A Phase 3, Multicenter, Randomized, Double-Blind, Placebo-Controlled Study to Assess the Efficacy and Safety of REL-1017 As Adjunctive Treatment for Major Depressive Disorder (MDD)

Study Overview This clinical trial is a Phase 3 research study designed to test the safety and effectiveness of an investigational drug called REL-1017 (esmethadone HCl). The goal is to determine if REL-1017 can help people with major depressive disorder (MDD) who are already taking other antidepressant medications but have not experienced enough improvement.
Why This Study Is Important MDD is a serious condition that affects mood, cognition, motivation, energy, and daily life. Some people do not respond fully to standard antidepressants. REL-1017 is being tested as an additional treatment to see if it can improve symptoms more effectively.
Who Can Participate The study is enrolling adults diagnosed with major depressive disorder who do not have enough relief from their current antidepressant medications. Specific criteria must be met to join the study.
What Happens in the Study Participants will be randomly assigned to receive either REL-1017 or a placebo (an inactive substance) along with their current antidepressant. This process helps researchers understand the effects of the drug. Neither the participants nor the researchers will know who receives REL-1017 or the placebo during the study.
Study Details Duration: The study involves several weeks of treatment and follow-up visits. Assessments: Participants will complete health evaluations, including physical exams and questionnaires, to monitor progress and side effects.
Costs: Study-related treatments and assessments are provided at no cost to participants.
Potential Benefits and Risks Benefits: Participants may experience improvements in depressive symptoms. Risks: As with any investigational medication, there may be side effects. All participants will be closely monitored by the study team.

Start Date27 Dec 2024

Sponsor / Collaborator-

NCT06011577

/ TerminatedPhase 3

A Randomized, Double-Blind, Placebo-Controlled Trial of REL-1017 as an Adjunctive Treatment for Major Depressive Disorder (RELIGHT)

A Phase 3, randomized, double-blind, placebo-controlled, multicenter trial of REL-1017 in patients with major depressive disorder (MDD).

Start Date17 Aug 2023

Sponsor / Collaborator

Relmada Therapeutics, Inc.

NCT04145674

/ RecruitingPhase 2IIT

A Proof of Concept, Multicentre, Phase 2, Double-Blind, Randomized, Placebo-Controlled Study on the Efficacy, Safety and Tolerability of d-Methadone in Moderate to Very Severe Restless Legs Syndrome With Periodic Limb Movements: the Glu-REST Study

Proof of concept, double-blind, randomized, placebo-controlled trial with d-methadone proposed for the first time for use in the treatment of patients diagnosed with primary, moderate to very severe Restless Legs Syndrome (RLS). Its glutamatergic mechanism of action might be effective on RLS arousal pattern and sleep disturbance which highly impair the quality of life of RLS's patients.
Patients will take the study drug/placebo once a day for 30 consecutive days.

Start Date22 Oct 2022

Sponsor / Collaborator

Ente Ospedaliero Cantonale

100 Clinical Results associated with (S)-Methadone

100 Translational Medicine associated with (S)-Methadone

100 Patents (Medical) associated with (S)-Methadone

330

Literatures (Medical) associated with (S)-Methadone

01 Feb 2025·INTERNATIONAL JOURNAL OF CLINICAL PHARMACOLOGY AND THERAPEUTICS

Warfarin pharmacokinetics and pharmacodynamics are not affected by concomitant administration of the long-acting GLP-1 receptor agonist polyethylene glycol loxenatide

Article

Author: Shentu, Jianzhong ; Lv, Duo ; Zhou, Huili ; Wu, Guolan ; Lin, Meihua

OBJECTIVE:

To evaluate potential drug-drug interactions between polyethylene glycol loxenatide (PEX-168) and warfarin.

