Alto Neuroscience has started a Phase 2b trial of ALTO-207 in treatment-resistant depression, with topline data expected in the second half of 2027.

The US biotech said the randomised, placebo-controlled study will enrol around 178 adults with treatment-resistant depression (TRD) across sites in the United States and United Kingdom. Participants must have experienced two to five prior treatment failures during their current depressive episode and remain on a stable background antidepressant.

Patients will be randomised 1:1 to receive ALTO-207 or placebo during an eight-week treatment period. The primary endpoint is change from baseline in the Montgomery-Åsberg Depression Rating Scale (MADRS), a commonly used measure in depression studies.

TRD remains one of the largest unmet needs in psychiatry, affecting patients who do not respond adequately to standard antidepressant medicines. Industry estimates suggest millions of adults in the United States may meet the criteria for treatment resistance, creating continued demand for faster-acting and more effective therapies.

ALTO-207 is a fixed-dose combination of pramipexole and ondansetron. Pramipexole is approved for Parkinson’s disease and has previously shown antidepressant activity in clinical research. Ondansetron is an anti-nausea medicine included in the combination to improve tolerability and help patients reach higher doses of pramipexole.

Alto said the Phase 2b design was informed by the PAX-D study, published in The Lancet Psychiatry in 2025, which evaluated pramipexole augmentation in treatment-resistant depression. Several National Health Service sites involved in that earlier study are expected to participate in the new trial.

Amit Etkin, founder and chief executive officer of Alto Neuroscience, said: “We are excited to be initiating this Phase 2b trial, which builds on one of the strongest efficacy signals observed in treatment-resistant depression.”

The company previously reported Phase 2a data in 32 patients with depression. Alto said ALTO-207 met primary and secondary endpoints in that earlier study, with significantly greater improvements on MADRS compared with placebo.

Biotech groups continue to invest in depression drug development despite a difficult history for central nervous system research, with renewed focus on treatment-resistant populations where commercial need remains high. Existing options for TRD include add-on antipsychotics, ketamine-based treatments and neuromodulation approaches, but many patients still fail to achieve durable symptom control.

For Alto, the Phase 2b trial represents an important clinical milestone as it looks to advance precision psychiatry programmes across its pipeline. Positive data could strengthen the case for later-stage development in a market where new mechanisms remain in demand.

Topline results are expected in the second half of 2027.