On October 13, Relmada Therapeutics announced that its REL-1017 for the treatment of major depressive disorder (MDD) failed to meet the primary endpoint of improvement in depression symptom scores in a Phase III study. Affected by this news, the company’s stock price fell 78%.
NMDA is a chemical that opens channels similar to the physiological neurotransmitter glutamate. Studies have shown that NMDA receptors are involved in the occurrence of depression and normal physiological functions.
REL-1017 (dexmethadone) is a novel NMDA receptor channel blocker that preferentially targets GluN1-GluN2D hyperactive channels while avoiding inhibition of other channels with normal physiological functions.
The mechanism of action of REL-1017:
①The presynaptic release of glutamate causes depolarization of the neuronal cell membrane, followed by the release of physiological magnesium blockers;
②Influx of sodium ions and calcium ions into neurons;
③REL-1017 only enters the NMDA receptor channel when the NMDA receptor channel is in a hyperactivated state;
④REL-1017 can effectively prevent excessive calcium ions from entering neurons by localizing in the center of the channel.
The trial (RELIANCE-III) included 232 patients and was designed to evaluate the efficacy and safety of REL-1017 monotherapy in patients with MDD. The primary endpoint of the trial was change in Montgomery-Asperger Depression Scale (MADRS10) score.
The results showed that on the 28th day of treatment, the improvement of MADRS10 score in the REL-1017 group (-14.8 points) was not statistically significant compared with the placebo group (-13.9 points). In this study, the placebo group had a higher-than-expected response, and conflicting results were observed in some study centers, with placebo being significantly better than REL-1017, Relmada said. Relmada is investigating the reasons behind these results.
To better understand those contradictory results, Relmada’s team performed a post-hoc exploratory analysis using the band-pass method. Bandpass analysis excluded data at some centers with high or low placebo response (defined as a mean decrease in MADRS10 score of >14 points or <3 points from There was a significant difference in the improvement of MADRS10 score between groups (MADRS10 score decreased by >4.9 points, P<0.05).
Relmada also has two ongoing Phase III studies (RELIANCE-I and RELIANCE-II) in MDD. In addition, Relmada plans to conduct a long-term safety study of REL-1017, which will enroll subjects from the three RELIANCE studies as well as new subjects.