MATERIALS AND METHODS:

This was an open-label, single-arm, two-treatment, sequential study. 16 healthy male subjects were administered warfarin (5 mg) alone on day 1 and received PEX-168 subcutaneously 200 µg once a week during days 14 - 42, with warfarin (5 mg) on day 44. Pharmacokinetics of R- and S-warfarin, as well as pharmacodynamics of warfarin, as measured by prothrombin time (PT) and international normalized ratio (INR), were assessed.

RESULTS:

The geometric mean ratios (GMRs) of area under the curve from time zero to the time of the last quantifiable concentration (AUC_0-t) for PEX-168 + warfarin vs. warfarin were 0.950 (90% CI: 0.898, 1.006) for R-warfarin and 0.989 (90% CI: 0.946, 1.033) for S-warfarin. The GMRs of maximum observed plasma concentration (C_max) values were 0.965 (90% CI: 0.893, 1.043) for R-warfarin and 0.983 (90% CI: 0.899, 1.075) for S-warfarin, both of which were contained in the interval 0.80 - 1.25. PEX-168 had no effect on the area under the effect-time curve from time 0 to 168 hours of INR and PT, as demonstrated by the GMRs of 0.987 (90% CI: 0.974, 1.000) and 0.990 (90% CI: 0.979, 1.002), respectively.

CONCLUSION:

Concomitant administration of PEX-168 and single-dose warfarin was well tolerated. PEX-168 had no effect on the pharmacokinetics or pharmacodynamics of warfarin.

01 Jan 2025·Clinical Pharmacology in Drug Development

A Phase 1 Study to Evaluate the Pharmacokinetic Drug‐Drug Interaction Between Islatravir and Methadone in Participants on Stable Methadone Therapy

Article

Author: Ankrom, Wendy ; Searle, Shawn ; Iwamoto, Marian ; Xu, Zhiqing ; Stoch, S. Aubrey ; Schwartz, Howard ; Matthews, Catherine ; Handy, Whitney ; Matthews, Randolph P. ; Gravesande, Kezia ; Patel, Munjal

Abstract:

Islatravir is a nucleoside reverse transcriptase translocation inhibitor in development for the treatment of HIV‐1. People living with HIV‐1 receiving methadone maintenance therapy may benefit from islatravir. This study was designed to evaluate single‐dose islatravir on steady‐state methadone pharmacokinetics. A nonrandomized, open‐label study (NCT04568603) was conducted and included adult participants receiving methadone therapy. Participants received their standard methadone therapy and a single oral dose of islatravir 60 mg concomitantly. Blood samples were collected to determine methadone and islatravir pharmacokinetics. Fourteen participants aged 26‐63 years were enrolled; 13 completed the study. The geometric mean ratios for methadone area under the concentration‐time curve from time 0 to 24 hours (AUC0‐24), maximum plasma concentration (Cmax), and concentration at 24 hours (C24) were 1.03, 1.01, and 1.07, respectively. Similar effects were seen for the R‐ and S‐enantiomer of methadone (R‐methadone: AUC0‐24, 1.03; Cmax, 1.02; and C24, 1.06; S‐methadone: AUC0‐24, 1.03; Cmax, 1.01; and C24, 1.08). For islatravir, based on a comparison with historical data, the geometric mean ratios for AUC0‐inf and Cmax were 1.18 and 0.86, respectively. Coadministration of a single dose of islatravir and methadone was generally well tolerated. Single‐dose islatravir did not affect steady‐state methadone pharmacokinetics in a clinically meaningful way.

01 Dec 2024·PSYCHOPHARMACOLOGY

Evaluation of (S)-T1 and (S)-T2 ligands targeting α3β4 nAChR as potential nicotine addiction pharmacotherapy

Article

Author: Thanusuwannasak, Thanundorn ; Limpikirati, Patanachai ; Vajragupta, Opa ; Kanasuwan, Apinan ; Islamie, Ridho ; Nianpanich, Saranda ; Sarasamkan, Jiradanai ; Rodsiri, Ratchanee

OBJECTIVES:

Substance use disorders (SUDs) represent a significant global health concern, demanding the development of effective pharmacological treatments. To address this, an investigation was conducted to examine the anti-addictive properties of two compounds, (S)-T1 and (S)-T2, which specifically target the α3β4 nicotinic acetylcholine receptor (nAChR).

