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Item 1. Business

2022-03-25 compared with 2021-03-24 · 860 added, 598 removed, 64 unchanged (96% of the section changed)

Business Overview

Relmada Therapeutics, Inc.

(Relmada, the

Company, we or us) (a Nevada corporation), is a clinical-stage biotechnology company focused on the development of esmethadone

(d-methadone, dextromethadone, REL-1017), an N-methyl-D-aspartate (NMDA) receptor antagonist.

esmethadone is a new chemical entity

(NCE) that potentially addresses areas of high unmet medical need in the treatment of central nervous system (CNS) diseases and

other disorders.

October 7, 2019, our application to list our common stock on the Nasdaq Capital Market was approved.

On October 10, 2019,

our common stock began trading on Nasdaq under our existing symbol, “RLMD.”

December 19, 2019, the Board of Directors of the Company approved a change to its end of fiscal year from June 30 to December

The change in fiscal year became effective for the Company’s 2020 fiscal year, which began January 1, 2020 and ended

December 31, 2020.

Accordingly the Company filed the transition report on Form 10-KT for the six-month period from July 1, 2019

through December 31, 2019 within the time period prescribed by the Securities and Exchange Commission.

Our lead product candidate, esmethadone,

is an NCE being developed as a rapidly acting, oral agent for the treatment of depression and other potential indications.

have previously completed Phase 1 single and multiple ascending dose studies and on October 15, 2019 we reported top-line data

from study REL-1017-202.

(Relmada, the Company,

we or us) (a Nevada corporation), is a clinical-stage biotechnology company focused on the development of esmethadone (d-methadone, dextromethadone,

REL-1017), an N-methyl-D-aspartate (NMDA) receptor antagonist.

Esmethadone is a new chemical entity (NCE) that potentially addresses areas

of high unmet medical need in the treatment of central nervous system (CNS) diseases and other disorders.

Our lead product candidate, esmethadone, is being

developed as a rapidly acting, oral agent for the treatment of depression and other potential indications.

On October 15, 2019 we reported

top-line data from study REL-1017-202.

This was a double-blind, placebo-controlled Phase 2 clinical trial evaluating the safety, tolerability

and efficacy of two oral doses of REL-1017, 25 mg once a day and 50 mg once a day, as an adjunctive treatment in patients with

major depressive disorder (MDD), who experienced an inadequate response to 1 to 3 adequate antidepressant treatments with an antidepressant

the REL-1017-202 study, 62 subjects, average age 49.2 years, with an average Hamilton Depression Rating Scale score of 25.3 and

an average Montgomery-Asberg Depression Rating Scale (MADRS) score of 34.0 (severe depression), were randomized.

Other demographic

characteristics were balanced across all arms.

After an initial screening period, subjects were randomized to one of three arms:

placebo, REL-1017 25 mg or REL-1017 50 mg, in addition to stable background antidepressant therapy.

Subjects in the REL-1017 treatment

arms received one loading dose of either 75 mg (25 mg arm) or 100 mg (50 mg arm) of REL-1017.

Subjects were treated inpatient

for 7 days and discharged home at Day 9.

They returned for follow-up visits at Day 14 and Day 21.

Efficacy was measured on Days

2, 4 and 7 in the dosing period and on Day 14, one week after treatment discontinuation.

61 subjects received all treatment doses

and were included in the per-protocol population (PPP) treatment analysis;

57 subjects completed all visits.

All 62 randomized

subjects were part of the intention-to-treat (ITT) analysis.

No differences were observed between the ITT and PPP analyses and

observed that subjects in both the REL-1017 25 mg and 50 mg treatment groups experienced statistically significant improvement

on all efficacy measures tested as compared to subjects in the placebo group, including:

the Montgomery-Asberg Depression Rating

Scale (MADRS);

the Clinical Global Impression –

Severity (CGI-S) scale;

the Clinical Global Impression –

(CGI-I) scale;

and efficacy of two oral doses of REL-1017, 25 mg once a day and 50 mg once a day, as an adjunctive treatment in patients with major depressive

disorder (MDD), who experienced an inadequate response to 1 to 3 adequate antidepressant treatments with an antidepressant medication.

In the REL-1017-202 study, 62 subjects, average

age 49.2 years, with an average Hamilton Depression Rating Scale score of 25.3 and an average Montgomery-Asberg Depression Rating Scale

(MADRS) score of 34.0 (severe depression), were randomized.

Other demographic characteristics were balanced across all arms.

initial screening period, subjects were randomized to one of three arms:

placebo, REL-1017 25 mg or REL-1017 50 mg, in addition to stable

background antidepressant therapy.

Subjects in the REL-1017 treatment arms received one loading dose of either 75 mg (25 mg arm) or 100

mg (50 mg arm) of REL-1017.

Subjects were treated inpatient for 7 days and discharged home at Day 9.

They returned for follow-up visits

at Day 14 and Day 21.

Efficacy was measured on Days 2, 4 and 7 in the dosing period and on Day 14, one week after treatment discontinuation.

61 subjects received all treatment doses and were included in the per-protocol population (PPP) treatment analysis;

57 subjects completed

All 62 randomized subjects were part of the intention-to-treat (ITT) analysis.

No differences were observed between the ITT

and PPP analyses and results.

Key findings:

We observed that subjects in both the REL-1017

25 mg and 50 mg treatment groups experienced statistically significant improvement on all efficacy measures tested as compared to subjects

in the placebo group, including:

the Montgomery-Asberg Depression Rating Scale (MADRS);

the Clinical Global Impression – Severity

(CGI-S) scale;

the Clinical Global Impression – Improvement (CGI-I) scale;

and the Symptoms of Depression Questionnaire (SDQ).

improvement on the MADRS appeared on Day 4 in both REL-1017 dose groups and continued through Day 7 and Day 14, seven days after

treatment discontinuation, with P values< 0.03 and large effect sizes (a measure of quantifying the difference between two

groups), ranging from 0.7 to 1.0.

Similar findings emerged from the CGI-S and CGI-I scales.

Analysis of Change from Baseline to Day 7 and to Day 14 ITT Population

Improvements on the MADRS endpoint appeared on

Day 4 in both REL-1017 dose groups and continued through Day 7 and Day 14, seven days after treatment discontinuation, with P values<

0.03 and large effect sizes (a measure of quantifying the difference between two groups), ranging from 0.7 to 1.0.

Similar findings emerged

from the CGI-S and CGI-I scales.

Analysis of Change from Baseline to

Day 7 and to Day 14 ITT Population

Means Difference

4 unchanged sentences

50mg vs Placebo

= Least Squares;

d = Cohen’s effect size

The study also supported the favorable

tolerability profile of REL-1017, which was also observed in the Phase 1 studies.

Subjects experienced mild and moderate adverse

events (AEs), and no serious adverse events, without significant differences between placebo and treatment groups.

The AEs observed

in the Phase 2 clinical study were of the same nature as those observed in the Phase 1 clinical studies in esmethadone, and importantly

there was no evidence of either treatment induced psychotomimetic and dissociative AEs or withdrawal signs and symptoms upon treatment

LS = Least Squares;

d = Cohen’s effect size

The study also confirmed the tolerability

profile of REL-1017, which was observed in the Phase 1 studies.

Subjects experienced only mild and moderate adverse events (AEs),

and no serious adverse events, without significant differences between placebo and treatment groups.

The AEs observed in the Phase

2a clinical study were of the same nature as those observed in the Phase 1 clinical studies in d-Methadone, and there was no

evidence of either treatment induced psychotomimetic and dissociative AEs or withdrawal signs and symptoms upon treatment

discontinuation.

December 20, 2020 we announced that the first patient had been enrolled in the first Phase 3 clinical trial (RELIANCE I) for the

Company's lead product candidate, REL-1017, as an adjunctive treatment for major depressive disorder (MDD).

points of the Phase 3 program agreed upon in discussions with FDA include:

Phase 3 program will consist of two sister, two-arm, placebo-controlled clinical trials.

Each trial will be conducted in 55 clinical sites in the United States and will include

approximately 400 MDD patients with inadequate response to standard antidepressants

in their current depression episode.

Patients will add either a 25 mg oral dose

of REL-1017 once per day or placebo to their ongoing antidepressant treatment.

primary endpoint to be evaluated will be the change from baseline on the Montgomery and

Asberg Depression Rating Scale (MADRS) score at day-28 for REL-1017 compared to

Success on this endpoint with the collection of sufficient safety data

would support the use of REL-1017 for chronic treatment, if approved.

change from baseline and the 7-day MADRS score will serve as a key secondary endpoint

and will provide data on the rapid onset of treatment effect;

statistically significant

separation between REL-1017 and the control group was achieved by day 4 in the Phase

2 proof-of-principle trial completed in 2019.

Company expects to initiate the second Phase 3 trial, RELIANCE II, in the first half

Patients who complete RELIANCE I and RELIANCE II will be eligible to rollover

into the long-term, open-label study, which is also expected to include subjects who

had not previously participated in a REL-1017 clinical trial.

Upcoming Anticipated Milestones

expect multiple key milestones over the next 12-18 months.

Phase 3 Program

On December 20, 2020, Relmada announced that the

first patient had been enrolled in the first Phase 3 clinical trial (RELIANCE I) for the Company's lead product candidate, REL-1017, as

an adjunctive treatment for major depressive disorder MDD.

Following discussions with the Food and Drug Administration

(FDA), Relmada’s adjunctive MDD Phase 3 program includes the following key attributes:

The Phase 3 program consists of two sister, two-arm, placebo-controlled

clinical trials.

Each trial is conducted in 55 clinical sites in the United States with planned enrollment of 364 MDD patients

with inadequate response to standard antidepressants in their current depression episode.

Patients will add either a 25 mg

oral dose of REL-1017 once per day or placebo to their ongoing antidepressant treatment.

The primary endpoint to be evaluated will be the change from baseline on the MADRS score at day-28 for REL-1017 compared to placebo.

Success on this endpoint with the collection of sufficient safety data would support the use of REL-1017 for chronic treatment, if approved.

The change from baseline and the 7-day MADRS score will serve as a key secondary endpoint and will provide information on the time to treatment effect.

On April 1, 2021, Relmada

announced the initiation of RELIANCE II, the second of two sister pivotal Phase 3 clinical trials (RELIANCE I and RELIANCE II) for the

Company’s lead product candidate, REL-1017, as an adjunctive treatment for MDD.

Patients who complete RELIANCE I and RELIANCE II

are eligible to rollover into the long-term, open-label study, which also includes subjects who had not previously participated in a REL-1017

clinical trial.

On October 4, 2021,

Relmada announced the initiation of RELIANCE III study, the ongoing monotherapy trial for the Company’s lead product candidate,

REL-1017, which aims to randomize 364 patients and it is expected to be completed in mid-2022.

In addition, in order

to support potential regulatory submissions seeking approval for REL-1017 as monotherapy and adjunctive treatment, the FDA confirmed that,

based on what is known at this time, Relmada will not be required to conduct a two-year carcinogenicity study of REL-1017, as sufficient

clinical data have been generated to date.

The FDA also confirmed that Relmada does not need to conduct a Thorough QT analysis (TQT) cardiac

study in humans to support cardiac safety in potential regulatory submissions for REL-1017, as the data provided so far and the data generated

by the Phase 3 program will be adequate to evaluate the cardiac safety profile of REL-1017.

Human Abuse Potential (HAP) Study top-line

results - Oxycodone:

On July 27, 2021, we

announced top-line results that showed that all three doses of REL-1017 (25 mg, 75 mg and 150 mg, the therapeutic, supratherapeutic and

maximum tolerated doses, respectively) tested in recreational opioid users, demonstrated a highly statistically significant difference

the active control drug, oxycodone 40 mg.

