Alto Neuroscience has announced favorable outcomes from an interim analysis of its Phase 2b clinical trial evaluating ALTO-300 as an adjunctive treatment for major depressive disorder (MDD). The study leverages a unique electroencephalogram (EEG) biomarker to identify patients most likely to respond to the therapy. This precision psychiatry approach aims to improve treatment outcomes in a condition where many patients fail to achieve remission with standard antidepressants. The company anticipates topline results by mid-2026.
Trial Design and Interim Results
The double-blind, placebo-controlled trial is enrolling subjects identified through an EEG biomarker signature. Patients are randomized to receive either ALTO-300 or a placebo in addition to their current antidepressant, to which they have had an inadequate response, over a six-week treatment period. The primary outcome measure is the change from baseline on the Montgomery-Åsberg Depression Rating Scale (MADRS) score.
Prior to the interim analysis, a blinded committee conducted a thorough review of site and subject eligibility, leading to the prospective exclusion of certain sites and subjects from the analysis population. Following this review, the biomarker-positive cohort for the interim analysis comprised 87 subjects. Based on the results of the interim analysis, the Phase 2b trial will continue with an increase of approximately 50 biomarker-positive patients in the final analysis sample, with the goal of enrolling approximately 200 biomarker-positive patients in the final analysis sample.
ALTO-300: Mechanism of Action
ALTO-300 is an oral, small molecule designed to act as a 5-HT2C antagonist and melatonin agonist. By blocking the 5-HT2C serotonin receptor, ALTO-300 aims to increase dopamine release and enhance neural signaling stability. Its melatonin agonist activity may also contribute to improved sleep and circadian rhythm regulation, which are often disrupted in individuals with MDD.
Precision Psychiatry Platform
Alto Neuroscience's Precision Psychiatry Platform is designed to leverage brain biomarkers by analyzing neurocognitive evaluations, EEG activity, wearable data, and more, to detect subjects likely to respond to its product candidates. This approach seeks to move beyond the traditional trial-and-error method of prescribing antidepressants, potentially leading to more effective and personalized treatment strategies.
Future Directions
"The outcome of this interim analysis marks an important milestone for the ALTO-300 program," said Amit Etkin, MD, PhD, CEO and founder of Alto Neuroscience. "The interim analysis was an opportunity to leverage valuable insight from the completed ALTO-100 Phase IIb trial, and we are encouraged by these results. We look forward to reporting topline data in mid-2026."
Alto Neuroscience is also developing ALTO-101 for cognitive impairment associated with schizophrenia and ALTO-203, a histamine inverse agonist for MDD targeting patients with ahedonia. The company's focus on identifying and validating biomarkers aims to transform the treatment landscape for mental health disorders.