METHODS:

The effects of (S)-T1 and (S)-T2 on nicotine-induced conditioned place preference (CPP), locomotor activity and dopamine levels in particular brain regions associated to addiction were investigated and compared in male C57BL/6N mice.

RESULTS:

The results demonstrate that neither (S)-T1 nor (S)-T2 induced place conditioning or conditioned place aversion (CPA), suggesting the absence of rewarding or aversive effects. Both compounds significantly attenuated nicotine-induced CPP, with (S)-T1 exhibiting a dose-dependent effect. Furthermore, the co-administration of (S)-T2 (10 mg/kg) with nicotine markedly reduced locomotor activity compared to nicotine treatment alone. Additionally, dopamine analysis revealed that nicotine increased dopamine levels in the nucleus accumbens (NAc) and dorsal striatum, whereas the co-administration of (S)-T1 (1, 3, and 10 mg/kg) and (S)-T2 (10 mg/kg) significantly decreased dopamine levels in these brain regions. No significant effects were observed in the prefrontal cortex (PFC).

CONCLUSIONS:

These findings suggest that (S)-T1 and (S)-T2 hold promise for treating nicotine addiction by attenuating nicotine-induced CPP and modulating dopamine release in key reward-related brain regions. Further research is needed to gain insights into the underlying mechanisms behind their anti-addictive effects and substantiate their potential for treating nicotine addiction.

News (Medical) associated with (S)-Methadone

09 Dec 2024

·www.globenewswire.com

Relmada Therapeutics to Discontinue the Reliance II and Relight Phase 3 Studies of REL-1017

Relmada Therapeutics has Commenced a Process to Explore Strategic Alternatives to Maximize Shareholder ValueCORAL GABLES, Fla., Dec. 09, 2024 (GLOBE NEWSWIRE) -- Relmada Therapeutics, Inc. (Nasdaq: RLMD, “Relmada”, “the Company”), a late-stage biotechnology company addressing diseases of the central nervous system (CNS), today announced that in light of the recent data monitoring committee (DMC) evaluation of the full dataset from the Reliance II Phase 3 study of the Company's REL-1017 program, the Company will discontinue the Reliance II and Relight Phase 3 studies. The Company will continue to advance the Phase 1 study of REL-P11, an investigational agent for the treatment of metabolic disease, currently in a Phase 1 first-in-human study. In connection with this decision, the Company has commenced a process to explore strategic alternatives to maximize shareholder value. As part of this process, the Company plans to consider a wide range of options with a focus on maximizing shareholder value, including, but not limited to, the sale of Company assets, a sale of the Company, a merger or a reverse merger, the acquisition of assets or rights for the development of other products, or other strategic transaction(s). There can be no assurance that the exploration of strategic alternatives will result in any agreements or transactions, or as to the timing of any such agreements or transactions. The Company is in the process of engaging a financial advisor to assist in the strategic review process. The Company has not set a timetable for completion of the evaluation process and does not intend to disclose further developments or guidance on the status of its exploration of strategic alternatives unless and until it is determined that further disclosure is appropriate or necessary. About REL-1017 REL-1017 is a new chemical entity (NCE) and novel NMDA receptor (NMDAR) channel blocker that preferentially targets hyperactive channels while maintaining physiological glutamatergic neurotransmission. About REL-P11 Relmada acquired the development and commercial rights to a novel psilocybin and derivatives program in July of 2021. Psilocybin has neuroplastogen™ effects that have the potential to ameliorate neurodegenerative conditions. Relmada identified the potential to use low-dose psilocybin as a treatment for metabolic diseases and published the data at the American Society for the Study of Liver Disease (AASLD 2023). About Relmada Therapeutics, Inc. Relmada Therapeutics is a late-stage biotechnology company addressing diseases of the central nervous system (CNS) and metabolic disorders. Relmada’s experienced and dedicated team is committed to making a difference in the lives of patients and their families. Learn more at www.relmada.com. Forward-Looking Statements The Private Securities Litigation Reform Act of 1995 provides a safe harbor for forward-looking statements made by us or on our behalf. This press release contains statements which constitute “forward-looking statements” within the meaning of Section 27A of the Securities Act of 1933 and Section 21E of the Securities Exchange Act of 1934. Any statement that is not historical in nature is a forward-looking statement and may be identified by the use of words and phrases such as “expects”, “anticipates”, “believes”, “will”, “will likely result”, “will continue”, “plans to”, “potential”, “promising”, and similar expressions. These statements are based on management’s current expectations and beliefs and are subject to a number of risks, uncertainties and assumptions that could cause actual results to differ materially from those described in the forward-looking statements, including potential failure of clinical trial results to demonstrate statistically and/or clinically significant evidence of efficacy and/or safety, failure of top-line results to accurately reflect the complete results of the trial, failure of the ongoing Phase 1 and planned Phase 2a trials of REL-P11, the Company’s low-dose, modified-release formulation of psilocybin, to be successfully carried out and the other risk factors described under the heading “Risk Factors” set forth in the Company’s reports filed with the SEC from time to time. No forward-looking statement can be guaranteed, and actual results may differ materially from those projected. Relmada undertakes no obligation to publicly update any forward-looking statement, whether as a result of new information, future events, or otherwise. Readers are cautioned that it is not possible to predict or identify all the risks, uncertainties and other factors that may affect future results and that the risks described herein should not be a complete list. Investor Contact: Tim McCarthy LifeSci Advisors Tim@LifeSciAdvisors.com Media Inquiries: Corporate Communications media@relmada.com