The study’s primary endpoint was a measure of “likability” with the subjects

rating the maximum effect (or Emax) for Drug Liking “at the moment”, using a 1=100 bipolar rating scale (known as a visual

analog scale or VAS), with 100 as the highest likability, 50 as neutral (placebo-like), and 0 the highest dislike.

In summary, all tested

doses of REL-1017, including the maximum tolerated dose, showed a highly statistically significant difference in abuse potential versus

oxycodone with p-values less than 0.001.

Results are detailed

in the table below:

Mean Emax for Drug Liking

P-value for Difference vs.

oxycodone 40 mg

P-value for REL-1017 vs.

These statistically significant data clearly demonstrate

a very meaningful difference between REL-1017 and oxycodone at all three tested doses.

These results, along with previously published

literature, support the lack of opioid effects of REL-1017.

Abuse Potential (HAP) Study top-line results - Ketamine:

On February 23, 2022, we announced top-line results that showed that

all three doses of REL-1017 (25 mg, 75 mg, and 150 mg, the therapeutic, supratherapeutic and maximum tolerated doses, respectively) tested

in recreational drug users, demonstrated a substantial (30+ points) and statistically significant difference vs.

the active control drug,

intravenous ketamine 0.5 mg/kg over 40 minutes, and were statistically equivalent to placebo.

The study's primary endpoint was a measure

of "likability" with the subjects rating the maximum effect (or Emax) for Drug Liking "at this moment", using a 1-100

bipolar rating scale (known as a visual analog scale or VAS), with 100 as the highest likability, 50 as neutral (placebo-like), and 0

the highest dislike.

Consistent results are seen for the secondary endpoints.

of the primary endpoint are summarized in the table below.

Mean Emax for Drug Liking

P-value for Difference vs.

ketamine 0.5mg/Kg over 40 minutes

P-value for REL-1017 vs.

These statistically significant data clearly demonstrate a very meaningful

difference between REL-1017 and ketamine at all three tested doses.

The REL-1017 results were also statistically equivalent to placebo.

Key Upcoming Anticipated Milestones

We expect multiple key milestones over the next

12-18 months.

These include:

of RELIANCE II, the second pivotal Phase 3 adjunctive MDD trial in the first half of 2021.

Start of Phase 2 monotherapy MDD trial in the first half of 2021.

Results of oxycodone human abuse potential study in the second quarter of 2021.

Results of IV ketamine human abuse potential study in the fourth quarter of 2021.

of RELIANCE I and RELIANCE II adjunctive MDD trials in the first half of 2022.

Development Program

Esmethadone (d-Methadone, dextromethadone, REL-1017) as a

treatment for MDD

2014, the National Institute of Mental Health (NIMH) estimated that 15.7 million adults aged 18 or older in the United States

had at least one major depressive episode in the past year.

According to data from nationally representative surveys supported

by NIMH, only about half of Americans diagnosed with major depression in a given year receive treatment.

Of those receiving treatment

with as many as four different standard antidepressants, 33% of drug-treated depression patients do not achieve adequate therapeutic

benefits according to the Sequenced Treatment Alternatives to Relieve Depression (STAR*D) trial published in the American Journal

of Psychiatry.

addition to the high failure rate, only one of the marketed products for depression, esketamine (marketed by Johnson and Johnson

as Spravato), an in-clinic nasal spray treatment can demonstrate rapid antidepressant effects, while the other currently approved

products can take two to four weeks to show activity.

The urgent need for improved, faster acting antidepressant treatments is

underscored by the fact that severe depression can be life-threatening, due to heightened risk of suicide.

Results of RELIANCE III monotherapy MDD trial in mid-2022.

Results of RELIANCE I and RELIANCE II adjunctive MDD trials in the second half of 2022.

Results of RELIANCE – OLS (Long-term, Open-label) study in MDD in the second half of 2022.

Our Development Program

Esmethadone (d-Methadone, dextromethadone, REL-1017) as a treatment

In 2014, the National Institute of Mental Health

(NIMH) estimated that 15.7 million adults aged 18 or older in the United States had at least one major depressive episode in the past

According to data from nationally representative surveys supported by NIMH, only about half of Americans diagnosed with major depression

in a given year receive treatment.

Of those receiving treatment with as many as four different standard antidepressants, 33% of drug-treated

depression patients do not achieve adequate therapeutic benefits according to the Sequenced Treatment Alternatives to Relieve Depression

(STAR*D) trial published in the American Journal of Psychiatry.

In addition to the high failure rate, only one of the marketed products

for depression, esketamine (marketed by Johnson and Johnson as Spravato), an in-clinic nasal spray treatment can demonstrate rapid antidepressant

effects, while the other currently approved products can take two to eight weeks to show activity.

The urgent need for improved, faster

acting antidepressant treatments is underscored by the fact that severe depression can be life-threatening, due to heightened risk of

Esmethadone Overview and Mechanism of Action

Esmethadone’s mechanism of action,

as a low affinity, non-competitive NMDA channel blocker or antagonist, is fundamentally differentiated from most currently FDA-approved

antidepressants, as well as all atypical antipsychotics used adjunctively with standard, FDA-approved antidepressants.

through the same brain mechanisms as ketamine and esketamine but potentially lacking its adverse side effects, esmethadone is being

developed as a rapidly acting, oral agent for the treatment of depression and potentially other CNS conditions.

In chemistry an enantiomer, also known

as an optical isomer, is one of two stereoisomers that are mirror images of each other that are non-superimposable (not identical),

much as one’s left and right hands are the same except for being reversed along one axis.

A racemic compound, or racemate,

is one that has equal amounts of left- and right-handed enantiomers of a chiral molecule.

For racemic drugs, often only one of

a drug’s enantiomers is responsible for the desired physiologic effects, while the other enantiomer is less active or inactive.

As a single isomer of racemic methadone,

esmethadone has been shown to possess NMDA antagonist properties with virtually no traditional opioid or ketamine-like adverse

events at the expected therapeutic doses.

In contrast, racemic methadone is associated with common opioid side effects that include

anxiety, nervousness, restlessness, sleep problems (insomnia), nausea, vomiting, constipation, diarrhea, drowsiness, and others.

It has been shown that the left (levo) isomer, l-methadone, is largely responsible for methadone’s opioid activity, while

the right (dextro) isomer, esmethadone, at the currently therapeutic doses used in development is virtually inactive as an opioid

while maintaining affinity for the NMDA receptor.

NMDA receptors are present in many parts

of the CNS and play important roles in regulating neuronal activity and promoting synaptic plasticity in brain areas important

for cognitive functions such as executive function, learning and memory.

Based on these premises, esmethadone could show benefits

in several different CNS indications.

Esmethadone (d-methadone, dextromethadone, REL-1017) in other

In addition to developing esmethadone as

an adjunctive treatment of MDD, we are planning to evaluate the utility of esmethadone as a front line monotherapy treatment for

Additionally, other indications that Relmada

may explore in the future, include, restless leg syndrome and other glutamatergic system activation related diseases.

Esmethadone’s mechanism of action, as a

low affinity, non-competitive NMDA channel blocker or antagonist, is fundamentally differentiated from most currently FDA-approved antidepressants,

as well as all atypical antipsychotics used adjunctively with standard, FDA-approved antidepressants.

Working through the same brain mechanisms

as ketamine and esketamine but potentially lacking its adverse side effects, esmethadone is being developed as a rapidly acting, oral

agent for the treatment of depression and potentially other CNS conditions.

In chemistry an enantiomer, also known as an optical

isomer, is one of two stereoisomers that are mirror images of each other that are non-superimposable (not identical), much as one’s

left and right hands are the same except for being reversed along one axis.

A racemic compound, or racemate, is one that has equal amounts

of left- and right-handed enantiomers of a chiral molecule.

For racemic drugs, often only one of a drug’s enantiomers is responsible

for the desired physiologic effects, while the other enantiomer is less active or inactive.

As a single isomer of racemic methadone, esmethadone

has been shown to possess NMDA antagonist properties with virtually no traditional opioid or ketamine-like adverse events at the expected

therapeutic doses.

In contrast, racemic methadone is associated with common opioid side effects that include anxiety, nervousness, restlessness,

sleep problems (insomnia), nausea, vomiting, constipation, diarrhea, drowsiness, and others.

It has been shown that the left (levo) isomer,

l-methadone, is largely responsible for methadone’s opioid activity, while the right (dextro) isomer, esmethadone, at the currently

therapeutic doses used in development is virtually inactive as an opioid while maintaining affinity for the NMDA receptor.

NMDA receptors are present in many parts of the

CNS and play important roles in regulating neuronal activity and promoting synaptic plasticity in brain areas important for cognitive

functions such as executive function, learning and memory.

Based on these premises, esmethadone could show benefits in several different

CNS indications.

Esmethadone (d-methadone, dextromethadone, REL-1017) in other indications

In addition to developing esmethadone as an adjunctive treatment of

MDD, we are evaluating the utility of esmethadone as a frontline monotherapy treatment for MDD.

Additionally, other indications that Relmada may

explore in the future, include, restless leg syndrome and other glutamatergic system activation related diseases.

Our Corporate History and Background

We are a clinical-stage, publicly traded

biotechnology company developing NCEs and novel versions of proven drug products that potentially address areas of high unmet medical

need in the treatment of depression and other CNS diseases.

Currently, none of our product candidates

have been approved for sale in the United States or elsewhere.

We have no commercial products nor do we have a sales or marketing

infrastructure.

In order to market and sell our prospective products we must conduct clinical trials on patients and obtain regulatory

approvals from appropriate regulatory agencies, like the FDA in the United States, and similar organizations elsewhere in the world.

We have not generated revenues and do not

anticipate generating revenues for the foreseeable future.

We had net loss of approximately $59,456,400 for the year ended December

31, 2020, $8,196,500 for the six months ended December 31, 2019, and $17,318,100 for the year ended June 30, 2019, respectively.

We are a clinical-stage, publicly traded biotechnology company developing

NCEs and novel versions of drug products that potentially address areas of high unmet medical need in the treatment of depression and

other CNS diseases.

Currently, none of our product candidates have

been approved for sale in the United States or elsewhere.

We have no commercial products nor do we have a sales or marketing infrastructure.

In order to market and sell our products we must conduct clinical trials on patients and obtain regulatory approvals from appropriate

regulatory agencies, like the FDA in the United States, and similar organizations elsewhere in the world.

We have not generated revenues and do not anticipate generating revenues

for the foreseeable future.

We had net loss of approximately $125,751,800 and $59,456,400 for the years ended December 31, 2021 and 2020,

respectively.

At December 31, 2021, we have an accumulated deficit of approximately $305,067,100.

Our strategy is to leverage our considerable

industry experience, understanding of CNS markets and development expertise to identify, develop and commercialize product candidates

with significant market potential that can fulfill unmet medical needs in the treatment of CNS diseases.

We have assembled a management

team along with both scientific, including recognized experts in the fields of depression, and business advisors with significant

industry and regulatory experience to lead and execute the development and commercialization of esmethadone.

We plan to further develop esmethadone

as our priority program.

As the drug esmethadone is an NCE, the regulatory pathway, under the Food and Drug Administration Amendment

Act Section 505(u) provision, required to support an NDA submission will consist of conducting a full clinical development program.

We plan to also generate intellectual property (IP) that will further protect our products from competition.

We will continue to

prioritize our product development activities after taking into account the resources we have available, market dynamics and potential

for adding value.

believe that the market for addressing areas of high unmet medical need in the treatment of CNS diseases will continue to be large

for the foreseeable future and that it will represent a sizable revenue opportunity for us.

For example, the World Health Organization

(WHO) has estimated that CNS diseases affect nearly 2 billion people globally, making up approximately 40% of total disease burden

(based on disability adjusted life years), compared with 13% for cancer and 12% for cardiovascular disease.

