Alto Neuroscience’s part 2 investigational oral H3 receptor blocker, ALTO-203, didn’t considerably enhance temper in members with main depressive dysfunction (MDD), lacking its major efficacy endpoint.1-3
The part 2 trial enrolled 69 members with MDD and elevated ranges of anhedonia. Of those 69, 63 sufferers accomplished the primary a part of the examine, which assessed the impact of single 25 µg or 75 µg doses of ALTO-203 on a measure of alertness and temper. The examine’s major end result was the change in constructive emotion as measured by the Bond-Lader Visible Analog Scale (BL-VAS). Sufferers within the multi-dose a part of the trial took ALTO-203 as soon as day by day for 28 days. Through the multi-dose a part of the trial, investigators noticed a imply placebo-adjusted enchancment on the Montgomery-Åsberg Melancholy Ranking Scale (MADRS) of two factors at week 3 and 0.9 factors at week 4. Roughly 5 hours after a single dose of ALTO-203, members reported vital enhancements in alertness and temper; nonetheless, ALTO-203 didn’t statistically separate itself from placebo.
Whereas the trial missed the endpoint, investigators reported vital modifications in an EEG marker, the theta/beta ratio. This has been flagged as a technique to establish people who would possibly reply to remedy: sufferers with extra irregular theta/beta ratios at baseline had the most important enhancements in consideration.
“We goal to leverage goal biomarkers to allow focused neuropsychiatric drug improvement in order that sufferers can get higher, quicker,” mentioned Amit Etkin, MD, PhD, the founder and CEO of Alto Neuroscience. “On this exploratory trial, we recognized a sturdy biomarker for ALTO-203, EEG high-theta/beta ratio, which is a well-validated measure of irregular cortical arousal and poor attentional management. Notably, this biomarker is FDA-cleared to be used alongside scientific analysis within the analysis of ADHD, reinforcing its scientific relevance. These constructive outcomes replicate findings from an ALTO-203 part 1 examine and improve our understanding of the affected person subtypes almost definitely to profit from the drug, additional strengthening the muse of our precision psychiatry method. We consider our platform has the potential to allow data-driven indication choice and trial design early in improvement—accelerating the trail to simpler, personalised remedy.”1
Etkin had additionally mentioned what Alto hoped to see within the outcomes at a previous occasion: “What we hope for is a few clear sign that helps you information the best way to develop it. Clearly, statistical significance is a crucial reduce level there, but additionally is that sign just like what we’ve seen in wholesome people? Does that sign assist let you know what sort of scientific populations to develop it, be it in melancholy the place it’s now or anyplace else?”2
“We’re inspired by the constructive pharmacodynamic exercise noticed within the examine, which aligns with the proposed mechanism of ALTO-203. The wake-promoting and pro-cognitive results demonstrated, recommend clear potential for ALTO-203 to be a significant remedy throughout varied neuropsychiatric situations wherein sleep and a focus are considerably impaired,” mentioned Adam Savitz, MD, PhD, the chief medical officer of Alto Neuroscience, regardless of the general unfavourable end result.1
References
1. Alto Neuroscience identifies biomarker and reviews constructive pharmacodynamic outcomes from exploratory part 2 proof-of-concept trial of ALTO-203. Information launch. June 26, 2025. Accessed June 27, 2025. https://buyers.altoneuroscience.com/information/news-details/2025/Alto-Neuroscience-Identifies-Biomarker-and-Experiences-Constructive-Pharmacodynamic-Outcomes-from-Exploratory-Part-2-Proof-of-Idea-Trial-of-ALTO-203/default.aspx
2. Taylor NP. Alto misses major efficacy endpoint in part 2 melancholy 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 melancholy drug misses part 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
