What changed in this filing

/stocks — the workspaceLOADING

Item 1. Business

2021-03-24 compared with 2019-09-24 · 637 added, 627 removed, 25 unchanged (98% of the section changed)

Business Overview

Relmada is a clinical-stage, publicly traded

biotechnology company focused on the development of d-methadone (dextromethadone, REL-1017), an N-methyl-D-aspartate (NMDA) receptor

d-methadone is a new chemical entity 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, d-methadone,

is a New Chemical Entity (NCE) being developed as a rapidly acting, oral agent for the treatment of depression and other potential

We have completed Phase 1 single and multiple ascending dose studies.

A Phase 2 study in major depressive disorder

is ongoing, with first patient dosed in June 2018 and last patient-last dose completed in July 2019.

We expect to have top line

results in the second half of 2019.

NMDA receptors are present in many parts

of the central nervous system and play important roles in regulating neuronal activity.

We believe that dextromethadone acting

as a NMDA receptor antagonist can have potential applications in a number of disease indications which mitigates risk and offers

significant upside.

In addition, the Company has a portfolio

of three 505b2 product candidates at various stages of development.

These products are:

LevoCap ER (REL-1015), an abuse resistant,

sustained release dosage form of the opioid analgesic levorphanol;

BuTab (oral buprenorphine, REL-1028), an oral dosage form of

the opioid analgesic buprenorphine;

and MepiGel (topical mepivacaine, REL-1021), an orphan drug designated topical formulation

of the local anesthetic mepivacaine.

Our four development projects are briefly described below:

d-Methadone (dextromethadone, REL-1017) and Treatment-Resistant

Depression (TRD)

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 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.

Accordingly, we believe

that approximately 3 million patients with such treatment-resistant depression are in need of new treatment options.

In addition to the high failure rate, none

of the marketed products for depression can demonstrate rapid antidepressant effects and most of the products take up to a month

to show effectiveness.

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.

Recent studies have shown that ketamine,

a drug known previously as an anesthetic, can lift depression in many patients within hours.

Like d-methadone, ketamine is an NMDA

receptor antagonist.

However, it is unlikely that ketamine itself will become a practical treatment for most cases of depression.

It must be administered through intravenous infusion or intranasally, requiring a hospital setting, and more importantly can potentially

trigger adverse side effects including psychedelic symptoms (hallucinations, memory defects, panic attacks), nausea/vomiting, somnolence,

cardiovascular stimulation and, in a minority of patients, hepatoxicity.

Ketamine also hasn’t been thoroughly studied for

long-term safety and effectiveness, and the FDA hasn’t approved it to treat depression.

d-Methadone Overview and Mechanism of Action

d-Methadone’s mechanism of action,

as a non-competitive NMDA channel blocker or antagonist, is fundamentally differentiated from all 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 but potentially lacking its adverse side effects, Relmada’s d-methadone is being developed as

a rapidly acting, oral agent for the treatment of depression and/or other potential CNS pathological conditions.

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.

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 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

Means Difference

25mg vs Placebo

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

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.

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.

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-superposable (not identical),

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.

3 unchanged sentences

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

Racemic methadone has been used since the

1950s as a treatment for opioid addiction and has remained the primary therapy for this condition for more than 40 years.

is a highly lipophilic molecule that is suitable for a variety of administration routes, with oral bioavailability close to 80%.

As a single isomer of racemic methadone,

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

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

events at the expected therapeutic doses.

2 unchanged sentences

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

the right (dextro) isomer, d-methadone, is much less active as an opioid while maintaining affinity for the NMDA receptor.

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 central nervous system 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, d-methadone could

show benefits in several different CNS indications.

d-Methadone Phase 1 Clinical Safety Studies

The safety data from two Company-funded

d-methadone Phase 1 clinical safety studies and a third study conducted by researchers at Memorial Sloan-Kettering Cancer Center

indicate that d-methadone was safe and well tolerated in both healthy subjects and cancer patients at all projected therapeutic

doses tested.

In November 2014, Health Canada approved

a Clinical Trial Application (CTA) to conduct the first Phase 1 study with d-methadone.

This was a Single Ascending Dose (SAD)

study and was followed by a Multiple Ascending Dose (MAD) study, both in healthy volunteers.

The two studies were designed to assess

the safety, tolerability and pharmacokinetics of d-methadone in healthy, opioid-naïve subjects.