The depression treatment market is segmented

on the basis of antidepressants drugs, devices, and therapies.

Business Strategy

Our strategy is to leverage our considerable industry

experience, understanding of CNS markets and development expertise to identify, develop and commercialize product candidates with significant

market potential that can fulfill unmet medical needs in the treatment of CNS diseases.

We have assembled a management team along with

both scientific, including recognized experts in the fields of depression, and business advisors with significant industry and regulatory

experience to lead and execute the development and commercialization of esmethadone.

We plan to further develop esmethadone as our

priority program.

As the drug esmethadone is an NCE, the regulatory pathway to support a new drug application (NDA) submission involves

a full clinical development program.

We plan to continue to generate intellectual property (IP) that will further protect our products

from competition.

We will continue to prioritize our product development activities after taking into account the resources we have available,

market dynamics and potential for adding value.

Market Opportunity

We believe that the market for addressing areas

of high unmet medical need in the treatment of CNS diseases will continue to be large for the foreseeable future and that it will represent

a sizable revenue opportunity for us.

For example, the World Health Organization (WHO) has estimated that CNS diseases affect nearly 2

billion people globally, making up approximately 40% of total disease burden (based on disability adjusted life years), compared with

13% for cancer and 12% for cardiovascular disease.

The depression treatment market is segmented on

the basis of antidepressants drugs, devices, and therapies.

Antidepressants are the largest and most popular market segment.

The antidepressants segment consists of large pharmaceutical and generic companies, such as Eli Lilly, Pfizer, GlaxoSmithKline,

Allergan, Sage Therapeutics and Johnson & Johnson.

Some of the notable drugs produced by these companies are Cymbalta ®

(Eli Lilly), Effexor ®

(Pfizer), Pristiq ®

(Pfizer), Zulresso (Sage) and Spravato (Johnson & Johnson).

Property Portfolio and Market Exclusivity

We have over 50 issued patents and pending

patent applications related to REL-1017 for multiple uses, including psychological and neurological conditions.

We have also secured

an Orphan Drug Designation from the FDA for d-methadone for “the treatment of postherpetic neuralgia’, which, if pursed

and upon potential NDA approval, would carry 7-year FDA Orphan Drug marketing exclusivity.

In the European Union, some of our actual

and prospective products may be eligible up to 10 years of market exclusivity, which includes 8 years data exclusivity and 2 years

market exclusivity.

In addition to any granted patents, REL-1017 will be eligible for market exclusivity to run concurrently with

the term of the patent for 5 years in the U.S.

(Hatch Waxman Act) plus additional 6 month of pediatric exclusivity and up to 10

years of in the E.U.

We believe an extensive intellectual property estate of US and foreign patents and applications, will protect

our technology and products once our patent applications for our products are approved.

The antidepressants

segment consists of large pharmaceutical and generic companies, such as Eli Lilly, Pfizer, GlaxoSmithKline, Allergan, Sage Therapeutics

and Johnson & Johnson.

Some of the notable drugs produced by these companies are Cymbalta ® (Eli Lilly), Effexor ®

(Pfizer), Pristiq ® (Pfizer), Zulresso (Sage) and Spravato (Johnson & Johnson).

Intellectual Property Portfolio and Market Exclusivity

We have over 50 issued patents and pending patent

applications related to REL-1017 for multiple uses, including psychological and neurological conditions.

We have also secured an Orphan

Drug Designation from the FDA for d-methadone for “the treatment of postherpetic neuralgia,” which, upon NDA approval, carries

7-year FDA Orphan Drug marketing exclusivity.

In the European Union, some of our actual and prospective products may be eligible up to

10 years of market exclusivity, which includes 8 years data exclusivity and 2 years market exclusivity.

In addition to any granted patents,

REL-1017 will be eligible for market exclusivity to run concurrently with the term of the patent for 5 years in the U.S.

(Hatch Waxman

Act) plus additional 6 month of pediatric exclusivity and up to 10 years in the E.U.

We believe an extensive intellectual property estate

of US and foreign patents and applications, will protect our technology and products.

Esmethadone License Agreement

As a result of a prior acquisition, the Company assumed an obligation

to pay third parties (Dr.

Inturrisi and Dr.

Paolo Manfredi –

(A) royalty payments up to 2% on net

sales of licensed products that are not sold by sublicensee and (B) on each and every sublicense earned royalty payment received

by licensee from its sublicensee on sales of license product by sublicensee, the higher of (i) 20% of the royalties received by

As a result of a prior acquisition, the Company assumed an obligation to pay third parties (Dr.

Paolo Manfredi – see below):

(A) royalty payments up to 2% on net sales of licensed products that are not sold by sublicensee

and (B) on each and every sublicense earned royalty payment received by licensee from its sublicensee on sales of license product by sublicensee,

the higher of (i) 20% of the royalties received by licensee;

or (ii) up to 2% of net sales of sublicensee.

The Company will also make milestone payments of up to $4 or $2 million,

for the first commercial sale of product in the field that has a single active pharmaceutical ingredient, and for the first commercial

sale of product in the field of product that has more than one active pharmaceutical ingredient, respectively.

As of December 31,

2020, the Company has not generated any revenue related to this license agreement.

The Company will also make

milestone payments of up to $4 or $2 million, for the first commercial sale of product in the field that has a single active pharmaceutical

ingredient, and for the first commercial sale of product in the field of product that has more than one active pharmaceutical ingredient,

respectively.

As of December 31, 2021, the Company has not generated any revenue related to this license agreement.

Inturrisi / Manfredi

5 unchanged sentences

Pursuant to the Agreements,

Relmada assigned its existing rights, including patents and patent applications, to esmethadone in the context of psychiatric use

(the Existing Invention) to Licensor.

Licensor then granted Relmada under the License Agreement a perpetual, worldwide, and exclusive

license to commercialize the Existing Invention and certain further inventions regarding esmethadone.

In consideration of the rights

granted to Relmada under the License Agreement, Relmada paid the Licensor an upfront, non-refundable license fee of $180,000.

Additionally,

Relmada will pay Licensor $45,000 every three months until the earliest to occur of the following events:

(i) the first commercial

sale of a licensed product anywhere in the world, (ii) the expiration or invalidation of the last to expire or be invalidated of

the patent rights anywhere in the world, or (iii) the termination of the License Agreement.

Relmada will also pay Licensor tiered

royalties with a maximum rate of 2%, decreasing to 1.75%, and 1.5% in certain circumstances, on net sales of licensed products

covered under the License Agreement.

Relmada will also pay Licensor tiered payments up to a maximum of 20%, and decreasing to 17.5%,

and 15% in certain circumstances, of all consideration received by Relmada for sublicenses granted under the License Agreement.

The License Agreement includes standard

termination rights for Licensor in the event of our insolvency, challenge of the licensed patents and uncured material breach of

our obligations under the License Agreement.

In addition, the License Agreement contains certain “Key Man”

such that Licensor may terminate the License Agreement if we terminate the employment of our Chief Executive Officer Dr Sergio

Traversa for any reason other than for specified causes determined by a majority of our Board of Directors (including fraud, gross

negligence, unauthorized use of our confidential information, conduct including harassment or discrimination, breach of fiduciary

duty or uncured material breach), or if we (a) substantially modify Dr.

Traversa’s job responsibilities or decision-making

rights in connection with the development and commercialization of esmethadone, (b) remove him from the role of Chief Executive

Officer other than in connection with a permitted change-of-control transaction, (c) materially reduce his compensation, or (d)

assign or transfer our rights under the License Agreement or the esmethadone intellectual property without Dr.

Traversa’s

consent, in each case (termination or the events in (a) through (d)) during the period commencing on the effective date and ending

on the later of five years from the original effective date of the License Agreement or December 31, 2022 (the “Key Man Term”).

Relmada assigned its existing rights, including patents and patent applications, to esmethadone in the context of psychiatric use (the

Existing Invention) to Licensor.

Licensor then granted Relmada under the License Agreement a perpetual, worldwide, and exclusive license

to commercialize the Existing Invention and certain further inventions regarding esmethadone.

In consideration of the rights granted to

Relmada under the License Agreement, Relmada paid the Licensor an upfront, non-refundable license fee of $180,000.

Additionally, Relmada

will pay Licensor $45,000 every three months until the earliest to occur of the following events:

(i) the first commercial sale of a licensed

product anywhere in the world, (ii) the expiration or invalidation of the last to expire or be invalidated of the patent rights anywhere

in the world, or (iii) the termination of the License Agreement.

Relmada will also pay Licensor tiered royalties with a maximum rate of

2%, decreasing to 1.75%, and 1.5% in certain circumstances, on net sales of licensed products covered under the License Agreement.

will also pay Licensor tiered payments up to a maximum of 20%, and decreasing to 17.5%, and 15% in certain circumstances, of all consideration

received by Relmada for sublicenses granted under the License Agreement.

As of December 31, 2021, no events have occurred, and the Company

continues to pay Licensor $45,000 every three months.

The License Agreement includes standard termination

rights for Licensor in the event of our insolvency, challenge of the licensed patents and uncured material breach of our obligations under

the License Agreement.

In addition, the License Agreement contains certain “Key Man” provisions such that Licensor may terminate

the License Agreement if we terminate the employment of our Chief Executive Officer, Dr Sergio Traversa, for any reason other than for

specified causes determined by a majority of our Board of Directors (including fraud, gross negligence, unauthorized use of our confidential

information, conduct including harassment or discrimination, breach of fiduciary duty or uncured material breach), or if we (a) substantially

Traversa’s job responsibilities or decision-making rights in connection with the development and commercialization of

esmethadone, (b) remove him from the role of Chief Executive Officer other than in connection with a permitted change-of-control transaction,

(c) materially reduce his compensation, or (d) assign or transfer our rights under the License Agreement or the esmethadone intellectual

property without Dr.

Traversa’s consent, in each case (termination or the events in (a) through (d)) during the period commencing

on the effective date and ending on the later of five years from the original effective date of the License Agreement or December 31,

The December 2019 amendment to the License Agreement made certain clarifications to the nature of a termination for Cause, including

to clarify that termination due to Dr.

Traversa’s death or disability does not give Licensor the right to terminate the License

Wonpung License Agreement

In 2007, the Company entered into a License Development and

Commercialization Agreement with Wonpung Mulsan Co, a shareholder of the Company.

In 2007, the Company entered into a License Development

and Commercialization Agreement with Wonpung Mulsan Co, a shareholder of the Company.

Wonpung has exclusive territorial rights in countries

it selects in Asia to market up to two drugs the Company is currently developing and a right of first refusal (“ROFR”)

for up to an additional five drugs that the Company may develop in the future as defined in more detail in the license agreement.

If the parties cannot agree to terms of a license agreement then the Company shall be able to engage in discussions with other

potential licensors.

As of March 2021, no discussions are active between the Company and Wonpung.

The Company received an upfront license

fee of $1,500,000 and will earn royalties of up to 12% of net sales for up to two licensed products it is currently developing.

The licensing terms for the ROFR products are subject to future negotiations and binding arbitration.

The terms of each licensing

agreement will expire on the earlier of any time from 15 years to 20 years after licensing or on the date of commercial availability

of a generic product to such licensed product in the licensed territory.

believe that the key elements for our market success include:

Compelling lead product opportunity, esmethadone currently in Phase 3 trial for the adjunctive treatment of MDD.

Successful Phase 1 safety studies of esmethadone and strong clinical activity signal in depression established in three independent animal models.

Potential in additional multiple indications in underserved markets with large patient population, such as MDD, other affective disorders, and cognitive disorders.

it selects in Asia to market up to two drugs the Company is currently developing and a right of first refusal (“ROFR”) for

up to an additional five drugs that the Company may develop in the future as defined in more detail in the license agreement.

