Data Readout

Alto's ALTO-100 bipolar depression trial tests a fix for its 2024 MDD miss

The Phase 2b readout, expected in H2 2026, is designed only as an adjunctive therapy after a compliance gap undercut the drug's prior depression trial.

By AppliedXLJuly 13, 2026Trial NCT06656416

Executive Summary

Alto Neuroscience is running its second Phase 2b test of ALTO-100, this time restricted to patients already on background therapy, after its first attempt in major depressive disorder missed its primary endpoint.
The redesign follows a specific finding from the prior trial: patients who took the drug without other treatment complied far less than those taking it alongside a background antidepressant, and the adjunctive subgroup showed the larger effect.
The sponsor's guidance for a second-half 2026 readout has stayed consistent across multiple disclosures, and the underlying trial protocol has changed only marginally since it opened.
No trial in this cognitive-biomarker-defined bipolar depression population shares ALTO-100's mechanism, so the readout has no direct precedent to benchmark against and stands as its own test.

The trial

NCT06656416 is a randomized, double-blind, placebo-controlled Phase 2b study testing ALTO-100 against placebo in adults with bipolar depression who are already on a mood stabilizer or an approved atypical antipsychotic. The primary endpoint measures the change from Day 1 to Week 6 on the Montgomery-Asberg Depression Rating Scale (MADRS) in a pre-defined subgroup of participants characterized by a cognitive biomarker. The company expects to enroll approximately 200 patients, with topline data expected in the second half of 2026. NCT06656416+1

Probability of Success

Endpoint Met65%

Completes88%

Clinical Significance5%

Regulatory54%

What preceded it

In October 2024, Alto reported that ALTO-100 did not demonstrate a statistically significant improvement over placebo on depressive symptoms in the biomarker-positive population (n=196) of its Phase 2b major depressive disorder trial. In a pre-specified analysis of biomarker-positive patients taking ALTO-100 adjunctively to a stable background antidepressant (n=61), the drug showed a Cohen's d of 0.47 against placebo at week 6, with a p-value of 0.09, in an analysis not powered for statistical significance. The company also found that patients on ALTO-100 alone complied with dosing 56% of the time, versus 100% among patients taking it adjunctively. Alto cited both the adjunctive signal and the compliance gap in its decision to continue developing ALTO-100 in bipolar depression as an adjunctive treatment only. Alto

Timing and protocol stability

The bipolar depression trial's primary completion date has moved once, from August 14, 2026 to August 1, 2026, a 13-day registry correction logged in July 2025. Sponsor guidance for the readout window has held at the second half of 2026 across four separate disclosures dated March 2025, May 2025, August 2025, and March 2026. The enrollment target has remained at 200 patients throughout, with no change in size or direction. NCT06656416+1

The competitive frame

No trial identified in this indication shares ALTO-100's target or mechanism class, and the nearest comparators, including esketamine, vortioxetine, and several NMDA-modulating candidates in Phase 2 and Phase 3 major depressive disorder programs, work through different mechanisms in an overlapping but distinct population. Within bipolar depression specifically, only two other industry-sponsored Phase 3 programs are active, evaluating endoxifen and cariprazine on different mechanistic hypotheses. ALTO-100's bipolar depression readout has no validated same-mechanism precedent to benchmark against, given the underpowered result in its own prior adjunctive subgroup is the closest available data point. Alto

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