The placebo effect has stymied many experimental drugs and its impact is particularly pronounced in tests of depression drugs. A Relmada Therapeutics drug candidate is the latest victim, flunking a pivotal clinical trial in major depressive disorder.
The Phase 3 study was testing the Relmada drug, REL-1017, as a monotherapy. Patients were evaluated according to a rating scale that assesses the severity of depression symptoms—the higher the score, the more severe the symptoms. Coral Gables, Florida-based Relmada said Thursday that the 232 patients who received its once-daily pill for 28 days showed a reduction in score of 14.8 points. However, results for those given a placebo were close behind with a 13.9 point reduction in score that the company described as “a higher than expected placebo response.”
“Paradoxical results were observed in certain study sites, where placebo dramatically outperformed REL-1017,” the company said in its announcement. “Relmada is investigating the nature of these results.”
Shares of Relmada plunged more than 78% after the news was announced Thursday morning.
Relmada had been positioning its drug as better alternative to the wide selection of depression drugs already on the market. For many of these medicines, the onset of effect can take weeks. Furthermore, most depression drugs address the same target, a brain enzyme called MAO. REL-1017 is intended to offer a rapid therapeutic effect and it also addresses a relatively untapped target, the NMDA receptor. This receptor is found throughout the central nervous system where it plays roles in neuronal activity and cognitive functions.
The two FDA-approved products that block NMDA are Auvelity, a pill from Axsome Therapeutics, and Johnson & Johnson’s Spravato, which is given as an infusion. Relmada has said its drug would offer a way to block NMDA with key advantages over the J&J product. REL-1017 comes in a more patient-friendly pill formulation. Also, Spravato’s main pharmaceutical ingredient is known to cause psychotic effects. The Relmada drug is intended to block NMDA without causing such effects. As a once-daily pill, Relmada’s drug would have a modest dosing advantage over Axsome’s Auvelity, a tablet taken twice daily.
Though Relmada’s drug failed to sufficiently distance itself from the placebo on efficacy, the safety results are holding up. Relmada said the drug was well tolerated by patients with no reports of opioid-like effects, withdrawal effects, or psychosis. Furthermore, no cardiovascular adverse effects were reported. Axsome’s Auvelity, which won its regulatory approval in August, had a clean safety record with no signs of psychotic effects or other problems in its clinical trials.
Relmada conducted an additional exploratory statistical analysis after the Phase 3 study concluded, an effort to better understand why the results differed from the statistically significant improvements observed in Phase 2. Excluding sites with high or low placebo responses, Relmada said its analysis showed “a meaningful difference” between its drug and placebo. However, the FDA typically frowns on such post-hoc analyses that aim to find a positive result from a failed study. William Blair analyst Myles Minter poured cold water on the additional Relmada findings.
“This is interesting but will not serve as sufficient evidence to support approval for a monotherapy label, in our view,” he wrote.
Relmada isn’t giving up on REL-1017 yet. Two additional Phase 3 studies are ongoing, both of them evaluating the drug as an additional treatment for major depressive disorder. Patients in these studies are receiving the Relmada drug or a placebo to be taken alongside their current anti-depression therapy.
Photo credit: Aleksei Morozov, Getty Images