Phase 1Phase 2Phase 3

04 Dec 2024

·www.globenewswire.com

Relmada Therapeutics Reports That Data Monitoring Committee (DMC) Assessment Indicates That the Phase 3 Reliance II Trial is Futile at its Interim Analysis and is Unlikely to Meet the Primary Efficacy Endpoint with Statistical Significance

The DMC did not identify any new safety concerns Relmada to evaluate potential next steps for the REL-1017 program Relmada to continue to focus on the development of REL-P11 for metabolic disease Relmada is well capitalized with approximately $54.1 million in cash and cash equivalents as of September 30, 2024 CORAL GABLES, Fla., Dec. 04, 2024 (GLOBE NEWSWIRE) -- Relmada Therapeutics, Inc. (Nasdaq: RLMD, “Relmada”, “the Company”), a late-stage biotechnology company addressing diseases of the central nervous system (CNS), today announced that the pre-planned interim analysis of Reliance II, conducted by the Independent Data Monitoring Committee (DMC), indicated that the Reliance II Phase 3 study is futile and is unlikely to meet the primary efficacy endpoint with statistical significance. Reliance II is designed to evaluate REL-1017 as an adjunctive treatment for major depressive disorder (MDD), to be used in combination with other approved anti-depressants. No new safety signals were reported. “We are disappointed with the outcome of this interim analysis,” said Sergio Traversa, Chief Executive Officer of Relmada. “Based on these results, Relmada will evaluate the full dataset to determine next steps for the REL-1017 program. The Company will continue to advance the Phase 1 study of REL-P11, an investigational agent for the treatment of metabolic disease, currently in a Phase 1 first-in-human study. We are grateful to the investigative sites and patients who participated in the REL-1017 program." About REL-1017 REL-1017 is a new chemical entity (NCE) and novel NMDA receptor (NMDAR) channel blocker that preferentially targets hyperactive channels while maintaining physiological glutamatergic neurotransmission. About REL-P11 Relmada acquired the development and commercial rights to a novel psilocybin and derivatives program in July of 2021. Psilocybin has neuroplastogen™ effects that have the potential to ameliorate neurodegenerative conditions. Relmada identified the potential to use low-dose psilocybin as a treatment for metabolic diseases and published the data at the American Society for the Study of Liver Disease (AASLD 2023). About Relmada Therapeutics, Inc. Relmada Therapeutics is a late-stage biotechnology company addressing diseases of the central nervous system (CNS) and metabolic disorders. Relmada's experienced and dedicated team is committed to making a difference in the lives of patients and their families. Learn more at www.relmada.com. Forward-Looking Statements The Private Securities Litigation Reform Act of 1995 provides a safe harbor for forward-looking statements made by us or on our behalf. This press release contains statements which constitute "forward-looking statements" within the meaning of Section 27A of the Securities Act of 1933 and Section 21E of the Securities Exchange Act of 1934. Any statement that is not historical in nature is a forward-looking