ALTO-203, Alto Neuroscience’s oral H3 receptor inverse agonist, did not significantly improve mood or meet its primary efficacy endpoint in a Phase 2 trial for major depressive disorder (MDD) patients with elevated anhedonia423.
Despite missing the depression endpoint, ALTO-203 demonstrated significant improvements in objective measures of attention and wakefulness, which were linked to reductions in the EEG theta/beta ratio—a biomarker for cortical arousal and attentional control14.
These findings were consistent with earlier Phase 1 results in healthy volunteers, where ALTO-203 also improved attention and reduced the theta/beta ratio1.
William Blair analysts interpreted the positive changes in EEG biomarkers and attention as evidence of predicted drug activity for ALTO-203, and suggested that other indications—potentially in cognition or attention disorders—might be more promising for future development4.
The company identified a patient selection biomarker (baseline EEG theta/beta ratio) that predicts attentional benefits from ALTO-203, supporting possible use in precision medicine approaches1.
Alto Neuroscience's trial design focused on both pharmacodynamic effects and exploratory endpoints, as it was not statistically powered to detect changes on clinical depression scales, such as the MADRS5.
Preclinical data showed ALTO-203 reversed anhedonia-like behavior in animal models via enhanced dopamine function, distinguishing it from pitolisant, an approved H3R inverse agonist that showed no such effect5.
Sources:
1. 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. https://www.fiercebiotech.com/biotech/alto-misses-primary-efficacy-endpoint-phase-2-depression-trial-sings-cheerful-tune-anyway
3. https://www.psychiatrictimes.com/view/alto-203-fails-to-primary-efficacy-endpoint-in-phase-2-major-depressive-disorder-trial
4. https://www.biospace.com/drug-development/alto-digs-into-exploratory-outcomes-as-depression-drug-misses-phase-ii-endpoint
5. https://www.businesswire.com/news/home/20250514582274/en/Alto-Neuroscience-Reports-First-Quarter-2025-Financial-Results-and-Recent-Business-Highlights