Relmada Therapeutics’ investigational NDMA receptor channel blocker, REL-1017, failed to meet its primary endpoint in major depressive disorder in a second Phase III trial, the Florida-based biotech announced Wednesday.
In the RELIANCE I study, REL-1017 decreased scores on the Montgomery-Asberg Depression Rating Scale (MADRS) by 15.1 points at the 28-day follow-up, while placebo patients saw a score drop of 12.9 points.
The 2.2-point difference between groups is clinically meaningful but fell short of statistical significance, Relmada reported. Response rate was significantly better in the REL-1017 arm, at 39.8% vs. 27.2% in the placebo group.
REL-1017 was safe and had a favorable tolerability profile, triggering no opioid-like side effects. There were also no withdrawal or psychotomimetic effects.
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Relmada’s shares dropped 37% in after-hours trading due to the news.
In an investor call Wednesday afternoon, Chief Executive Sergio Traversa attributed the drug’s failure to two high-enrolling study sites, where “placebo dramatically outperformed REL-1017.”
Relmada conducted a post-hoc analysis excluding patients from these sites to interrogate the impact of these two outlier test centers. Results showed that REL-1017 decreased the MADRS score by 16.7 points. Compared with placebo, Relmada’s MDD hopeful resulted in a 4.1-point advantage, which was statistically significant with a p-value less than 0.02.
“We believe these posthoc analyses show a clear efficacy signal for REL-1017,” Traversa said, adding that the company understands these data are “not sufficient alone to be used in an FDA submission.”
Past Failures and Future Directions
A strong placebo effect has derailed Relmada’s MDD plans before. In October, the company reported that REL-1017 likewise fell short of its primary efficacy endpoint in RELIANCE III, a trial assessing the candidate as monotherapy for MDD.
As in RELIANCE I, the drug failed to induce a statistically superior improvement in MADRS scores after 28 days. The company called the results “paradoxical” at the time.
The same two high-enrolling sites with high placebo responses were likewise responsible for the null effect of REL-1017 as compared with placebo, Relmada claimed. Post-hoc analyses excluding these trial centers revealed statistical superiority of Relmada’s candidate over placebo.
During the investor call, company scientific advisor Maurizio Fava, M.D. explained that Relmada ran both trials “in parallel,” such that sites were able to participate in both RELIANCE I and RELIANCE III. “These were exactly the same centers with known implausible results.”
Despite failing its main efficacy bar in RELIANCE I, Relmada is pushing through with RELIANCE II, another Phase III, two-armed, placebo-controlled study assessing REL-1017 as an adjunctive treatment for MDD. The company will use its learnings from RELIANCE I and RELIANCE III to improve operations and protocol for RELIANCE II.
Traversa noted that Relmada has enough financial flexibility to continue advancing REL-1017 in the clinic.
Source: BioSpace
