Alto Neuroscience's Depression Trial Misses Primary Endpoint, Company Highlights Secondary Outcomes

Alto Neuroscience has reported mixed results from its phase 2 trial of ALTO-203, a histamine H3 receptor inverse agonist, in patients with major depressive disorder and elevated anhedonia. While the study failed to meet its primary efficacy endpoint, the company is emphasizing positive secondary outcomes and biomarker data to support further development of the drug candidate.

Primary Endpoint Missed, Placebo Effect Stronger Than Expected

The phase 2 trial, which enrolled 69 patients with 63 completing the first part of the study, evaluated the effect of single 25 µg or 75 µg doses of ALTO-203 on alertness and mood. Despite observing significant improvements in these measures five hours after a single dose, there was no significant separation between ALTO-203 and placebo. Alto attributed this to a higher-than-expected placebo response.

Secondary Outcomes and Biomarker Data Show Promise

Despite the setback in the primary endpoint, Alto reported several encouraging secondary findings:

1. EEG Biomarker: Significant changes were observed in the theta/beta ratio, an EEG marker that Alto believes could help identify potential responders to treatment. Patients with more abnormal baseline theta/beta ratios showed the most substantial improvements in attention.

2. Wearable Data: ALTO-203 was linked to increased wakefulness, as measured by wearable devices.

3. Depression Rating Scale: In the multi-dose part of the trial, the low dose of ALTO-203 showed a mean placebo-adjusted improvement of 2 points at week 3 and 0.9 points at week 4 on the Montgomery-Åsberg Depression Rating Scale (MADRS). Interestingly, the high dose performed no better than placebo.

Next Steps and Company Outlook

Alto Neuroscience is currently conducting a complete analysis of the dataset before deciding on the next steps for ALTO-203. CEO Amit Etkin, M.D., Ph.D., emphasized the importance of finding clear signals to guide future development, stating, "What we're hoping for is some clear signal that helps you guide how to develop it. Obviously, statistical significance is an important cut point there, but also is that signal similar to what we've seen in healthy individuals? Does that signal help tell you what kind of clinical populations to develop it, be it in depression where it is now or anywhere else?"

The company's approach to drug development, which relies heavily on biomarkers and precision medicine techniques, will likely play a crucial role in determining the future of ALTO-203 and Alto's broader pipeline in neuropsychiatry.