Aticaprant

iStock, Wel_nofri The development saga for the depression molecule has been rocky for years, unable to ease symptoms in multiple late-stage trials. Relmada Therapeutics has halted development of its investigational NMDA receptor blocker esmethadone, ending what has been a rough journey for the asset. The company made the announcement in an SEC filing on Friday. The company said that it will terminate a January 2018 licensing agreement , under which it obtained global rights to esmethadone. The molecule was originally deveoped by Charles Inturrisi, a professor at Weill Cornell Medical. Inturrisi then himself licensed it to Medeor, co-founded Paolo Manfredi. Medeor merged with Relmada in 2013. As per the terms of the original contract, Relmada paid a nonrefundable sum of $180,000 upfront to Inturrisi and Manfredi, plus $45,000 every three months ever since. Those quarterly payments were intended to continue until certain conditions were met, including the first market sale of esmethadone or the expiration of its patent. None of such events occurred over the course of the partnership. Esmethadone’s development history has been fraught for some time now. In October 2022, the drug asset failed the Phase III RELIANCE III trial in major depressive disorder (MDD), unable to significantly ease the severity of depressive symptoms as a monotherapy versus placebo. Esmethadone delivered another late-stage disappointment in December of the same year, when the drug again showed no significant benefit in the RELIANCE I study, this time as an adjunctive MDD treatment. For both RELIANCE I and RELIANCE III trials, Relmada blamed an “unplausible placebo response” for the lack of significant efficacy signals for esmethadone. Then, in December 2024, the Phase III RELIANCE II also ended in failure , with an interim analysis finding a high likelihood of futility. A couple of weeks later, Relmada discontinued RELIANCE II and the Phase III RELIGHT study, also in MDD. With esmethadone now gone from its pipeline, Relmada has “made the exploration of strategic product acquisitions our primary focus,” according to a note to investors on its website . The company is focusing its efforts on NDV-01, a Phase II proprietary sustained-release formulation of gemcitabine and docetaxel being trialed for non-muscle invasive bladder cancer. Relmada licensed NDV-01 from Trigone Pharma in March. Phase II data presented in April showed an 85% three-month overall response rate . Relmada is the latest biotech to stumble in the difficult depression space. Last month, for example, Alto Neuroscience’s ALTO-203 was unable to significantly boost mood in patients with MDD in a Phase II study, forcing the California company to dig into exploratory endpoints and look at EEG biomarkers for signals of efficacy. In February, Supernus Pharmaceuticals likewise had a mid-stage stumble when its asset SPN-820 failed to improve symptom burden in patients with treatment-resistant depression. Even Big Pharma seems to have been having trouble making headway into depression, with Johnson & Johnson in March discontinuing the late-stage VENTURA program after its kappa opioid receptor blocker aticaprant failed to demonstrate sufficient efficacy signals to support continued development.

iStock, Nazan Akpolat While ALTO-203 missed its depression-related endpoints, improvements in EEG biomarkers, attention and wakefulness point to signals of drug activity, William Blair said, though the analysts pointed to other indications as potentially more promising for future development. Alto Neuroscience’s investigational oral H3 receptor blocker ALTO-203 failed to significantly improve mood in patients with major depressive disorder. The California-based biotech ended Thursday with a 10% dip versus the day before but nevertheless did not seem discouraged by the trial outcome. In its news release on Thursday, Alto focused on the exploratory endpoints of the Phase II study, touting significant improvements in the theta/beta ratio, an EEG biomarker associated with attentional control, according to the biotech. Compared with placebo, a 25-µg dose of ALTO-203 led to a significant reduction in the theta/beta ratio. Alto also reported significant improvements in sustained attention, an effect that it said aligned with the theta/beta ratio results. ALTO-203 treatment likewise resulted in significantly increased wakefulness. William Blair analysts concurred that the biomarker outcome, supported by better attention, is “evidence of predicted drug activity” for ALTO-203. Meanwhile, the analysts also found the drug’s positive effects on attention “intriguing,” noting that this could signal cognitive benefits as well. Still, William Blair said that the mixed results for depression-related outcomes does not de-risk future development of ALTO-203 in this indication. The totality of evidence “suggests an alternative patient population with hypersomnia or a different indication”—such as narcolepsy or ADHD—“would likely be better suited to ALTO-203,” the analysts added. Analysts at Stifel agreed, telling investors on Thursday that Alto’s readout is “interesting” but not make-or-break for the biotech. “Ultimately, this was an exploratory trial and expectations were low, so some optionality maintained with this program is intriguing,” they wrote. Thursday’s Phase II data come from more than 60 patients with major depressive disorder (MDD) suffering from heightened levels of anhedonia. The study’s primary outcome was the change in positive emotion as measured by the Bond-Lader Visual Analog Scale (BL-VAS), a validated tool for measuring subjective feelings. While results showed improvements in BL-VAS alertness and mood scores from baseline, ALTO-203 failed to statistically separate from placebo. Alto’s mid-stage stumble on Thursday adds to the growing list of clinical roadblocks that depression drugmakers have hit in recent months. In February, for instance, Supernus announced that its oral mTORC activator SPN-820 failed a Phase IIb trial in treatment-resistant depression, being unable to significantly boost patients’ scores on the Montgomery-Åsberg Depression Rating Scale (MADRS). Just a few weeks earlier, in January, Neumora’s own depression drug navacaprant, a kappa opioid receptor inhibitor, likewise failed to demonstrate a significant MADRS benefit in a pivotal study. Not even Big Pharma is exempted from the difficulties of drug development in depression. In March, Johnson & Johnson discontinued its Phase III VENTURA program for aticaprant, also a kappa opioid receptor blocker, for major depressive disorder. The move comes after the molecule demonstrated “insufficient efficacy” in VENTURA.