The SAD study included single

escalating oral doses of d-methadone to determine the maximum tolerated dose, defined as the highest dose devoid of unacceptable

adverse events.

In the MAD study, healthy subjects received daily oral doses of d-methadone for several days to assess its safety,

pharmacokinetics and tolerability.

In March 2015, we reported that d-methadone demonstrated an acceptable safety profile with no

dose limiting side effects after four cohorts were exposed to increasing higher doses.

In April 2015, the Company received clearance

from Health Canada to continue with dose escalation and explore even higher single doses of d-methadone.

In June 2015, the Company

successfully completed the SAD study identifying the maximum tolerated dose and subsequently received a No Objection Letter (NOL)

from Health Canada to conduct the MAD clinical study in August 2015.

The MAD study was completed in January 2016 and the results

successfully demonstrated a potential therapeutic dosing regimen for d-methadone with a favorable side effect and tolerability

The data from these studies was used to design a Phase 2a study in patients with depression.

d-Methadone In Vivo Study for Depression

In May 2016, we announced the results of

an in vivo study showing that administration of d-methadone results in antidepressant-like effects in a well-validated animal model

of depression, known as the forced swim test (FST), providing preclinical support for its potential as a novel treatment of depression.

According to the Journal of Visualized

Experiments, the FST is based on the assumption that when placing an animal in a container filled with water, it will first make

efforts to escape by swimming or climbing, but eventually will exhibit “immobility”

that may be considered to reflect

a measure of behavioral despair.

This test has been extensively used because it involves the exposure of the animals to stress,

which was shown to have a role in the tendency for major depression.

Additionally, the FST has been shown to be influenced by some

of the factors that are altered by or worsen depression in humans, including changes in food consumption and sleep abnormalities.

The main advantages of this procedure are that it is relatively easy to perform and that its results are easily and quickly analyzed.

Importantly, the FST’s sensitivity to a broad range of antidepressant drugs makes it a suitable screening test and is one

of the most important features leading to its high predictive validity.

In the Company’s FST study, male

Sprague Dawley rats were administered single doses of placebo, ketamine, or d-methadone on day one (after habituation;

prior to forced swim testing).

At all doses tested, d-methadone significantly decreased immobility of the rats compared to the

placebo, suggesting antidepressant-like activity.

In addition, the effect of d-methadone on immobility at the two highest doses

tested was larger than the effect seen with ketamine.

Moreover, the effects of d-methadone in the forced swim test were not caused

by a stimulant effect on spontaneous locomotor activity of the rats.

Locomotor activity of lab animals is often monitored to assess

the behavioral effects of drugs.

In September 2017 we completed two additional

in vivo studies to confirm and support the antidepressant-like effect of dextromethadone in validated animal models, the Novelty

Suppressed Feeding Test (NSFT) and the Female Urine-Sniffing test (FUST) test.

The studies were performed by Professor Ronald S.

at Yale University School of Medicine.

For FUST, rats are first exposed to a cotton

tip dipped in tap water and later exposed to another cotton tip infused with fresh female urine.

Male behavior was video recorded

and total time spent sniffing the cotton-tipped applicator is determined.

For NSFT, rats were food deprived for 24 hr and then

placed in an open field with food pellets in the center;

latency to eat is recorded in seconds.

As a control, food consumption

in the home cage is quantified.

Rats were administered vehicle, ketamine or d-methadone.

The results of the FUST demonstrate that

administration of ketamine significantly increases the time male rats spent engaged in sniffing female urine compared to vehicle

Similarly, a single dose of d-methadone significantly increased the time spent sniffing female urine compared to vehicle.

In contrast, ketamine or d-methadone had no effect on time sniffing water, demonstrating that the effect of drug treatment was

specific to the rewarding effects of female urine.

The results of the NSFT demonstrate that a single dose of ketamine significantly

decreases the latency to eat in a novel open field.

Similarly, a single dose of d-methadone also significantly decreased the latency

to enter and eat in the novel feed.

In contrast, neither ketamine nor methadone influenced latency to feed in the home cage.

These findings demonstrate that ketamine

and d-methadone produce rapid antidepressant actions in the FUST and NSFT, effects that are only observed after chronic administration

of an SSRI antidepressant.

A separate in vitro electrophysiology study

of d-methadone was conducted using 2 subtypes of cloned human NMDA receptors.

The results of this study demonstrated

functional antagonist activity with d-methadone comparable to that of both racemic ketamine and the isomer [S]-ketamine.