If the parties

cannot agree to terms of a license agreement then the Company shall be able to engage in discussions with other potential licensors.

of March 23, 2022, no discussions are active between the Company and Wonpung.

The Company received an upfront license fee of

$1,500,000 and will earn royalties of up to 12% of net sales for up to two licensed products it is currently developing.

The licensing

terms for the ROFR products are subject to future negotiations and binding arbitration.

The terms of each licensing agreement will expire

on the earlier of any time from 15 years to 20 years after licensing or on the date of commercial availability of a generic product to

such licensed product in the licensed territory.

Psilocybin License Agreement

In July 2021, we executed

a License Agreement with Arbomentis, LLC which gives us the development and commercial rights to a novel psilocybin and derivate program.

Under the terms of the agreement, we paid Arbormentis, LLC an up-front fee of $12.7 million consisting of a mix of cash and warrants to

purchase the Company’s common stock, in addition to potential milestone payments totaling up to approximately $160 million related

to pre-specified development and commercialization milestones.

Arbormentis, LLC is also eligible to receive a low single digit percentage

royalty on net sales of any commercialized therapy resulting from this agreement.

The license agreement is terminable by us but is perpetual

and not terminable by the licensor absent material breach of its terms by us.

We will collaborate with Arbormentis, LLC on the development

of new therapies targeting neurological and psychiatric disorders, leveraging its understanding of neuroplasticity, and focusing on this

emerging new class of drugs targeting the neuroplastogen mechanism of action.

Importantly, neuroplasticity also plays a key role in the

activity of REL-1017, Relmada’s lead program.

Paolo Manfredi, our Acting Chief Scientific Officer and co-inventor of REL-1017,

Marco Pappagallo, our Acting Chief Medical Officer, are among the scientists affiliated with Arbormentis, LLC.

Key Strengths

We believe that the key elements for our market success include:

Compelling lead product opportunity, REL-1017 currently in Phase 3 trials

for the adjunctive and monotherapy treatment of MDD.

Robust, and highly statistically significant, efficacy seen with esmethadone in a randomized Phase 2 trial, the primary endpoint at 7 days, with onset of action seen at 4 days, and the effect carrying through to 14 days (7 days post-treatment).

Completed Phase 1 safety studies of esmethadone and strong clinical activity signal in depression established in three independent animal models in preclinical studies.

Potential in additional multiple indications in underserved markets

with large patient population in other affective disorders, and cognitive disorders.

Scientific support of leading experts:

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approved and filed patent applications provide coverage beyond 2033.

In addition, some of our drugs, including esmethadone have also been designated as Orphan Drugs by the FDA, thereby providing seven years of market exclusivity at launch.

pharmaceutical and biotechnology industry is characterized by intense competition, rapid product development and technological

Competition is intense among manufacturers of prescription pharmaceuticals and other product areas where we may develop

and market products in the future.

Most of our competitors are large, well-established pharmaceutical or healthcare companies

with considerable financial, marketing, sales and technical resources than are available to us.

Additionally, many of our competitors

have research and development capabilities that may allow such competitors to develop new or improved products that may compete

with our products.

The pharmaceutical and biotechnology industry is characterized by intense

competition, rapid product development and technological change.

Competition is intense among manufacturers of prescription pharmaceuticals

and other product areas where we may develop and market products in the future.

Most of our competitors are large, well-established pharmaceutical

or healthcare companies with considerably more financial, marketing, sales and technical resources than are available to us.

Additionally,

many of our competitors have research and development capabilities that may allow such competitors to develop new or improved products

that may compete with our products.

Our products could be rendered obsolete or made uneconomical by the development of new products.

Regarding our competitive position in

the industry, we currently have no product approved for sale.

authorities in the United States, at the federal, state and local level, and in other countries and jurisdictions extensively

regulate, among other things, the research, development, testing, manufacture, quality control, approval, packaging, storage,

recordkeeping, labeling, advertising, promotion, distribution, marketing, post-approval monitoring and reporting, and import and

export of pharmaceutical products.

The processes for obtaining regulatory approvals in the United States and in foreign countries

and jurisdictions, along with subsequent compliance with applicable statutes and regulations and other regulatory authorities,

require the expenditure of substantial time and financial resources.

Regarding our competitive position in the industry,

we currently have no products approved for sale.

Government Regulation

Government authorities in the United States, at

the federal, state and local level, and in other countries and jurisdictions extensively regulate, among other things, the research, development,

testing, manufacture, quality control, approval, packaging, storage, recordkeeping, labeling, advertising, promotion, distribution, marketing,

post-approval monitoring and reporting, and import and export of pharmaceutical products.

The processes for obtaining regulatory approvals

in the United States and in foreign countries and jurisdictions, along with subsequent compliance with applicable statutes and regulations

and other regulatory authorities, require the expenditure of substantial time and financial resources.

FDA Approval Process

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are subject to extensive regulation by the FDA.

The Federal Food, Drug, and Cosmetic Act (FD&C Act) and other federal and state

statutes and regulations govern, among other things, the research, development, testing, manufacture, storage, recordkeeping, approval,

labeling, promotion and marketing, distribution, post-approval monitoring and reporting, sampling and import and export of pharmaceutical

The Federal Food, Drug, and Cosmetic Act (FD&C Act) and other federal and state statutes

and regulations govern, among other things, the research, development, testing, manufacture, storage, recordkeeping, approval, labeling,

promotion and marketing, distribution, post-approval monitoring and reporting, sampling and import and export of pharmaceutical products.

Failure to comply with applicable U.S.

requirements may subject a company to a variety of administrative or judicial

sanctions, such as FDA refusal to approve pending new drug applications (NDAs), warning or untitled letters, product recalls, product

seizures, total or partial suspension of production or distribution, injunctions, fines, civil penalties and criminal prosecution.

Pharmaceutical product development for

a new product or certain changes to an approved product in the U.S.

typically involves preclinical laboratory and animal tests,

the submission to FDA of an investigational new drug application (IND) which must become effective before clinical testing may

commence, and adequate and well-controlled clinical trials to establish the safety and effectiveness of the drug for each indication

for which FDA approval is sought.

Satisfaction of FDA pre-market approval requirements typically takes many years and the actual

time required may vary substantially based upon the type, complexity and novelty of the product or disease.

requirements may subject a company to a variety of administrative or judicial sanctions, such as

FDA refusal to approve pending NDAs, warning or untitled letters, product recalls, product seizures, total or partial suspension of production

or distribution, injunctions, fines, civil penalties and criminal prosecution.

Pharmaceutical product development for a new product or certain changes

to an approved product in the U.S.

typically involves preclinical laboratory and animal tests, the submission to FDA of an investigational

new drug application (IND) which must become effective before clinical testing may commence, and adequate and well-controlled clinical

trials to establish the safety and effectiveness of the drug for each indication for which FDA approval is sought.

Satisfaction of FDA

pre-market approval requirements typically takes many years and the actual time required may vary substantially based upon the type, complexity

and novelty of the product or disease.

Preclinical tests include laboratory evaluation

of product chemistry, formulation and toxicity, as well as animal trials to assess the characteristics and potential safety and

efficacy of the product.

The conduct of the preclinical tests must comply with federal regulations and requirements, including

good laboratory practices.

The results of preclinical testing are submitted to FDA as part of an IND along with other information,

including information about product chemistry, manufacturing and controls, and a proposed clinical trial protocol.

Long-term preclinical

tests, such as animal tests of reproductive toxicity and carcinogenicity, may continue after the IND is submitted.

A 30-day waiting

period after the submission of each IND is required prior to the commencement of clinical testing in humans.

If FDA has neither

commented on nor questioned the IND within this 30-day period, the clinical trial proposed in the IND may begin.

Clinical trials

involve the administration of the investigational new drug to healthy volunteers or patients under the supervision of a qualified

investigator.

of product chemistry, formulation and toxicity, as well as animal trials to assess the characteristics and potential safety and efficacy

of the product.

The conduct of the preclinical tests must comply with federal regulations and requirements, including good laboratory

The results of preclinical testing are submitted to FDA as part of an IND along with other information, including information

about product chemistry, manufacturing and controls, and a proposed clinical trial protocol.

Long-term preclinical tests, such as animal

tests of reproductive toxicity and carcinogenicity, may continue after the IND is submitted.

A 30-day waiting period after the submission

of each IND is required prior to the commencement of clinical testing in humans.

If FDA has neither commented on nor questioned the IND

within this 30-day period, the clinical trial proposed in the IND may begin.

Clinical trials involve the administration of the investigational

new drug to healthy volunteers or patients under the supervision of a qualified investigator.

Clinical trials must be conducted:

(i) in compliance with federal regulations;

(ii) in compliance with good clinical

practice, or GCP, an international standard meant to protect the rights and health of patients and to define the roles of clinical

trial sponsors, administrators and monitors;

as well as (iii) under protocols detailing the objectives of the trial, the parameters

to be used in monitoring safety and the effectiveness criteria to be evaluated.

compliance with federal regulations;

(ii) in compliance with good clinical practice, or GCP, an international standard meant to protect

the rights and health of patients and to define the roles of clinical trial sponsors, administrators and monitors;

as well as (iii) under

protocols detailing the objectives of the trial, the parameters to be used in monitoring safety and the effectiveness criteria to be evaluated.

Each protocol involving testing on U.S.

and subsequent protocol amendments must be submitted to FDA as part of the IND.

patients and subsequent protocol amendments must be submitted to FDA as part of the IND.

FDA may order the temporary, or permanent, discontinuation of a clinical

trial at any time, or impose other sanctions, if it believes that the clinical trial either is not being conducted in accordance with

FDA requirements or presents an unacceptable risk to the clinical trial patients.

The study protocol and informed consent information

for patients in clinical trials must also be submitted to an institutional review board (IRB) for approval.

An IRB may also require the

clinical trial at the site to be halted, either temporarily or permanently, for failure to comply with the IRB’s requirements, or

may impose other conditions.

Clinical trials to support NDAs for marketing

approval are typically conducted in three sequential phases, but the phases may overlap.

In Phase 1, the initial introduction of

the drug into healthy human subjects or patients, the drug is tested to assess metabolism, pharmacokinetics, pharmacological actions,

side effects associated with increasing doses, and, if possible, early evidence of effectiveness.

Phase 2 usually involves trials

in a limited patient population to determine the effectiveness of the drug for a particular indication, dosage tolerance and optimum

dosage, and to identify common adverse effects and safety risks.

If a drug demonstrates evidence of effectiveness and an acceptable

safety profile in Phase 2 evaluations, Phase 3 trials are undertaken to obtain the additional information about clinical efficacy

and safety in a larger number of patients, typically at geographically dispersed clinical trial sites, to permit FDA to evaluate

the overall benefit-risk relationship of the drug and to provide adequate information for the labeling of the drug.

In most cases,

FDA requires two adequate and well-controlled Phase 3 clinical trials to demonstrate the efficacy of the drug.

A single Phase 3

trial with other confirmatory evidence may be sufficient in rare instances, such as where the study is a large multicenter trial

demonstrating internal consistency and a statistically very persuasive finding of a clinically meaningful effect on mortality,

irreversible morbidity or prevention of a disease with a potentially serious outcome and confirmation of the result in a second

trial would be practically or ethically impossible.

After completion of the required clinical

testing, an NDA is prepared and submitted to FDA.

FDA approval of the NDA is required before marketing of the product may begin

The NDA must include the results of all preclinical, clinical and other testing and a compilation of data relating

to the product’s pharmacology, chemistry, manufacture and controls.

In Phase 1, the initial introduction of the drug

into healthy human subjects or patients, the drug is tested to assess metabolism, pharmacokinetics, pharmacological actions, side effects

associated with increasing doses, and, if possible, early evidence of effectiveness.

