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NOTE REGARDING FORWARD-LOOKING STATEMENTS
Current Report on Form 8-K (this Report) contains forward looking statements that involve risks and uncertainties. All statements
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Therapeutics, Inc. (Relmada, the Company, we, our or us) (a Nevada corporation), is a clinical-stage biotechnology company focused
on the development of d-methadone (dextromethadone, REL-1017), an N-methyl-D-aspartate (NMDA) receptor antagonist. d-methadone
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."
lead product candidate, d-methadone, is an NCE being developed as a rapidly acting, oral agent for the treatment of depression
and other potential indications. We 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, a double-blind, placebo-controlled Phase 2a clinical trial evaluating
the safety, tolerability and efficacy of two doses of REL-1017, 25 mg once a day and 50 mg once a day, as an adjunctive treatment
in patients with treatment resistant depression (TRD).
were adults with major depressive disorder (MDD), who did not respond to one to three courses of antidepressant treatment in their
current episode and are typically classified as having TRD. 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 population (ITT) analysis. No differences
were observed between the ITT and PPP analyses and results.
observed that subjects in both the REL-1017 25 mg and 50 mg treatment groups experienced statistically significant improvement
of 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). SDQ scores demonstrated moderate effect size differences between
subjects receiving REL-1017 and a placebo from day 4 to day 7 and demonstrated statistically significant differences and large
effect size for both 25 mg (P=0.0066; d=0.9) and 50 mg (P=0.0014; d=1.1) arms at day 14.
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
| Day 2 | Day 4 | Day 7 | Day 14 | |||||||||||||||||||||||||||||||||||||||||||||
| LS Means Difference | P-value | d | LS Means Difference | P-value | d | LS Means Difference | P-value | D | LS Means Difference | P-value | d | |||||||||||||||||||||||||||||||||||||
| REL-1017 25mg vs Placebo | -1.9 | 0.4340 | 0.3 | -7.9 | 0.0087 | 0.9 | -8.7 | 0.0122 | 0.8 | -9.4 | 0.0103 | 0.9 | ||||||||||||||||||||||||||||||||||||
| REL-1017 50mg vs Placebo | -0.3 | 0.9092 | 0.0 | -7.6 | 0.0096 | 0.8 | -7.2 | 0.0308 | 0.7 | -10.4 | 0.0039 | 1.0 |
= Least Squares; d = Cohen's effect size
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 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.
receptors are present in many parts of the central nervous system and play important roles in regulating neuronal activity. We
believe that d-methadone acting as a NMDA receptor antagonist can have potential applications in a number of disease indications
which mitigates risk and offers significant upside.
addition to REL-1017, we have a portfolio of three Section 505(b)(2) product candidates at various stages of development. These
product candidates are: LevoCap ER (REL-1015), a sustained release dosage form of the opioid analgesic levorphanol designed to
be abuse deterrent; 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. These products
are not currently in active development.
Upcoming Anticipated Milestones
expect multiple key milestones over the next 12-18 months (our fiscal year ends June 30; however, the anticipated milestones set
forth below refer to calendar year periods). These include:
| Presentation of full details of the Phase 2a data for REL-1017 in TRD in the first half of 2020. | ||
| Meeting with the U.S. Food and Drug Administration (FDA) in an End-of-Phase 2 meeting for REL-1017 in TRD at the end of the first half of 2020. | ||
| Start of pivotal studies for TRD. We intend to propose a Phase 3 study design of REL-1017 in TRD at the End-of-Phase 2 meeting with the FDA. | ||
| Start of Phase 2 study in MDD. At the End-of-Phase 2 meeting with the FDA, we intend to also propose a Phase 2 study design of REL-1017 in MDD. We plan to start both the Phase 3 TRD and Phase 2 MDD studies in the second half of 2020, though development plans may be delayed based on the FDA's feedback and other factors. |
Development Programs
four development projects are briefly described below:
(dextromethadone, REL-1017) and Treatment-Resistant Depression (TRD)
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. In 2017, approximately 17.3 million people in the United States suffered from MDD and approximately 10 to 30% of
patients suffered from TRD.
addition to the high failure rate, none of the marketed products for depression can demonstrate rapid antidepressant effects and
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.
studies have shown that ketamine, a drug known previously as an anesthetic, can lift depression in many patients within hours.
However, we believe it is unlikely that ketamine itself will become a practical treatment for most cases of depression. It must
be administered through intravenous infusion, 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 has not been thoroughly studied for long-term safety and
effectiveness, and the FDA has not approved it to treat depression.
Overview and Mechanism of Action
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, d-methadone is being developed
as a rapidly acting, oral agent for the treatment of depression, neuropathic pain, and/or other potential CNS pathological conditions.
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), 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.