Phase 2 Program for d-Methadone in Depression

Combined with the results of our Phase

1 studies, the encouraging results of in vivo and in vitro studies strongly support further evaluation of d-methadone in a Phase

2 study as a rapidly acting, oral agent for the treatment of major depressive disorder.

Relmada filed an Investigational New Drug

(IND) application for the Phase 2 study with the FDA, which was accepted on January 25, 2017.

On April 13, 2017, we announced that the

FDA granted Fast Track designation for d-methadone (REL-1017 dextromethadone) for the adjunctive treatment of major depressive

Fast Track designation is a process designed to facilitate the development and expedite the review of drugs to treat

serious conditions and fill an unmet medical need.

The purpose, according to the FDA, is to get important new drugs to the patient

Drugs that receive Fast Track designation may be eligible for more frequent meetings and written communications with the

FDA, accelerated review and priority approval, and rolling New Drug Application (NDA) review.

On January 17, 2018, we announced that

Relmada had acquired the global rights to develop and market dextromethadone for the treatment of neurological conditions including

certain rare diseases with symptoms affecting the CNS.

In February 2018, Relmada initiated its

Phase 2 study of d-methadone in patients with major depressive disorder.

In July 2019, Relmada announced the completion

of dosing of the last patient in its Phase 2 study of d-methadone in patients with major depressive disorder.

d-Methadone (dextromethadone, REL-1017) in other indications

In addition to developing dextromethadone

in major depression, Relmada is initiating work in additional indications.

In particular, we have initiated a preclinical program

to test the potential efficacy of dextromethadone in Rett syndrome.

Rett syndrome is an X-linked neurodevelopmental disorder with

high unmet need caused by Mecp2 gene mutation.

Loss of Mecp2 disrupts synaptic function and structure and neuronal networks.

syndrome is an Orphan Disease affecting ~15,000 in U.S., primarily girls, with no approved therapy.

The disease begins with a short

period of developmental stagnation, then rapid regression in language and motor skills, followed by long-term stability.

Studies of ketamine, an NMDAR antagonist

with mechanistic similarities with dextromethadone, in Rett Syndrome mouse models show that low-dose ketamine acutely reverses

multiple disease manifestations and chronic administration of ketamine improves Rett Syndrome progression, providing a solid rationale

to pursue this indication with dextromethadone.

Other indications that Relmada may explore

in the future, potentially includes restless leg syndrome, and other glutamatergic system activation related diseases.

In January 2018, we entered into an Intellectual

Property Assignment Agreement (the Assignment Agreement) and License Agreement (the “License Agreement”

with the Assignment Agreement, the Agreements) with Dr.

Inturrisi and Dr.

Paolo Manfredi (collectively, the Licensor).

Pursuant to the Agreements, Relmada assigned its existing rights, including patents and patent applications, to d-methadone 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

d-methadone in the context of other indications such as those contemplated above.

LevoCap ER (REL-1015)

LevoCap ER (REL-1015) is a novel version

of a proven drug product.

LevoCap ER -is an extended release, abuse deterrent, and proprietary formulation of levorphanol (levo-3-hydroxy-N-methyl-morphinan),

a unique, broad spectrum opioid with additional “non-opioid”

mechanisms of action.

In particular, levorphanol binds

to all three opioid receptor subtypes involved in analgesia (mu, kappa, and delta), the NMDA receptor, and the norepinephrine and

serotonin reuptake pumps, whereas morphine, oxycodone, hydrocodone, and other opioids are highly selective for the mu receptor

Due to its multi-modal mechanism of action, levorphanol could achieve analgesia in patients resistant to other strong

In clinical studies, levorphanol has demonstrated a remarkably broad spectrum of analgesic activity against many different

types of pain including neuropathic pain, post-surgical pain, and chronic pain in patients refractory to other opioids.

Levorphanol is a potent opioid analgesic

first introduced in the U.S.

around 1953 for the treatment of moderate to severe pain where an opioid analgesic is appropriate.

Extended-release (long-acting opioid) agents may be preferable to immediate release formulations due to better patient adherence,

less dose-watching, and result in improved sleep.

Both immediate- and extended-release opioids can potentially be crushed to produce

concentrated drug with greater appeal to abusers.

Intentional crushing or extracting the active ingredient from the extended-release

dosage form by addicts and recreational drug users can destroy the timed-release mechanism and result in a rapid surge of drug

into the bloodstream for the purpose of achieving a high or euphoric feeling.