statement and may be identified by the use of words and phrases such as "expects”, "anticipates”, "believes”, "will”, "will likely result”, "will continue”, "plans to”, "potential”, "promising”, and similar expressions. These statements are based on management's current expectations and beliefs and are subject to a number of risks, uncertainties and assumptions that could cause actual results to differ materially from those described in the forward-looking statements, including potential failure of clinical trial results to demonstrate statistically and/or clinically significant evidence of efficacy and/or safety, failure of top-line results to accurately reflect the complete results of the trial, failure of the Reliance-OLS (study 310) to accurately reflect the results of the ongoing Reliance II (study 302) and Relight (study 304) blinded, randomized and controlled studies of REL-1017, failure of the ongoing Phase 1 and planned Phase 2a trials of REL-P11, the Company’s low-dose, modified-release formulation of psilocybin, to be successfully carried out, failure to obtain regulatory approval of REL-1017 for the treatment of major depressive disorder, and the other risk factors described under the heading "Risk Factors" set forth in the Company's reports filed with the SEC from time to time. No forward-looking statement can be guaranteed, and actual results may differ materially from those projected. Relmada undertakes no obligation to publicly update any forward-looking statement, whether as a result of new information, future events, or otherwise. Readers are cautioned that it is not possible to predict or identify all the risks, uncertainties and other factors that may affect future results and that the risks described herein should not be a complete list. Investor Contact:Tim McCarthyLifeSci AdvisorsTim@LifeSciAdvisors.com Media Inquiries:Corporate Communicationsmedia@relmada.com

Phase 1Phase 2Phase 3

04 Dec 2024

·endpts.com

Relmada's rapid-acting NMDA depression drug expected to fail second Phase 3

Relmada Therapeutics said Wednesday morning that a Phase 3 study testing its major depression drug, REL-1017, is likely to fail, cratering its stock price. The study’s data monitoring committee said the trial will hit futility ahead of an interim analysis and won’t achieve its primary endpoint, according to a press release. Relmada’s stock $RLMD fell more than 70% in premarket trading on Wednesday to below $1.00 per share. REL-1017 is an NMDA receptor channel blocker designed to be given in combination with other antidepressants. Last year, an open-label study showed that 204 patients previously untreated with REL-1017 increased scores on the Montgomery–Åsberg Depression Rating Scale by an average of 11.3 points after one week and 22.5 points after one year. Wednesday’s news also follows a Phase 3 failure for REL-1017 in 2022, when a placebo-controlled study measuring severe depressive episodes did not reach its primary endpoint. At the time, Relmada blamed a spike in the placebo responses, describing results from certain trial sites as “paradoxical.” The company said it will continue to advance a separate program, REL-P11, in a Phase 1 study for metabolic diseases.

