Alto's Depression Drug Misses Primary Endpoint in Phase II Trial, Shows Promise in Exploratory Outcomes

Alto Neuroscience's investigational oral H3 receptor blocker, ALTO-203, failed to meet its primary endpoint in a Phase II trial for major depressive disorder (MDD). Despite this setback, the company reported encouraging results in exploratory outcomes, suggesting potential applications in other indications.

Mixed Results in Phase II Study

The Phase II study, which included over 60 patients with MDD and heightened levels of anhedonia, aimed to evaluate ALTO-203's efficacy in improving positive emotion as measured by the Bond-Lader Visual Analog Scale (BL-VAS). While the drug showed improvements in BL-VAS alertness and mood scores from baseline, it failed to statistically separate from placebo in the primary outcome.

However, Alto Neuroscience highlighted significant improvements in exploratory endpoints:

• A 25-μg dose of ALTO-203 led to a significant reduction in the theta/beta ratio, an EEG biomarker associated with attentional control.
• Patients demonstrated significant improvements in sustained attention, aligning with the theta/beta ratio results.
• Treatment with ALTO-203 resulted in significantly increased wakefulness.

Analysts' Perspectives and Future Directions

William Blair analysts interpreted the biomarker outcome and attention improvements as "evidence of predicted drug activity" for ALTO-203. They found the drug's positive effects on attention "intriguing," suggesting potential cognitive benefits.

However, both William Blair and Stifel analysts agreed that the mixed results for depression-related outcomes do not de-risk future development of ALTO-203 in MDD. They suggested that alternative patient populations or indications might be better suited for the drug's development:

• Patients with hypersomnia
• Narcolepsy
• Attention-deficit/hyperactivity disorder (ADHD)

Stifel analysts noted that while the readout is "interesting," it is not make-or-break for Alto Neuroscience. They emphasized that the trial was exploratory in nature, and some optionality maintained with the program remains intriguing.

Recent Setbacks in Depression Drug Development

Alto's Phase II results add to a growing list of clinical roadblocks faced by depression drug developers in recent months:

• Supernus Pharmaceuticals' oral mTORC activator SPN-820 failed a Phase IIb trial in treatment-resistant depression in February.
• Neumora Therapeutics' kappa opioid receptor inhibitor navacaprant failed to demonstrate significant benefit in a pivotal study for depression in January.
• Johnson & Johnson discontinued its Phase III VENTURA program for aticaprant, another kappa opioid receptor blocker, in March due to "insufficient efficacy" in MDD.

These setbacks underscore the challenges in developing effective treatments for depression and highlight the need for innovative approaches and careful consideration of target indications in drug development.