Alto Neuroscience announces ALTO-101 did not achieve statistical significance

Alto Neuroscience (ANRO) announced topline data from its Phase 2 proof-of-concept clinical trial evaluating ALTO-101 for the treatment of cognitive impairment associated with schizophrenia, and provided an update on the company’s pipeline and prioritization. ALTO-101 did not achieve statistical significance on primary electroencephalography or cognitive endpoints versus placebo; however, the study demonstrated directional improvements across certain EEG measures, including a near-significant effect on theta-ITC – a measure correlated with cognitive performance across datasets. In a pre-specified analysis in a more cognitively impaired subgroup, ALTO-101 exhibited nominally significant effects on theta-ITC compared to placebo. Further, certain EEG measures, including theta-ITC, showed improvements from day 5 to day 10 in the trial, suggesting a longer treatment period may elucidate greater effects. ALTO-101 demonstrated a favorable tolerability profile, with rates of nausea and vomiting – hallmark side effects associated with the PDE4 inhibitor class – in line with placebo rates. This finding suggests the pharmacokinetic profile of ALTO-101 may overcome a key tolerability barrier that has historically limited PDE4 inhibitor adoption. High rates of application site skin reactions were observed across both active and placebo arms. Separately, the company has developed a modified-release oral formulation of ALTO-101 that has demonstrated an improved pharmacokinetic and tolerability profile relative to the immediate-release formulation. Alto believes this formulation may offer potential benefits across multiple therapeutic areas and intends to explore partnering opportunities. The formulation is covered by a pending patent application. Based on these results, the company does not plan to independently advance ALTO-101 in CIAS and will instead prioritize resources toward its lead program, ALTO-207, while exploring strategic partnering opportunities for ALTO-101. The company expects to present more data from this study at a future medical conference. Alto’s most advanced and differentiated program, ALTO-207, remains on track to initiate a Phase 2b clinical trial in the first half of 2026. ALTO-207 is a fixed-dose combination of pramipexole (a dopamine D3/D2 agonist) and ondansetron, designed to enable rapid titration to higher pramipexole doses by mitigating dose-limiting nausea and vomiting. The planned Phase 2b trial is a randomized, double-blind, placebo-controlled study evaluating ALTO-207 as an adjunctive treatment in approximately 178 adults with treatment-resistant depression who have experienced two to five prior treatment failures. The core mechanism of ALTO-207 is supported by the PAX-D study, published in The Lancet Psychiatry and conducted by the University of Oxford, which demonstrated a Cohen’s d=0.87 effect size for pramipexole versus placebo at 12 weeks – substantially larger than the effect sizes observed for current approved treatment resistant depression treatments. The Phase 2a trial of ALTO-207 met primary and secondary endpoints. Following a successful FDA meeting in 2025, Alto is positioned to advance ALTO-207 through Phase 3 and a potential NDA submission.