Serious side effects and death have been reported

from such misuse.

LevoCap ER is the first product candidate

utilizing SECUREL™, Relmada’s proprietary abuse deterrent extended release technology for opioid drugs.

SECUREL dosage

forms cannot be easily crushed for inhalation or to obtain rapid euphoria from high blood levels when swallowed.

It is also exceedingly

difficult for intravenous abusers to extract the active drug from the dosage form using common solvents, including alcohol.

LevoCap ER can be developed under the 505(b)(2)

regulatory pathway.

Following an exchange of correspondence and meeting with the FDA in January 2017, we have defined a path forward

for the Phase 3 clinical study for LevoCap ER and a new drug application (NDA) filing.

In light of the promising data generated

by Relmada’s d-methadone research program, and Relmada’s focus on the d-methadone program, Relmada is currently limiting

the investments in LevoCap ER.

BuTab (REL-1028)

BuTab (REL-1028) represents a novel formulation

of oral, modified release buprenorphine as a potential therapeutic for both chronic pain and opioid dependence.

Buprenorphine has

been widely used by the sublingual and transdermal routes of administration, but was believed to be ineffective by the oral route

because of poor oral bioavailability.

We have completed a preclinical program to better define the pharmacokinetic profile of BuTab

and to assess the time course of systemic absorption of buprenorphine using several different oral modified release formulations

of buprenorphine in dogs, compared to an intravenous administration.

Based on the results of this work, we obtained approval from

Health Canada and initiated a Phase 1 pharmacokinetic study in healthy volunteers in the second quarter of 2015.

This trial was

completed in the fourth quarter of 2015.

The absolute bioavailability of BuTab relative to intravenous (IV) administration exceeded

published data with non-modified buprenorphine when administered orally and compares favorably with a currently marketed transdermal

There were no safety or tolerability issues.

The data generated by this study will guide formulation optimization and inform

the design of subsequent clinical pharmacology studies.

BuTab can be developed under the 505(b)(2) regulatory pathway.

of the promising data generated by Relmada’s d-methadone research program, and Relmada’s focus on the d-methadone program,

Relmada is currently limiting the investments in BuTab.

MepiGel (REL-1021)

MepiGel (REL-1021), is a proprietary topical

dosage form of the local anesthetic mepivacaine for the treatment of painful peripheral neuropathies, such as painful diabetic

neuropathy, postherpetic neuralgia and painful HIV-associated neuropathy.

Mepivacaine is an anesthetic (numbing medicine) that

blocks the nerve impulses that send pain signals to the brain.

It is chemically related to bupivacaine but pharmacologically related

to lidocaine.

Mepivacaine is currently indicated for infiltration, nerve block and epidural anesthesia.

Relmada has received two

FDA Orphan Drug Designations for mepivacaine, one each for “the treatment of painful HIV-associated neuropathy”

for “the management of postherpetic neuralgia,”

We have selected the formulations to be advanced into clinical

studies for MepiGel after the evaluation of results from in vitro and ex vivo studies comparing various topical prototypes of

mepivacaine that were conducted by MedPharm Ltd, a specialist formulation development company recognized internationally for its

expertise in topical and transdermal products.

Multiple toxicology studies were successfully conducted and completed in 2015.

MepiGel can be developed under the 505(b)(2) regulatory pathway.

In light of the promising data generated by Relmada’s d-methadone

research program, and Relmada’s focus on the d-methadone program, Relmada is currently limiting the investments in MepiGel.

Overview of the 505(b)(2) Pathway

Part of our strategy is the utilization

of FDA’s 505(b)(2) NDA for approval.

The 505(b)(2) NDA is one of three FDA drug approval pathways and represents an appealing

regulatory strategy for many companies.

The pathway was created by the Hatch-Waxman Amendments of 1984, with 505(b)(2) referring

to a section of the Federal Food, Drug, and Cosmetic Act.

The provisions of 505(b)(2) were created, in part, to help avoid unnecessary

duplication of studies already performed on a previously approved (reference or listed) drug;

the section gives

the FDA express permission to rely on data not developed by the NDA applicant.

A 505(b)(2) NDA contains full safety and

effectiveness reports but allows at least some of the information required for NDA approval, such as safety and efficacy information

on the active ingredient, to come from studies not conducted by or for the applicant.