Phase 2 usually involves trials in a limited patient

population to determine the effectiveness of the drug for a particular indication, dosage tolerance and optimum dosage, and to identify

common adverse effects and safety risks.

If a drug demonstrates evidence of effectiveness and an acceptable safety profile in Phase 2

evaluations, Phase 3 trials are undertaken to obtain the additional information about clinical efficacy and safety in a larger number

of patients, typically at geographically dispersed clinical trial sites, to permit FDA to evaluate the overall benefit-risk relationship

of the drug and to provide adequate information for the labeling of the drug.

In most cases, FDA requires two adequate and well-controlled

Phase 3 clinical trials to demonstrate the efficacy of the drug.

A single Phase 3 trial with other confirmatory evidence may be sufficient

in rare instances, such as where the study is a large multicenter trial demonstrating internal consistency and a statistically very persuasive

finding of a clinically meaningful effect on mortality, irreversible morbidity or prevention of a disease with a potentially serious outcome

and confirmation of the result in a second trial would be practically or ethically impossible.

After completion of the required clinical testing,

an NDA is prepared and submitted to FDA.

FDA approval of the NDA is required before marketing of the product may begin in the U.S.

NDA must include the results of all preclinical, clinical and other testing and a compilation of data relating to the product’s

pharmacology, chemistry, manufacture and controls.

The cost of preparing and submitting an NDA is substantial.

The submission of most NDAs is additionally subject to a substantial application user fee, and the applicant under an approved

NDA is also subject to an annual program fee for each prescription product.

The submission of most

NDAs is additionally subject to a substantial application user fee, and the applicant under an approved NDA is also subject to an annual

program fee for each prescription product.

These fees are typically increased annually.

of applications for drugs granted Orphan Drug Designation are exempt from these user fees.

FDA may also refer applications for novel

drug products, or drug products that present difficult questions of safety or efficacy, to an outside advisory committee –

typically a panel that includes clinicians and other experts –

for review, evaluation and a recommendation as to whether

the application should be approved.

FDA is not bound by the recommendation of an advisory committee, but it generally follows such

recommendations.

Before approving an NDA, FDA will typically

inspect one or more clinical sites to assure compliance with GCP.

Additionally, FDA will inspect the facility or the facilities

at which the drug is manufactured.

FDA will not approve the product unless compliance with current good manufacturing practices

(cGMPs) is satisfactory and the NDA contains data that provide substantial evidence that the drug is safe and effective in the

indication studied.

Sponsors of applications for drugs granted Orphan

Drug Designation are exempt from these user fees.

FDA has 60 days from its receipt of an NDA to determine whether the

application will be accepted for filing based on the agency’s threshold determination that it is sufficiently complete to permit

substantive review.

Once the submission is accepted for filing, FDA begins an in-depth review.

FDA has agreed to certain performance goals

in the review of NDAs to encourage timeliness.

Applications for most standard review drug products are reviewed within twelve months from

submission of NDAs for new molecular entities (NMEs) and ten months from submission of NDAs for non-NMEs.

Priority review can be applied

to drugs that FDA determines offer major advances in treatment or provide a treatment where no adequate therapy exists.

The review process

for both standard and priority review may be extended by FDA for three additional months to consider certain late-submitted information

or information intended to clarify information already provided in the submission.

FDA may also refer applications for novel drug

products, or drug products that present difficult questions of safety or efficacy, to an outside advisory committee – typically

a panel that includes clinicians and other experts – for review, evaluation and a recommendation as to whether the application should

FDA is not bound by the recommendation of an advisory committee, but it generally follows such recommendations.

Before approving an NDA, FDA will typically inspect

one or more clinical sites to assure compliance with GCP.

Additionally, FDA will inspect the facility or the facilities at which the drug

is manufactured.

FDA will not approve the product unless compliance with current good manufacturing practices (cGMPs) is satisfactory

and the NDA contains data that provide substantial evidence that the drug is safe and effective in the indication studied.

After FDA evaluates the NDA and the manufacturing facilities, it issues

either an approval letter or a complete response letter.

A complete response letter generally outlines the deficiencies in the submission

and may require substantial additional testing, or information, in order for FDA to reconsider the application.

If, or when, those deficiencies

have been addressed to FDA’s satisfaction in a resubmission of the NDA, FDA will issue an approval letter.

FDA has committed to

reviewing such resubmissions in two or six months depending on the type of information included.

An approval letter authorizes commercial

marketing of the drug with specific prescribing information for specific indications.

As a condition of NDA approval, FDA may require

a risk evaluation and mitigation strategy (REMS) to help ensure that the benefits of the drug outweigh the potential risks.

REMS can include

medication guides, communication plans for healthcare professionals, and elements to assure safe use (ETASU).

ETASU can include, but are

not limited to, special training or certification for prescribing or dispensing, dispensing only under certain circumstances, special

monitoring and the use of patient registries.

The requirement for a REMS can materially affect the potential market and profitability

Moreover, product approval may require substantial post-approval testing and surveillance to monitor the drug’s safety

Once granted, product approvals may be withdrawn if compliance with regulatory standards is not maintained or problems are

identified following initial marketing.

Changes to some of the conditions established in an approved application,

including changes in indications, labeling, or manufacturing processes or facilities, require submission and FDA approval of a new NDA

or NDA supplement before the change can be implemented.

An NDA supplement for a new indication typically requires clinical data similar

to that in the original application, and FDA uses the same procedures and actions in reviewing NDA supplements as it does in reviewing

Fast Track Designation

FDA is required to facilitate the development,

and expedite the review, of drugs that are intended for the treatment of a serious or life-threatening disease or condition for

which there is no effective treatment and which demonstrate the potential to address unmet medical needs for the condition.

the Fast Track program, the sponsor of a new drug candidate may request that FDA designate the drug candidate for a specific indication

as a Fast Track drug concurrent with, or after, the filing of the IND for the drug candidate.

FDA must determine if the drug candidate

qualifies for Fast Track Designation within 60 days of receipt of the sponsor’s request.

and expedite the review, of drugs that are intended for the treatment of a serious or life-threatening disease or condition for which

there is no effective treatment and which demonstrate the potential to address unmet medical needs for the condition.

Under the Fast Track

program, the sponsor of a new drug candidate may request that FDA designate the drug candidate for a specific indication as a Fast Track

drug concurrent with, or after, the filing of the IND for the drug candidate.

FDA must determine if the drug candidate qualifies for Fast

Track Designation within 60 days of receipt of the sponsor’s request.

If a submission is granted Fast Track Designation,

the sponsor may engage in more frequent interactions with FDA, and FDA may review sections of the NDA before the application is

This rolling review is available if the applicant provides, and FDA approves, a schedule for the submission of the remaining

information and the applicant pays applicable user fees.

However, FDA’s time period goal for reviewing an application does

not begin until the last section of the NDA is submitted.

Additionally, Fast Track Designation may be withdrawn by FDA if FDA believes

that the designation is no longer supported by data emerging in the clinical trial process.

the sponsor may engage in more frequent interactions with FDA, and FDA may review sections of the NDA before the application is complete.

This rolling review is available if the applicant provides, and FDA approves, a schedule for the submission of the remaining information

and the applicant pays applicable user fees.

However, FDA’s time period goal for reviewing an application does not begin until the

last section of the NDA is submitted.

Additionally, Fast Track Designation may be withdrawn by FDA if FDA believes that the designation

is no longer supported by data emerging in the clinical trial process.

Under the Orphan Drug Act, FDA may grant Orphan

Drug Designation to drugs intended to treat a rare disease or condition – generally a disease or condition that affects fewer than

200,000 individuals in the U.S.

Orphan Drug designation must be requested before submitting an NDA.

After FDA grants Orphan Drug Designation,

the generic identity of the drug and its potential orphan use are disclosed publicly by FDA.

Orphan Drug Designation does not convey any

advantage in, or shorten the duration of, the regulatory review and approval process.

The first NDA applicant to receive FDA approval

for a particular active ingredient to treat a particular disease with FDA Orphan Drug Designation is entitled to a seven-year exclusive

marketing period in the U.S.

for that product, for that indication.

During the seven-year exclusivity period, FDA may not approve any

other applications to market the same drug for the same disease, except in limited circumstances, such as a showing of clinical superiority

to the product with orphan drug exclusivity.

Orphan drug exclusivity does not prevent FDA from approving a different drug for the same

disease or condition, or the same drug for a different disease or condition.

Among the other benefits of Orphan Drug Designation are tax

credits for certain research and an exemption from the NDA application user fee.

Disclosure of Clinical Trial Information

Sponsors of clinical trials of FDA regulated products,

including drugs, are required to register and disclose certain clinical trial information.

Information related to the product, patient

population, phase of investigation, study sites and investigators, and other aspects of the clinical trial is then made public as part

of the registration.

Sponsors are also obligated to discuss the results of their clinical trials after completion.

Disclosure of the results

of these trials can be delayed in certain circumstances for up to two years after the date of completion of the trial.

Competitors may

use this publicly available information to gain knowledge regarding the progress of development programs.

Pediatric Information

Under the Pediatric Research Equity Act (PREA),

NDAs or supplements to NDAs must contain data to assess the safety and effectiveness of the drug for the claimed indications in all relevant

pediatric subpopulations and to support dosing and administration for each pediatric subpopulation for which the drug is safe and effective.

FDA may grant full or partial waivers, or deferrals, for submission of data.

With certain exceptions, PREA does not apply to any drug

for an indication for which orphan designation has been granted.

The Best Pharmaceuticals for Children Act (BPCA) provides NDA holders

a six-month extension of any exclusivity – patent or nonpatent – for a drug if certain conditions are met.

Conditions for

exclusivity include FDA’s determination that information relating to the use of a new drug in the pediatric population may produce

health benefits in that population, FDA making a written request for pediatric studies, and the applicant agreeing to perform, and reporting

on, the requested studies within the statutory timeframe.

Applications under the BPCA are treated as priority applications, with all of

the benefits that designation confers.

Post-Approval Requirements

Once an NDA is approved, a product will

be subject to certain post-approval requirements.

For instance, FDA closely regulates the post-approval marketing and promotion

of drugs, including standards and regulations for direct-to-consumer advertising, off-label promotion, industry-sponsored scientific

and educational activities and promotional activities involving the internet.

Drugs may be marketed only for the approved indications

and in accordance with the provisions of the approved labeling.

Adverse event reporting and submission

of periodic reports are required following FDA approval of an NDA.

FDA also may require post-marketing testing, known as Phase

4 testing, REMS and surveillance to monitor the effects of an approved product, or FDA may place conditions on an approval that

could restrict the distribution or use of the product.

In addition, quality control, drug manufacture, packaging and labeling procedures

must continue to conform to cGMPs after approval.

Drug manufacturers and certain of their subcontractors are required to register

their establishments with FDA and certain state agencies.

Registration with FDA subjects entities to periodic unannounced inspections

by FDA, during which the Agency inspects manufacturing facilities to assess compliance with cGMPs.

Accordingly, manufacturers must

continue to expend time, money and effort in the areas of production and quality-control to maintain compliance with cGMPs.

authorities may withdraw product approvals or request product recalls if a company fails to comply with regulatory standards, if

it encounters problems following initial marketing, or if previously unrecognized problems are subsequently discovered.

Once an NDA is approved, a product will be subject

to certain post-approval requirements.

For instance, FDA closely regulates the post-approval marketing and promotion of drugs, including

standards and regulations for direct-to-consumer advertising, off-label promotion, industry-sponsored scientific and educational activities

and promotional activities involving the internet.

Drugs may be marketed only for the approved indications and in accordance with the

provisions of the approved labeling.

