Alto Neuroscience has completed patient enrollment in its Phase 2 proof-of-concept trial evaluating ALTO-101 for cognitive impairment associated with schizophrenia (CIAS), with topline data expected around the end of the first quarter.

The randomized, double-blind, placebo-controlled crossover study (NCT06502964) enrolled 83 patients across 13 clinical sites in the United States. The trial is designed to evaluate the effects of ALTO-101, a transdermal phosphodiesterase-4 (PDE4) inhibitor, on electroencephalography (EEG) biomarkers linked to cognitive dysfunction in schizophrenia.

Cognitive impairment affects the majority of people living with schizophrenia and remains a major contributor to long-term disability. There are currently no approved pharmacological treatments specifically for CIAS.

Participants in the study receive 10 days of treatment with ALTO-101 or placebo, followed by a washout period and crossover to the alternate treatment. The design enables within-subject comparisons and aims to increase sensitivity in detecting treatment-related changes in EEG measures and cognitive performance.

The primary endpoint is theta-band inter-trial coherence (ITC), an EEG measure associated with cognitive performance, assessed during an auditory oddball task. Secondary EEG endpoints include resting-state theta power, mismatch negativity and auditory steady-state response. Cognitive outcomes are measured using select domains of the MATRICS Consensus Cognitive Battery and a computerized assessment of processing speed. The study is powered at 80% to detect a 0.3 Cohen’s d effect size on the primary endpoint.

Amit Etkin, founder and CEO of Alto Neuroscience, said: “This milestone brings us closer to potentially delivering a first-of-its-kind treatment for the millions of patients suffering from the debilitating cognitive effects of schizophrenia. Our baseline results have already replicated findings from three independent datasets, reinforcing our confidence in ALTO-101’s mechanism and our biomarker-driven approach. We look forward to reporting data from this study around the end of the first quarter.”

Baseline analyses from screened participants showed a statistically significant association between reduced theta ITC and slower processing speed, replicating findings from previously analysed schizophrenia datasets. The company said this supports the use of theta ITC as a translational biomarker in CIAS and underpins its patient selection strategy based on processing speed deficits.

ALTO-101 is administered using a proprietary transdermal delivery system developed in collaboration with MEDRx. The formulation is intended to reduce gastrointestinal adverse effects associated with oral PDE4 inhibitors while maintaining central nervous system target engagement.

ALTO-101 has received Fast Track designation from the FDA for CIAS. In Phase 1 trials, the compound demonstrated brain penetration, pharmacodynamic activity consistent with central nervous system engagement, and tolerability across evaluated dose ranges.

Topline data from the Phase 2 study are expected to inform future development decisions for the programme.