This can result in a much less expensive

and much faster route to approval, compared with a traditional development path [such as 505(b)(1)], while creating new, differentiated

products with tremendous commercial value.

Overview of Orphan Drug Status

In accordance with laws and regulations

pertaining to the Regulatory Agencies, a sponsor may request that the Regulatory Agencies designate a drug intended to treat a

“Rare Disease or Condition”

as an “Orphan Drug.”

For example, in the United States, a “Rare Disease

or Condition”

is defined as one which affects less than 200,000 people in the United States, or which affects more than 200,000

people but for which the cost of developing and making available the product is not expected to be recovered from sales of the

product in the United States.

Upon the approval of the first NDA or BLA for a drug designated as an orphan drug for a specified

indication, the sponsor of that NDA or BLA is entitled to 7 years of exclusive marketing rights in the United States unless the

sponsor cannot assure the availability of sufficient quantities to meet the needs of persons with the disease.

In Europe, this

exclusivity is 10 years, and in Australia it is 5 years.

However, orphan drug status is particular to the approved indication and

does not prevent another company from seeking approval of an off-patent drug that has other labeled indications that are not under

orphan or other exclusivities.

Orphan drugs may also be eligible for federal income tax credits for costs associated with such

as the disease state, the strength and complexity of the data presented, the novelty of the target or compound, risk-management

approval and whether multiple rounds of review are required for the agency to evaluate the submission.

There is no guarantee that

a potential treatment will receive marketing approval or that decisions on marketing approvals or treatment indications will be

consistent across geographic areas.

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.

Our Corporate History and Background

We are a clinical-stage, publicly traded

biotechnology company developing NCEs together with 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 drugs 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 $17,318,000 and $8,961,000 for

the years ended June 30, 2019 and June 30, 2018, respectively.

At June 30, 2019, we have an accumulated deficit of approximately

$111,662,000.

Business Strategy

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.

At December 31, 2020, we have an accumulated deficit of approximately $179,315,300.

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 depression.

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 and business advisors, including recognized experts in the fields of depression, with significant

industry and regulatory experience to lead and execute the development and commercialization of d-methadone.

We plan to further develop d-methadone

as the priority program for the Company.

As the drug d-methadone is a NCE, the regulatory pathway to approval will consist of conducting

a full clinical development program.

Depending on the resources available to us, we may also develop REl-1028, REl-1015, REL-1021

via the 505(b)(2) development pathway and also to gain exclusivity under the Hatch-Waxman Act for new indications and also orphan

drug designation in certain indications.

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.

We will continue to outsource development of our products, while

retaining scientific, operational and financial oversight and control.

We intend to seek and execute licensing

and/or co-development agreements with companies capable of supporting the final stage development of the Company’s products

and their subsequent commercialization in the U.S.

and international markets.

We may in-license late-stage or approved

drugs to accelerate the pathway to become a fully integrated biopharmaceutical company with commercial capability.

Alternatively,

we might consider a trade sale of our products or the entire company if we deem that it is in the best interests of our shareholders.

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 Relmada.

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.

We also believe that each of our product

candidates is designed to have value added features that will provide product related competitive advantages versus the existing

drugs available on the market.

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

1 unchanged sentence

Antidepressants are the largest and most popular market segment.

According to Research and Markets, every year more than 5 billion antidepressant prescriptions are written globally.

The antidepressants

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

and Johnson & Johnson.

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

(Eli Lily), Effexor®

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

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.

We have secured three Orphan Drug Designations

from the FDA:

1) d-methadone for “the treatment of postherpetic neuralgia”;

2) MepiGel for “the treatment of

painful HIV-associated neuropathy”;

and MepiGel for “the management of postherpetic neuralgia.”

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

In the European Union, some of our 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, our products will be eligible for market exclusivity to run concurrently with the term of the patent for 3 years

(Hatch Waxman plus pediatric exclusivity) and up to 10 years of in the E.U.

We believe an extensive intellectual property

estate of several patents will protect our technology and products once our patent applications for our products are approved.

The following is a summary of our patents

and patent applications:

These patents

and patent applications cover the Levorphanol product.

US Patent No.

9,125,833, filed 4/28/08,

granted on 9/8/15.

Multimodal Abuse Resistant and Extended Release Opioid Formulations.

Owned by Relmada.

Estimated expiry in 2030.