Phase 3Clinical ResultPhase 1Phase 2Clinical Trial Failure

100 Deals associated with (S)-Methadone

External Link

KEGG	Wiki	ATC	Drug Bank
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Indication	Highest Phase	Country/Location	Organization	Date
Depressive Disorder, Major	Phase 3	US	Relmada Therapeutics, Inc.	08 Jan 2021
Depressive Disorder, Treatment-Resistant	Phase 2	US	Relmada Therapeutics, Inc.	11 May 2018
Neuralgia	Phase 1	-	Relmada Therapeutics, Inc.	04 Dec 2014
Rett Syndrome	Preclinical	US	Relmada Therapeutics, Inc.	20 Feb 2019
Amyotrophic Lateral Sclerosis	Preclinical	US	Relmada Therapeutics, Inc.	-

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Study	Phase	Population	Analyzed Enrollment	Group	Results	Evaluation	Publication Date


NCT04855747 (Reliance II, GlobeNewswire) Manual	Phase 3	Depressive Disorder, Major	-	REL-1017	oqzgybitge(jpltqfqfbv) = futile and is unlikely to meet the primary efficacy endpoint. ztdwelzden (wfmbpcwraj ) Not Met View more	Negative	04 Dec 2024
NCT04855760 (RELIANCE-OLS, CTgov)	Phase 3	Depressive Disorder, Major	627	REL-1017	bexqzdqzfb(neektpfxqo) = ikanumavlp ycncvaeyjl (donfiqrwij, tibiphoytx - bjohcempvv) View more	-	09 Aug 2024
NCT04688164 (Psychiatry) Manual	Phase 3	Depressive Disorder, Major	227	REL-1017	ezxbfdbzoy(wmgqnmoius) = lippnkcuxl yzdogfhsye (frxqtxqupx, 11.3) View more	Negative	17 Jun 2024
				Placebo	ezxbfdbzoy(wmgqnmoius) = eppyqgrcbt yzdogfhsye (frxqtxqupx, 10.4) View more
NCT03051256 (REL-1017, Pubmed)	Phase 2	Depressive Disorder, Major	62	Esmethadone 25 mg	roardekqpn(esrlmigbjk) = frqxgpthvn fgwxgtpnss (xhkzghkubm ) View more	Positive	13 May 2024
				Esmethadone 50 mg	roardekqpn(esrlmigbjk) = sdixseirzj fgwxgtpnss (xhkzghkubm ) View more
NCT05081167 (Reliance III, CTgov)	Phase 3	Depressive Disorder, Major	232	Placebo	zjpvrlimxo(lusnrmravu) = jkczrwcwqq snayratjcv (yuxytvscwg, kgjboztscz - adegxdbujh) View more	-	26 Mar 2024
NCT04855760 (RELIANCE-OLS, Biospace) Manual	Phase 3	Depressive Disorder, Major	627	REL-1017	zesahrxspx(ncdwgrewae) = COVID-19 (9.7%), headache (9.7%), upper respiratory tract infection (8.6%), and nausea (5.0%). snyjkrseix (lulnavumyj ) View more	Positive	20 Sep 2023
NCT03051256 (REL-1017, CTgov)	Phase 2	Depressive Disorder, Major \| Depressive Disorder, Treatment-Resistant	62	REL-1017 (REL-1017 25 mg)	hegdfbzzxk(dimjcmzayg) = cycxstlyzi akvzdsfamo (frjfpbwnop, dsdejwnfjl - lmxbfzpyke) View more	-	17 Mar 2021
				REL-1017 (REL-1017 50 mg)	hegdfbzzxk(dimjcmzayg) = qzagewcndj akvzdsfamo (frjfpbwnop, cgjanebfzq - wlyqcleitq) View more
NCT00588640 (CTgov)	Phase 1/2	Colonic Cancer \| Esophageal Carcinoma \| Central Nervous System Neoplasms ... View more	10	d-methadone (Phase I, Cohort l)	vfddcbzfsb(fdhzmrgsns) = wychxpvupd tvpolopdco (qycdlnagsi, mfsyygmbce - shtqfplldu)	-	10 Aug 2016
				D-methadone (Patients Receiving D-methadone 40 mg)	gyzrrkftci(pspzofawod) = hosjjicjtm rbmbjpidbg (jnnuscmbuq, lydtsbeqxg - ddbaewafdb) View more

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