ALTO-203, an H3 Inverse Agonist, in Depression: Biomarker and Pharmacodynamic Findings

Amit Etkin, MD, PhD, discussed Alto Neuroscience's investigational compound ALTO-203, a histamine H3 inverse agonist, and reported findings from a phase 2 biomarker and pharmacodynamic trial in patients with depression.¹

Etkin explained that the H3 receptor is uniquely brain-restricted and tonically active at baseline, meaning that an inverse agonist not only inhibits the receptor but suppresses it to levels below baseline activity. He characterized ALTO-203 as a multimodal tool, noting that H3 receptor blockade modulates multiple downstream neurotransmitter systems simultaneously—including histamine, dopamine, norepinephrine, and acetylcholine—with downstream effects on arousal, wakefulness, mood, and cognition.

The phase 2 trial employed a within-subject crossover design in which each participant received placebo as well as 2 doses of ALTO-203. Etkin noted that the trial was designed broadly, capturing cognitive outcomes, electroencephalography (EEG) measures of cortical excitability, and momentary assessments of well-being and mood. A key finding was replication of results previously observed in a phase 1 healthy volunteer study. ALTO-203 improved performance on an attention task relevant to attention-deficit hyperactivity disorder (ADHD), and improved a specific EEG measure (the theta-beta ratio) that is cleared as a diagnostic test for ADHD.² Notably, participants with the most impaired baseline theta-beta ratio showed the greatest attentional benefit, suggesting that this biomarker may identify patients most likely to respond. The compound also improved alertness and reduced daytime sleepiness, an effect consistent with the mechanism of pitolisant, an approved agent for narcolepsy and excessive daytime sleepiness that shares the same receptor target, though the 2 compounds have not been compared head-to-head.

Etkin emphasized that the ability to replicate pharmacodynamic findings across both patient and healthy volunteer populations strengthened confidence in the drug's mechanism and helped establish dose-selection parameters for future development. He framed the overall program as a precision psychiatry approach in which biomarker-identified subpopulations—particularly those with hypersomnia, cognitive impairment, or an abnormal theta-beta ratio—may represent the most relevant target populations for Alto-203.

Dr Etkin is the founder and chief executive officer of Alto Neuroscience.

References

1. 2026 ASCP annual meeting abstract book. American Society for Clinical Psychopharmacology. 2026. Accessed June 8, 2026. https://ascp.societyconference.com/documents/1005/69f376ed2e16bc0da0124612.pdf

2. Pipeline. Alto Neuroscience. Accessed June 8, 2026. https://altoneuroscience.com/pipeline/