Kappa Opioid Receptor Agonist(Entera)

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.