ALTO-203 Fails to Primary Efficacy Endpoint in Phase 2 Major Depressive Disorder Trial

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Alto Neuroscience’s phase 2 investigational oral H3 receptor blocker, ALTO-203, failed to significantly improve mood in participants with major depressive disorder (MDD), missing its primary efficacy endpoint.^1-3

The phase 2 trial enrolled 69 participants with MDD and elevated levels of anhedonia. Of these 69, 63 patients completed the first part of the study, which assessed the effect of single 25 µg or 75 µg doses of ALTO-203 on a measure of alertness and mood. The study’s primary outcome was the change in positive emotion as measured by the Bond-Lader Visual Analog Scale (BL-VAS). Patients in the multi-dose part of the trial took ALTO-203 once daily for 28 days. During the multi-dose part of the trial, investigators saw a mean placebo-adjusted improvement on the Montgomery-Åsberg Depression Rating Scale (MADRS) of 2 points at week 3 and 0.9 points at week 4. Approximately 5 hours after a single dose of ALTO-203, participants reported significant improvements in alertness and mood; however, ALTO-203 failed to statistically separate itself from placebo.

While the trial missed the endpoint, investigators reported significant changes in an EEG marker, the theta/beta ratio. This has been flagged as a way to identify individuals who might respond to treatment: patients with more abnormal theta/beta ratios at baseline had the biggest improvements in attention.

“We aim to leverage objective biomarkers to enable targeted neuropsychiatric drug development so that patients can get better, faster,” said Amit Etkin, MD, PhD, the founder and CEO of Alto Neuroscience. “In this exploratory trial, we identified a robust biomarker for ALTO-203, EEG high-theta/beta ratio, which is a well-validated measure of abnormal cortical arousal and poor attentional control. Notably, this biomarker is FDA-cleared for use alongside clinical evaluation in the diagnosis of ADHD, reinforcing its clinical relevance. These positive results replicate findings from an ALTO-203 phase 1 study and enhance our understanding of the patient subtypes most likely to benefit from the drug, further strengthening the foundation of our precision psychiatry approach. We believe our platform has the potential to enable data-driven indication selection and trial design early in development—accelerating the path to more effective, personalized treatment.”¹

Etkin had also discussed what Alto was hoping to see in the results at a prior event: “What we are 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 have 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?”²

“We are encouraged by the positive pharmacodynamic activity observed in the study, which aligns with the proposed mechanism of ALTO-203. The wake-promoting and pro-cognitive effects demonstrated, suggest clear potential for ALTO-203 to be a meaningful treatment across various neuropsychiatric conditions in which sleep and attention are significantly impaired,” said Adam Savitz, MD, PhD, the chief medical officer of Alto Neuroscience, despite the overall negative outcome.¹

References

1. Alto Neuroscience identifies biomarker and reports positive pharmacodynamic results from exploratory phase 2 proof-of-concept trial of ALTO-203. News release. June 26, 2025. Accessed June 27, 2025. https://investors.altoneuroscience.com/news/news-details/2025/Alto-Neuroscience-Identifies-Biomarker-and-Reports-Positive-Pharmacodynamic-Results-from-Exploratory-Phase-2-Proof-of-Concept-Trial-of-ALTO-203/default.aspx

2. Taylor NP. Alto misses primary efficacy endpoint in phase 2 depression trial. Fierce Biotech. June 26, 2025. Accessed June 27, 2025. https://www.fiercebiotech.com/biotech/alto-misses-primary-efficacy-endpoint-phase-2-depression-trial-sings-cheerful-tune-anyway

3. Manalac T. Alto digs into exploratory outcomes as depression drug misses phase II endpoint. Biospace. June 27, 2025. Accessed June 27, 2025. https://www.biospace.com/drug-development/alto-digs-into-exploratory-outcomes-as-depression-drug-misses-phase-ii-endpoint