Relmada Therapeutics’ RELIANCE III trial studying REL-1017 as a treatment for Major Depressive Disorder failed to hit the primary endpoint, the company reported Thursday.
Relmada Therapeutics’ RELIANCE III trial studying REL-1017 as a treatment for Major Depressive Disorder failed to hit the primary endpoint, the company announced Thursday. At some study sites, there were “paradoxical results,” Relmada reported.
In an attempt to understand the paradoxical data, the company ran a post hoc, exploratory analysis utilizing the band-pass method. That analysis excluded both sites with “implausibly high or low placebo responses,” and the company ultimately found a meaningful difference between REL-1017 and placebo.
The primary endpoint was a statistically significant improvement in depression symptoms versus placebo on Day 28, according to the Montgomery-Asberg Depression Rating Scale (MADRS). The treatment arm demonstrated a MADRS decrease of 14.8 points on day 28 compared to 13.0 for the placebo cohort.
The placebo arm results were significantly higher and unexpected, particularly associated with certain trial sites.
Maurizio Fava, M.D., psychiatrist-in-chief, Massachusetts General Hospital and Slater Family Professor of Psychiatry, Harvard Medical School, called the results “disappointing for patients.”
The company continues to enroll patients in RELIANCE I and RELIANCE II, ongoing Phase III studies of REL-1017, as a potential adjunctive (supplemental) treatment for MDD. The program also includes RELIANCE-OLS, a long-term open-label safety trial currently enrolling both new patients and patients from the other three RELIANCE studies.
REL-1017 is a new chemical entity. It is a novel NMDA receptor channel blocker that preferentially targets hyperactive channels and maintains physiological glutamatergic neurotransmission. In August, the FDA granted the drug Fast Track designation as a monotherapy for MDD.
In a Phase II trial, the drug showed fast, robust and sustained antidepressant effects and statistically significant improvements versus placebo. As with the current study, the drug had a favorable tolerability and safety profile, demonstrating no opioid-like or withdrawal effects or psychotomimetic effects, which is to say, no states of altered consciousness.
Relmada declined BioSpace‘s request for comment.
Competition in a Difficult-to-Treat Disease Space
Although MDD is a tough indication to develop new drugs for, there has been some progress in the space.
In August, the FDA approved Axsome Therapeutics’ Auvelity for MDD in adults. It was the first and only oral N-methyl D-aspartate (NMDA) receptor antagonist approved for the indication. Notably, this was the first new oral mechanism of action for MDD in more than 60 years.
In May, Sage Therapeutics and Biogen initiated a rolling submission to the FDA for zuranolone to treat MDD. Zuranolone is a two-week, once-daily oral drug being developed for MDD as well as postpartum depression (PPD). It is an investigational oral neuroactive steroid (NAS) GABA-A receptor-positive allosteric modulator (PAM).
The partners submitted the nonclinical module of the NDA to the FDA and expect to submit the rest before the end of this year. The drug received Fast Track Designation from the FDA in 2017 in MDD and Breakthrough Therapy designation in 2018.
In September, the two companies presented 11 new analyses from the zuranolone program at the 2022 Psych Congress in New Orleans. This included more data from the SHORELINE study. The data bolstered support for the drug as a potential episodic treatment for MDD.
