In 2016, the CARA was enacted to address the national

epidemics of prescription opioid abuse and heroin use.

Consistent with the initiatives of HHS, this legislation sought to, among

other things, expand the availability of naloxone for law enforcement and other first responders;

form an interagency task force

to develop best practices for pain management with opioid medications;

and provide resources to improve state monitoring of controlled

substances, including opioids.

In 2018, CARA 2.0 was introduced as follow-up legislation to limit initial prescriptions for opioids

to 3 days, while exempting initial prescriptions for chronic care, cancer care, hospice or end of life care, and palliative care.

of the Substance Use-Disorder Prevention that Promotes Opioid Recovery and Treatment for Patients and Communities Act (“ SUPPORT

1) determining whether or not to initiate opioids for pain,

2) selecting opioids and determining opioid dosages, 3) deciding duration of initial opioid prescription and conducting follow-up,

and 4) assessing risk and addressing potential harms of opioid use.

FDA 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.

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.

Enhanced Warnings and Safety

In March 2016, the FDA announced required enhanced warnings for immediate-release opioid pain medications related to risks

of misuse, abuse, addiction, overdose, and death.

Subsequently, there have been several class-wide labeling changes, including the

addition of boxed warnings relating to serious risks of using certain opioids medications along with benzodiazepines and other central

nervous system depressants, including alcohol (Decembers 2016);

and additional information relating to the new class-wide REMS (Septembers

Enactment of the Comprehensive

Addiction and Recovery Act (“ CARA ”):

In 2016, the CARA was enacted to address the national epidemics of prescription

opioid abuse and heroin use.

Consistent with the initiatives of HHS, this legislation sought to, among other things, expand the availability

of naloxone for law enforcement and other first responders;

form an interagency task force to develop best practices for pain management

with opioid medications;

and provide resources to improve state monitoring of controlled substances, including opioids.

CARA 2.0 was introduced as follow-up legislation to limit initial prescriptions for opioids to 3 days, while exempting initial prescriptions

for chronic care, cancer care, hospice or end of life care, and palliative care.

Enactment of the Substance

Use-Disorder Prevention that Promotes Opioid Recovery and Treatment for Patients and Communities Act (“ SUPPORT Act ”):

In November 2018, the SUPPORT Act was enacted as a comprehensive legislative response to the continuing opioid epidemic.

It includes a number of measures directed towards regulation and improvement of treatment for substance use-disorder and increased

coverage by CMS of medically assisted treatment options.

In addition, the SUPPORT Act requires HHS to report to Congress on existing

barriers to access to abuse-deterrent opioid formulations by Medicare Part C and D beneficiaries.

a number of measures directed towards regulation and improvement of treatment for substance use-disorder and increased coverage by

CMS of medically assisted treatment options.

In addition, the SUPPORT Act requires HHS to report to Congress on existing barriers

to access to abuse-deterrent opioid formulations by Medicare Part C and D beneficiaries.

It also includes a number of requirements

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Capital Resources (Employees)

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

have eight full-time employees and two part-time employees.

Of these, five have a Ph.D.

From 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.

From 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.

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