This patent covers the SECUREL technology platform and Relmada’s lead product candidate, LevoCap ER (REL-1015, levorphanol

extended-release, abuse deterrent capsules) as well as providing additional coverage for multiple opioid molecules that are prone

EU patent No.

2,448,406, filed 2/26/10,

granted on 4/20/16.

Extended Release Oral Pharmaceutical Compositions of 3-Hydroxy-N-Methylmorphinan and Method of Use.

Estimated expiry in 2030.

Patent application 12/223.327 filed 1/29/07,

Abuse Resistant and Extended Release Formulations and Method of Use Thereof.

Owned by Relmada.

Currently pending.

Patent application 13/320,989 filed 2/26/10

Extended Release Oral Pharmaceutical Compositions of 3-Hydroxy-N-Methylmorphinan and Method of Use.

Owned by Relmada.

These patents

and patent application cover the d-methadone product.

9,468,611 issued on 10/18/2016

(filed 3/14/2013), “d-Methadone for the Treatment of Psychiatric Symptoms.”

Owned by Relmada.

Estimated expiry in 2032.

9,855,226 issued on 1/2/2018

(filed 7/7/2016), “d-Methadone for the Treatment of Psychiatric Symptoms.”

Owned by Relmada.

Estimated expiry in 2032.

Patent Application No.

(filed 1/31/2018), “Compounds for the treatment or prevention of disorders of the Nervous system and symptoms and manifestations

thereof, and for cyto-protection against diseases and aging of cells and symptoms and manifestations thereof.”

Australian Patent No.

2013323645 issued

on 2/15/2018 (filed 9/25/2013), “d-Methadone for the Treatment of Psychiatric Symptoms.”

Owned by Relmada.

expiry in 2032.

European Patent No.

2,906,209 granted on

6/20/2018 (filed 9/25/2013), “d-Methadone for the Treatment of Psychiatric Symptoms.”

Owned by Relmada.

Estimated expiry

Australian Patent Application No.

(filed 9/25/2013), “d-Methadone for the Treatment of Psychiatric Symptoms.”

Owned by Relmada.

Canadian Patent Application No.

(filed 9/25/2013), “d-Methadone for the Treatment of Psychiatric Symptoms.”

Owned by Relmada.

Chinese Patent Application No.

201380061197.3

(filed 9/25/2013), “d-Methadone for the Treatment of Psychiatric Symptoms.”

Owned by Relmada.

Currently allowed and

awaiting issuance.

Hong Kong Patent Application No.

(filed 9/25/2013), “d-Methadone for the Treatment of Psychiatric Symptoms.”

Owned by Relmada.

Currently allowed and

awaiting issuance.

Indian Patent Application No.

3481/DELNP/2015

(filed 9/25/2013), “d-Methadone for the Treatment of Psychiatric Symptoms.”

Owned by Relmada.

South Korean Patent Application No.

(filed 9/25/2013), “d-Methadone for the Treatment of Psychiatric Symptoms.”

Owned by Relmada.

International (PCT) Patent Application

PCT/US2018/16159 (filed 1/31/2018), “Compounds for the treatment or prevention of disorders of the Nervous system and

symptoms and manifestations thereof, and for cyto-protection against diseases and aging of cells and symptoms and manifestations

thereof.”

Taiwanese Patent Application No.

(filed 3/16/2018), “Compounds for the treatment or prevention of disorders of the Nervous system and symptoms and manifestations

thereof, and for cyto-protection against diseases and aging of cells and symptoms and manifestations thereof.”

Buprenorphine :

application covers the buprenorphine product.

Patent application 12/989,209 filed 3/9/09,

Oral Pharmaceutical Compositions of Buprenorphine and Method of Use cover US.

EP 9719755.2 covers EU.

Owned by Relmada.

currently pending.

Mepivacaine :

These patents

and patent applications cover the Mepivacaine product.

Canadian Patent No.

2,796,575 issued on

5/15/2018 (filed 4/13/2011), “Dermal Pharmaceutical Compositions of 1-Methyl-2,6-Pipecoloxylidide and Method of Use.”

Owned by Relmada.

Estimated expiry in 2030.

Chinese Patent No.

103491778 issued on

5/31/2017 (filed 4/13/2011), “Dermal Pharmaceutical Compositions of 1-Methyl-2,6-Pipecoloxylidide and Method of Use.”

Owned by Relmada.

Estimated expiry in 2030.

Japanese Patent No.

5927506 issued on 5/13/2016