Adverse event reporting and submission of periodic

reports are required following FDA approval of an NDA.

FDA also may require post-marketing testing, known as Phase 4 testing, REMS and

surveillance to monitor the effects of an approved product, or FDA may place conditions on an approval that could restrict the distribution

or use of the product.

In addition, quality control, drug manufacture, packaging and labeling procedures must continue to conform to cGMPs

after approval.

Drug manufacturers and certain of their subcontractors are required to register their establishments with FDA and certain

state agencies.

Registration with FDA subjects entities to periodic unannounced inspections by FDA, during which the Agency inspects manufacturing

facilities to assess compliance with cGMPs.

Accordingly, manufacturers must continue to expend time, money and effort in the areas of

production and quality-control to maintain compliance with cGMPs.

Regulatory authorities may withdraw product approvals or request product

recalls if a company fails to comply with regulatory standards, if it encounters problems following initial marketing, or if previously

unrecognized problems are subsequently discovered.

Generic Competition

In seeking approval for a drug through

an NDA, applicants are required to list with the FDA each patent whose claims cover the applicant’s product.

Upon approval

of a drug, each of the patents listed in the application for the drug is then published in the FDA’s Approved Drug Products

with Therapeutic Equivalence Evaluations, commonly known as the Orange Book.

Drugs listed in the Orange Book can, in turn, be cited

by potential generic competitors in support of approval of an abbreviated new drug application (ANDA).

An ANDA provides for marketing

of a drug product that has the same active ingredients in the same strengths and dosage form as the listed drug and has been shown

through bioequivalence testing to be therapeutically equivalent to the listed drug.

Other than the requirement for bioequivalence

testing, ANDA applicants are not required to conduct, or submit results of, preclinical or clinical tests to prove the safety or

effectiveness of their drug product.

Drugs approved in this way are commonly referred to as “generic equivalents”

the listed drug and can often be substituted by pharmacists under prescriptions written for the original listed drug.

The ANDA applicant is required to certify

to the FDA concerning any patents listed for the approved product in the FDA’s Orange Book.

Specifically, the applicant must

certify that (i) the required patent information has not been filed;

In seeking approval for a drug through an NDA,

applicants are required to list with the FDA each patent whose claims cover the applicant’s product.

Upon approval of a drug, each

of the patents listed in the application for the drug is then published in the FDA’s Approved Drug Products with Therapeutic Equivalence

Evaluations, commonly known as the Orange Book.

Drugs listed in the Orange Book can, in turn, be cited by potential generic competitors

in support of approval of an abbreviated new drug application (ANDA).

An ANDA provides for marketing of a drug product that has the same

active ingredients in the same strengths and dosage form as the listed drug and has been shown through bioequivalence testing to be therapeutically

equivalent to the listed drug.

Other than the requirement for bioequivalence testing, ANDA applicants are not required to conduct, or

submit results of, preclinical or clinical tests to prove the safety or effectiveness of their drug product.

Drugs approved in this way

are commonly referred to as “generic equivalents” to the listed drug and can often be substituted by pharmacists under prescriptions

written for the original listed drug.

The ANDA applicant is required to certify to the

FDA concerning any patents listed for the approved product in the FDA’s Orange Book.

Specifically, the applicant must certify that

(i) the required patent information has not been filed;

(ii) the listed patent has expired;

listed patent has not expired but will expire on a particular date and approval is sought after patent expiration;

listed patent is invalid or will not be infringed by the new product (a Paragraph IV certification).

The ANDA applicant may also

elect to submit a section viii statement certifying that its proposed ANDA label doe s not contain (or carve out) any language

regarding the patented method-of-use rather than certify to a listed method-of-use patent.

If the applicant does not challenge

the listed patents or certifies that the listed patents will not be infringed by the new product, the ANDA application will not

be approved until all the listed patents claiming the referenced product have expired.

If the ANDA applicant has provided a Paragraph

IV certification, the NDA and patent holders may then initiate a patent infringement lawsuit in response.

The filing of a patent

infringement lawsuit within 45 days of the receipt of a such certification automatically prevents the FDA from approving the ANDA

until the earlier of 30 months, expiration of the patent, settlement of the lawsuit, or a decision in the infringement case that

is favorable to the ANDA applicant.

Upon NDA approval of a new chemical entity

(NCE) such as esmethadone, which is a drug that contains no active moiety that has been approved by FDA in any other NDA, that

drug receives five years of marketing exclusivity during which FDA cannot receive any ANDA seeking approval of a generic version

of that drug.

An ANDA may be submitted one year before NCE exclusivity expires if a Paragraph IV certification is filed.

is no listed patent in the Orange Book, there may not be a Paragraph IV certification, and, thus, no ANDA may be filed before the

expiration of the exclusivity period.

Certain changes to a drug, such as the addition of a new indication to the package insert,

can be the subject of a three-year period of exclusivity if the application contains reports of new clinical investigations (other

than bioavailability studies) conducted or sponsored by the sponsor that were essential to approval of the application.

approve an ANDA for a generic drug that includes the change during the period of exclusivity.

(iii) the listed patent has

not expired but will expire on a particular date and approval is sought after patent expiration;

or (iv) the listed patent is invalid

or will not be infringed by the new product (a Paragraph IV certification).

The ANDA applicant may also elect to submit a section viii

statement certifying that its proposed ANDA label doe s not contain (or carve out) any language regarding the patented method-of-use rather

than certify to a listed method-of-use patent.

If the applicant does not challenge the listed patents or certifies that the listed patents

will not be infringed by the new product, the ANDA application will not be approved until all the listed patents claiming the referenced

product have expired.

If the ANDA applicant has provided a Paragraph IV certification, the NDA and patent holders may then initiate a

patent infringement lawsuit in response.

The filing of a patent infringement lawsuit within 45 days of the receipt of a such certification

automatically prevents the FDA from approving the ANDA until the earlier of 30 months, expiration of the patent, settlement of the lawsuit,

or a decision in the infringement case that is favorable to the ANDA applicant.

Upon NDA approval of a new chemical entity (NCE)

such as esmethadone, which is a drug that contains no active moiety that has been approved by FDA in any other NDA, that drug receives

five years of marketing exclusivity during which FDA cannot receive any ANDA seeking approval of a generic version of that drug.

may be submitted one year before NCE exclusivity expires if a Paragraph IV certification is filed.

If there is no listed patent in the

Orange Book, there may not be a Paragraph IV certification, and, thus, no ANDA may be filed before the expiration of the exclusivity period.

Certain changes to a drug, such as the addition of a new indication to the package insert, can be the subject of a three-year period of

exclusivity if the application contains reports of new clinical investigations (other than bioavailability studies) conducted or sponsored

by the sponsor that were essential to approval of the application.

FDA cannot approve an ANDA for a generic drug that includes the change

during the period of exclusivity.

In the case of a non-racemic drug containing as an active ingredient

a single enantiomer that is contained in a racemic drug approved in another NDA, the NDA for the non-racemic drug may elect to have the

single enantiomer not be considered the same active ingredient as that contained in the approved racemic drug and therefore eligible for

NCE exclusivity, if certain conditions are met.

These conditions include:

(1) the single enantiomer has not been previously approved except

in the approved racemic drug, (2) the NDA for the non-racemic drug includes full reports of new clinical investigations necessary for

the approval of the product conducted or sponsored by the applicant and not submitted for approval of the racemic drug, and (3) the NDA

for the non-racemic drug is not submitted for approval of a condition of use in a therapeutic category in which the approved racemic drug

has been approved or for which any other enantiomer of the racemic drug has been approved.

In addition, FDA will not approve the non-racemic

drug for any condition of use in the therapeutic category in which the racemic drug has been approved for a period of 10 years after approval

of the non-racemic drug, and the labeling of the non-racemic drug will include a statement in the indication that the non-racemic drug

is not approved, and has not been shown to be safe and effective, for any condition of use of the racemic drug.

The applicant for the

non-racemic drug may make this election only in an application submitted before October 1, 2022.

Patent Term Extension

After NDA approval, owners of relevant

drug patents may apply for up to a five-year patent extension.

The allowable patent term extension is calculated as half of the

drug’s testing phase (the time between IND application and NDA submission) and all of the review phase (the time between

NDA submission and approval up to a maximum of five years).

The time can be shortened if FDA determines that the applicant did

not pursue approval with due diligence.

The total patent term after the extension may not exceed 14 years, and only one patent

can be extended.

For patents that might expire during the application phase, the patent owner may request an interim patent extension.

An interim patent extension increases the patent term by one year and may be renewed up to four times.

For each interim patent

extension granted, the post-approval patent extension is reduced by one year.

The director of the United States Patent and Trademark

Office must determine that approval of the drug covered by the patent for which a patent extension is being sought is likely.

patent extensions are not available for a drug for which an NDA has not been submitted.

Controlled Substances

The active ingredients in esmethadone are

listed by the United States Drug Enforcement Administration, or DEA, as controlled substances under the U.S.

After NDA approval, owners of relevant drug patents

may apply for up to a five-year patent extension.

The allowable patent term extension is calculated as half of the drug’s testing

phase (the time between IND application and NDA submission) and all of the review phase (the time between NDA submission and approval

up to a maximum of five years).

The time can be shortened if FDA determines that the applicant did not pursue approval with due diligence.

The total patent term after the extension may not exceed 14 years, and only one patent can be extended.

For patents that might expire

during the application phase, the patent owner may request an interim patent extension.

An interim patent extension increases the patent

term by one year and may be renewed up to four times.

For each interim patent extension granted, the post-approval patent extension is

reduced by one year.

The director of the United States Patent and Trademark Office must determine that approval of the drug covered by

the patent for which a patent extension is being sought is likely.

Interim patent extensions are not available for a drug for which an

NDA has not been submitted.

Controlled Substances

Act of 1970, or CSA.

The Controlled Substances Act and its implementing regulations establish a closed chain of distribution for

entities handling controlled substances.

The CSA and regulations enforced by the DEA impose registration, security, recordkeeping

and reporting, storage, manufacturing, distribution, importation, exportation, and other requirements on entities handling controlled

The DEA requires those individuals or entities that handle controlled substances to comply with these requirements

The active ingredients in esmethadone are listed in the Comprehensive

Drug Abuse Prevention and Control Act of 1970 (CSA) and regulations promulgated by the United States Drug Enforcement Administration (DEA)

as controlled substances.

The CSA and its implementing regulations establish a closed chain of distribution for entities handling controlled

The DEA is responsible for enforcing the law and regulations that impose registration, security, inventory, recordkeeping,

reporting and storage requirements on entities that manufacture, distribute, import and export, and other entities handling controlled

The law and regulations require those individuals or entities that handle controlled substances to comply with these requirements

in order to ensure legitimate use and prevent the diversion of controlled substances to illicit channels of commerce.

Facilities that manufacture, distribute,

import or export any controlled substance must register annually with the DEA.

The DEA registration is specific to a particular

location, activity, and controlled substance schedule.

The CSA categorizes controlled substances

into one of five schedules –

Schedule I, II, III, IV, or V –

depending on the potential for abuse and physical or psychological

Schedule I substances by definition have a high potential for abuse, have no currently accepted medical use in

treatment in the U.S.

and lack accepted safety for use under medical supervision.

They may not be marketed or sold for dispensing

to patients in the U.S.

Pharmaceutical products having a currently accepted medical use and that are otherwise approved for marketing

may be listed as Schedule II, III, IV, or V substances, with Schedule II substances presenting the highest potential

for abuse and physical or psychological dependence, and Schedule V substances presenting the lowest relative potential for

abuse and dependence.

Schedule II substances (as well as substances defined as narcotics in any Schedule) are subject to most regulatory

requirements and restrictions, such as recordkeeping, reporting and security.

For example, all Schedule II drug prescriptions

must be signed by a physician, physically presented to a pharmacist in most situations unless they are electronically prescribed

pursuant to DEA regulations, and cannot be refilled.

Schedules III, IV and V controlled substances are subject to fewer restrictions.

DEA inspects manufacturers, distributors, importers, and exporters to review compliance with the CSA and DEA regulations including

security, record keeping and reporting prior to issuing a controlled substance registration.

The specific security requirements

vary by the type of business activity and the schedule and quantity of controlled substances handled by the registrant.

stringent requirements apply to manufacturers of Schedule I and Schedule II substances.

Manufacturers and distributors

must also submit regular reports to the DEA of the distribution of Schedule I and II controlled substances, Schedule III

narcotic substances, and other designated substances.

All DEA registrants must report any controlled substance thefts or significant

losses and must obtain authorization to destroy or dispose of controlled substances.

In addition to maintaining an importer and/or

exporter registration, importers and exporters of controlled substances must obtain a permit for every import or export of a Schedule

I or II substance and a narcotic substance in Schedule III, IV and V.

For all other drugs in Schedule III, IV and V, importers

and exporters must submit an import or export declaration.

DEA establishes annually an aggregate production quota for the amount of substances within Schedules I and II and certain Schedule

Facilities that manufacture, distribute, import or export any controlled

substance must register annually with the DEA.

The DEA registration is specific to a particular location, activity, and controlled substance

For example, separate registrations are required for importation and manufacturing activities, and the authority granted under

each registration determines which schedules of controlled substances the registrant may handle.

However, certain DEA registrations permit

coincident activities without obtaining a separate DEA registration, such as authorizing a manufacturer to also distribute controlled

substances produced by that registrant.

The CSA classifies controlled substances into one of five schedules

– Schedule I, II, III, IV, or V – depending on the potential for abuse and physical or psychological dependence.

substances by definition have a high potential for abuse, have no currently accepted medical use in treatment in the U.S.

and lack accepted

safety for use under medical supervision.

They may not be marketed or sold for dispensing to patients in the U.S.

Pharmaceutical products

having a currently accepted medical use and that are otherwise approved for marketing may be listed as Schedule II, III, IV, or V

substances depending on the comparative abuse potential of the drug or substance, with Schedule II substances presenting the highest

potential for abuse and physical or psychological dependence, and Schedule V substances presenting the lowest relative potential

for abuse and dependence.

Schedule II substances are subject to the strictest regulatory requirements involving registration, storage,

recordkeeping, reporting and security.

In particular, distribution and dispensing of Schedule II drugs are strictly controlled.

all Schedule II drug prescriptions cannot be refilled and must contain a written or electronic signature of a practitioner when presented

to a pharmacy.

Schedules III, IV and V controlled substances are subject to recordkeeping, reporting and security requirements, but these

requirements are less restrictive than Schedule II drugs.

The DEA inspects manufacturers, distributors, importers, and exporters

to review compliance with the CSA and DEA regulations including security, record keeping and reporting prior to issuing a controlled substance

registration.

The specific security requirements vary by the type of business activity and the schedule and quantity of controlled substances

handled by the registrant.

The most stringent requirements apply to manufacturers of Schedule I and Schedule II substances.

For example, manufacturers and distributors must store Schedule I and II drugs in secure vault with specific structural requirements.

Other physical security requirements that apply to all controlled substances include safes and cages, and the use of alarm systems and

surveillance cameras.

Regulations also require that registrants restrict employee access to controlled substances.

Once registered, manufacturing,

distribution, exporting or importing facilities must maintain records documenting the manufacture, receipt, distribution, import, or export

of all controlled substances.

Manufacturers and distributors must also submit regular reports to the DEA of the distribution of Schedule I

and II controlled substances, Schedule III narcotic substances, and certain other designated substances.

All DEA registrants must

report any controlled substance thefts or significant losses and must obtain authorization to destroy or dispose of controlled substances.

In addition to maintaining an importer and/or exporter registration, importers and exporters of controlled substances must obtain a permit

for every import or export of a Schedule I or II substance and a narcotic substance in Schedule III, IV and V.

For all other drugs in

Schedule III, IV and V, importers and exporters must submit an import or export declaration.

DEA conducts cyclic inspections to determine

whether registrants are complying with these requirements.

Practitioners such as pharmacies and physicians, as well as other types

of entities that handle controlled substances, such as researchers and analytical laboratories, are also subject to DEA registration,

recordkeeping, reporting, and security requirements on the receipt, storage, and dispensing of controlled substances.

The CSA also imposes quota requirements on certain controlled substances.

The DEA establishes annually an aggregate production quota for the amount of substances within Schedules I and II and certain Schedule

III substances, that may be produced in the U.S.

based on the DEA’s estimate of the quantity needed to meet legitimate medical,

scientific, research and industrial needs.

The aggregate quota for each controlled substance is allocated among the various individual

manufacturers through an application process.

Manufacturers may not exceed the manufacturing or procurement quota granted in a

bulk manufacturers through an application process.

Manufacturers of dosage forms are also subject to procurement quotas to obtain the

bulk active pharmaceutical ingredients to make finished drugs.

Manufacturers may not exceed the manufacturing or procurement quota granted

in a given year.

The quotas apply equally to the manufacturing of the active pharmaceutical ingredient and production of dosage forms.

The DEA may adjust aggregate production quotas and individual manufacturing or procurement quotas from time to time during the

year, although the DEA has substantial discretion concerning whether or not to make such adjustments.

Failure to maintain compliance with applicable

DEA requirements, particularly as manifested in the loss or diversion of controlled substances, can result in an enforcement action.

The DEA may seek civil penalties, refuse to renew necessary registrations, or initiate administrative proceedings to revoke those

registrations.

In certain circumstances, violations could lead to criminal prosecution.

The various states, commonwealths, and

the District of Columbia, also regulate controlled substances and impose similar licensing, recordkeeping, and reporting requirements

on entities that handle controlled substances.

Entities must independently comply with the various state requirements in addition

to the federal controlled substance requirements.

The DEA may adjust aggregate production quotas and individual manufacturing or procurement quotas from time to time during the year, although

the DEA has substantial discretion concerning whether or not to make such adjustments.

Failure to maintain compliance with applicable DEA requirements, particularly

as manifested in the loss or diversion of controlled substances, can result in an enforcement action.

The DEA may seek civil penalties,

refuse to renew necessary registrations, or initiate administrative proceedings to revoke those registrations.

In certain circumstances,

violations of the CSA and DEA regulations could lead to criminal prosecution.

The various states, commonwealths, and the District

of Columbia, also regulate controlled substances and impose similar licensing, recordkeeping, and reporting requirements on entities that

handle controlled substances.

Entities must independently comply with the various state requirements in addition to the federal controlled

substance requirements.

Other Healthcare Laws

In the United States, biotechnology company

activities are subject to regulation by various federal, state and local authorities in addition to the FDA, including but not

limited to, the Centers for Medicare & Medicaid Services (CMS), other divisions of the U.S.

Department of Health and Human

Services (e.g., the Office of Inspector General and the Office for Civil Rights), the U.S.

Department of Justice (DOJ) and individual

Attorney offices within the DOJ, and state and local governments.

For example, research, sales, marketing and scientific/educational

grant programs have to comply with the anti-fraud and abuse provisions of the Social Security Act, the federal false claims laws,

the privacy and security provisions of the Health Insurance Portability and Accountability Act (HIPAA) and similar state laws,

each as amended, as applicable.

Also, many states have similar fraud and

abuse statutes or regulations that apply to items and services reimbursed under Medicaid and other state programs, or, in several

states, apply regardless of the payor.

Data privacy and security regulations by

both the federal government and the states in which business is conducted may also be applicable.

HIPAA, as amended by the Health

Information Technology for Economic and Clinical Health Act, or HITECH, and its implementing regulations, imposes requirements

relating to the privacy, security and transmission of individually identifiable health information.

HIPAA requires covered entities

to limit the use and disclosure of protected health information to specifically authorized situations and requires covered entities

to implement security measures to protect health information that they maintain in electronic form.

Among other things, HITECH

made HIPAA’s security standards directly applicable to business associates, independent contractors or agents of covered

entities that receive or obtain protected health information in connection with providing a service on behalf of a covered entity.

HITECH also created four new tiers of civil monetary penalties, amended HIPAA to make civil and criminal penalties directly applicable

to business associates, and gave state attorneys general new authority to file civil actions for damages or injunctions in federal

courts to enforce the federal HIPAA laws and seek attorneys’

fees and costs associated with pursuing federal civil actions.

In addition, state laws govern the privacy and security of health information in specified circumstances, many of which differ

from each other in significant ways and may not have the same effect, thus complicating compliance efforts.

In the United States, biotechnology company activities are subject

to regulation by various federal, state and local authorities in addition to the FDA, including but not limited to, the Centers for Medicare

& Medicaid Services (CMS), other divisions of the U.S.

Department of Health and Human Services (e.g., the Office of Inspector General

and the Office for Civil Rights), the U.S.

Department of Justice (DOJ) and individual U.S.

Attorney offices within the DOJ, and state

and local governments.

The federal Anti-Kickback Statute prohibits, among

other things, persons and entities from knowingly and willfully offering, soliciting or receiving or providing remuneration, directly

or indirectly, in cash or in kind, to induce, or in return for, purchasing, leasing, ordering or arranging for the purchase, lease or

order of any healthcare item or service reimbursable under Medicare, Medicaid, or other federally financed healthcare programs.

has been interpreted to apply to arrangements between pharmaceutical manufacturers on the one hand and prescribers, purchasers and formulary

managers, among others, on the other.

Although there are a number of statutory exceptions and regulatory safe harbors protecting certain

common activities from prosecution or other regulatory sanctions, the exceptions and safe harbors are drawn narrowly, and practices that

involve remuneration intended to induce prescribing, purchases or recommendations may be subject to scrutiny if they do not qualify for

an exception or safe harbor.

In addition, a person or entity does not need to have actual knowledge of the Anti-Kickback Statute or specific

intent to violate it in order to commit a violation.

Federal civil and criminal false claims laws,

including the federal civil False Claims Act, prohibit any person or entity from knowingly presenting, or causing to be presented, a false

claim for payment to the federal government, or knowingly making, or causing to be made, a false statement to have a false claim paid.

This includes claims made to programs where the federal government reimburses, such as Medicare and Medicaid, as well as programs where

the federal government is a direct purchaser, such as when it purchases off the Federal Supply Schedule.

Recently, several pharmaceutical

and other healthcare companies have been prosecuted under these laws for allegedly inflating drug prices they report to pricing services,

which in turn were used by the government to set Medicare and Medicaid reimbursement rates, and for allegedly providing free product to

customers with the expectation that the customers would bill federal programs for the product.

In addition, certain marketing practices,

including off-label promotion, may also violate false claims laws.

Additionally, the government may assert that a claim including items

or services resulting from a violation of the federal Anti-Kickback Statute constitutes a false or fraudulent claim for purposes of the

federal civil False Claims Act.

Most states also have statutes or regulations similar to the federal Anti-Kickback Statute and civil False

Claims Act, which apply to items and services reimbursed under Medicaid and other state programs, or, in several states, apply regardless

of the payor.

Other federal statutes pertaining to healthcare

fraud and abuse include the civil monetary penalties statute, which prohibits, among other things, the offer or payment of remuneration

to a Medicaid or Medicare beneficiary that the offeror or payor knows or should know is likely to influence the beneficiary to order a

receive a reimbursable item or service from a particular supplier, and the additional federal criminal statutes created by the Health

Insurance Portability and Accountability Act of 1996 (HIPAA), which prohibits, among other things, knowingly and willfully executing or

attempting to execute a scheme to defraud any healthcare benefit program or obtain by means of false or fraudulent pretenses, representations

or promises of any money or property owned by or under the control of any healthcare benefit program in connection with the delivery of

or payment for healthcare benefits, items or services.

Similar to the federal Anti-Kickback Statute, a person or entity does not need

to have actual knowledge of the statute or specific intent to violate it in order to commit a violation.

Further, pursuant to the Patient Protection and

Affordable Care Act (ACA), the Centers for Medicare & Medicaid Services, or CMS, has issued a final rule that requires manufacturers

of prescription drugs to collect and report information on certain payments or transfers of value to physicians (defined to include doctors,

dentists, optometrists, podiatrists and chiropractors), physician assistants, certain types of advance practice nurses and teaching hospitals,

as well as ownership and investment interests held by physicians and their immediate family members.

The reported data is made available

in searchable form on a public website on an annual basis.

Failure to submit required information may result in civil monetary penalties.

In addition, several states now require prescription

drug companies to report certain expenses relating to the marketing and promotion of drug products and to report gifts and payments to

individual healthcare practitioners in these states.

Other states prohibit various marketing-related activities, such as the provision

of certain kinds of gifts or meals.

Still other states require the posting of information relating to clinical studies and their outcomes.

Some states require the reporting of certain drug pricing information, including information pertaining to and justifying price increases.

In addition, certain states require pharmaceutical companies to implement compliance programs and/or marketing codes.

Certain states and

local jurisdictions also require the registration of pharmaceutical sales and medical representatives.

Compliance with these laws is difficult

and time consuming, and companies that do not comply with these state laws face civil penalties.

Efforts to ensure that business arrangements with

third parties comply with applicable healthcare laws and regulations involve substantial costs.

If a drug company’s operations are

found to be in violation of any such requirements, it may be subject to significant penalties, including civil, criminal and administrative

penalties, damages, fines, disgorgement, imprisonment, the curtailment or restructuring of its operations, loss of eligibility to obtain

approvals from the FDA, exclusion from participation in government contracting, healthcare reimbursement or other federal or state government

healthcare programs, including Medicare and Medicaid, integrity oversight and reporting obligations, imprisonment, and reputational harm.

Although effective compliance programs can mitigate the risk of investigation and prosecution for violations of these laws, these risks

cannot be entirely eliminated.

Any action for an alleged or suspected violation can cause a drug company to incur significant legal expenses

and divert management’s attention from the operation of the business, even if such action is successfully defended.

Data privacy and security regulations by both the federal government

and the states in which business is conducted may also be applicable.

HIPAA, as amended by the Health Information Technology for Economic

and Clinical Health Act (HITECH), and its implementing regulations, imposes requirements relating to the privacy, security and transmission

of individually identifiable health information.

HIPAA requires covered entities to limit the use and disclosure of protected health information

to specifically authorized situations and requires covered entities to implement security measures to protect health information that

they maintain in electronic form.

Among other things, HITECH made HIPAA’s security standards directly applicable to business associates,

independent contractors or agents of covered entities that receive or obtain protected health information in connection with providing

a service on behalf of a covered entity.

HITECH also created four new tiers of civil monetary penalties, amended HIPAA to make civil and

criminal penalties directly applicable to business associates, and gave state attorneys general new authority to file civil actions for

damages or injunctions in federal courts to enforce the federal HIPAA laws and seek attorneys’ fees and costs associated with pursuing

federal civil actions.

In addition, state laws govern the privacy and security of health information in specified circumstances, many

of which differ from each other in significant ways and may not have the same effect, thus complicating compliance efforts.

Healthcare Reform

Healthcare reforms that have been adopted, and

that may be adopted in the future, could result in further reductions in coverage and levels of reimbursement for pharmaceutical products,

increases in rebates payable under U.S.

government rebate programs and additional downward pressure on pharmaceutical product prices.

On September 9, 2021, the Biden administration published a wide-ranging list of policy proposals, most of which would need to be carried

out by Congress, to reduce drug prices and drug payment.

The Department of Health and Human Services (HHS) plan includes, among other

reform measures, proposals to lower prescription drug prices, including by allowing Medicare to negotiate prices and disincentivizing

price increases, and to support market changes that strengthen supply chains, promote biosimilars and generic drugs, and increase price

transparency.

Many similar proposals, including the plans to give Medicare Part D authority to negotiate drug prices, require drug manufacturers

to pay rebates on drugs whose prices increase greater than the rate of inflation, and cap out-of-pocket costs, have already been included

in policy statements and legislation currently being considered by Congress.

It is unclear to what extent these and other statutory, regulatory,

and administrative initiatives will be enacted and implemented.

Insurance Coverage and Reimbursement

Significant uncertainty exists as to the

insurance coverage and reimbursement status of any products for which we may obtain regulatory approval.

In the United States,

sales of any product candidates for which regulatory approval for commercial sale is obtained will depend in part on the availability

of coverage and adequate reimbursement from third-party payors.

Third-party payors include government authorities and health programs

in the United States such as Medicare and Medicaid, managed care providers, private health insurers and other organizations.

third-party payors are increasingly reducing reimbursements for medical products and services.

The process for determining whether

a payor will provide coverage for a drug product may be separate from the process for setting the reimbursement rate that the payor

will pay for the drug product.

Third-party payors may limit coverage to specific drug products on an approved list, or formulary,

which might not include all of FDA-approved drugs for a particular indication.

A payor’s decision to provide coverage for

a drug product does not imply that an adequate reimbursement rate will be approved.

Further, coverage and reimbursement for drug

products can differ significantly from payor to payor.

As a result, the coverage determination process is often a time-consuming

and costly process that will require us to provide scientific and clinical support for the use of our products to each payor separately,

with no assurance that coverage and adequate reimbursement will be applied consistently or obtained in the first instance.

principal executive offices are located at 880 Third Avenue, 12th Floor, New York, New York 10022 and our telephone number is

(646) 876-3459.

Significant uncertainty exists as to the insurance

coverage and reimbursement status of any products for which we may obtain regulatory approval.

In the United States, sales of any product

candidates for which regulatory approval for commercial sale is obtained will depend in part on the availability of coverage and adequate

reimbursement from third-party payors.

Third-party payors include government authorities and health programs in the United States such

as Medicare and Medicaid, managed care providers, private health insurers and other organizations.

These third-party payors are increasingly

reducing reimbursements for medical products and services.

The process for determining whether a payor will provide coverage for a drug

product may be separate from the process for setting the reimbursement rate that the payor will pay for the drug product.

payors may limit coverage to specific drug products on an approved list, or formulary, which might not include all of FDA-approved drugs

for a particular indication.

A payor’s decision to provide coverage for a drug product does not imply that an adequate reimbursement

rate will be approved.

Further, coverage and reimbursement for drug products can differ significantly from payor to payor.

the coverage determination process is often a time-consuming and costly process that will require us to provide scientific and clinical

support for the use of our products to each payor separately, with no assurance that coverage and adequate reimbursement will be applied

consistently or obtained in the first instance.

Corporate Information

Our principal executive offices are located at

2222 Ponce de Leon Blvd., Floor 3, Coral Gables, Florida 33134 and our telephone number is (786) 629-1376.

Our website address is www.relmada.com.

The information contained in, or that can be accessed

through, our website is not part of, and is not incorporated in, this Report.

we file with the Securities and Exchange Commission (SEC) pursuant to the Exchange Act of 1934, as amended (the Exchange Act),

including annual and quarterly reports, and other reports we file, can be inspected and copied at the public reference facilities

maintained by the SEC at 100 F Street NE, Washington, D.C.

information contained in, or that can be accessed through, our website is not part of, and is not incorporated in, this Report.

A vailable Information

Reports we file with the Securities and Exchange

Commission (SEC) pursuant to the Exchange Act of 1934, as amended (the Exchange Act), including annual and quarterly reports, and other

reports we file, can be inspected and copied at the public reference facilities maintained by the SEC at 100 F Street NE, Washington,

Human Capital

As of December 31, 2020, we had a total

of 14 employees.

We understand people are our greatest asset and that our innovation and operational excellence are ultimately

noted in our human capital.

Our success depends in large part on our ability to recruit, develop and retain a qualified, productive,

and engaged workforce.

As of December 31, 2021, we had a total of 10

We understand people are our greatest asset and that our innovation and operational excellence are ultimately noted in our

human capital.

Our success depends in large part on our ability to recruit, develop and retain a qualified, productive, and engaged workforce.

Inclusion & Diversity

Inclusion and

diversity is a focus of our corporate human capital strategy.

By embracing inclusion and diversity, we enhance our work environment

and drive business success.

We endeavor to create a culture of inclusion in which our employees feel empowered to bring their full,

authentic selves to work and pursue their professional goals in a setting of equality.

Fostering such a culture welcomes different

perspectives and generates innovation and growth.

We honor the diversity of our employees—in gender, race/ethnicity, age,

gender identity, sexual orientation, socio-economic status, language, nationality, abilities and life experiences.

As of December

31, 2020, our employee population was approximately 64% female.

Total Rewards

and Employee Engagement

We maintain a

competitive compensation and benefits package including incentive compensation tied to both company and individual performance,

and retirement benefits.

Our performance-based compensation strategy is designed to recognize and reward employees for their contribution

to our success, and we strive to provide strong, equitable incentives for performance.

Inclusion and diversity is a focus of our corporate

human capital strategy.

By embracing inclusion and diversity, we enhance our work environment and drive business success.

to create a culture of inclusion in which our employees feel empowered to bring their full, authentic selves to work and pursue their

professional goals in a setting of equality.

Fostering such a culture welcomes different perspectives and generates innovation and growth.

We honor the diversity of our employees—in gender, race/ethnicity, age, gender identity, sexual orientation, socio-economic status,

language, nationality, abilities and life experiences.

As of December 31, 2021, our employee population was approximately 60% female.

Total Rewards and

Employee Engagement

We maintain a competitive

compensation and benefits package including incentive compensation tied to both company and individual performance, and retirement benefits.

Our performance-based compensation strategy is designed to recognize and reward employees for their contribution to our success, and we

strive to provide strong, equitable incentives for performance.

Compensation is comprised of two elements:

base compensation, which is determined based upon a number of factors, including size, scope and impact of the employee’s

role, the market value associated with the employee’s role, leadership skills, length of service and individual performance;

and an annual bonus, which is a cash award determined based on a combination of individual and company performance during the period

to which the bonus relates.

We seek to determine compensation on the basis of merit and without regard to demographic characteristics.

During 2020, we employed a third-party consultant to assist us in evaluating our pay practices.

In conducting this exercise, we

found no meaningful difference in compensation based upon gender, race or any other defining characteristic examined.

base compensation, which is

determined based upon a number of factors, including size, scope and impact of the employee’s role, the market value associated

with the employee’s role, leadership skills, length of service and individual performance;

and an annual bonus, which is a cash

award determined based on a combination of individual and company performance during the period to which the bonus relates.

determine compensation on the basis of merit and without regard to demographic characteristics.

During 2021, we employed a third-party

consultant to assist us in evaluating our pay practices.

In conducting this exercise, we found no meaningful difference in compensation

based upon gender, race or any other defining characteristic examined.

COVID-19 Response

We moved swiftly

in our response to the COVID-19 pandemic to promote the safety of our associates and best serve our members and communities.

March of 2020, we transitioned the out workforce to remote work environments, while maintaining service operations.

to pay employees who missed work for COVID-19 related reasons and avoided role reductions as a direct result of COVID-19.

We moved swiftly in our

response to the COVID-19 pandemic to promote the safety of our associates and best serve our members and communities.

In March of 2020,

we transitioned our workforce to remote work environments, while maintaining service operations.

We continued to pay employees who missed

work for COVID-19 related reasons and avoided role reductions as a direct result of COVID-19.

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