Alto Neuroscience Announces Completion of Enrollment in Phase 2 Proof-of-Concept Study of ALTO-101 in Cognitive Impairment Associated with Schizophrenia
Alto Neuroscience, Inc. a clinical-stage biopharmaceutical company focused on the development of novel precision medicines for neuropsychiatric disorders, today announced the completion of patient enrollment in its Phase 2 proof-of-concept clinical trial evaluating ALTO-101, a novel, transdermal phosphodiesterase-4 (PDE4) inhibitor, for the treatment of cognitive impairment associated with schizophrenia (CIAS). Topline data from the Phase 2 proof-of-concept study are expected following completion of dosing and data analysis and are anticipated to guide future development decisions for ALTO-101.
Cognitive impairment represents a core, persistent feature of schizophrenia affecting nearly all patients and is a major driver of long-term functional disability, for which there are currently no approved pharmacologic treatments.
Alto met its enrollment goal for the Phase 2 proof-of-concept trial (NCT06502964) with 83 CIAS patients enrolled across 13 clinical sites in the United States. The randomized, double-blind, placebo-controlled crossover study is designed to assess the effects of ALTO-101 on electroencephalography (EEG) measures that have been consistently linked to cognitive dysfunction in schizophrenia. Participants in the study receive 10 days of treatment with ALTO-101 or placebo, followed by a washout period, and then 10 days of treatment with the opposite intervention than was received in the first period. This design enables within-subject comparisons and is intended to enhance sensitivity for detecting treatment-related effects on brain-based EEG measures and cognitive endpoints.
“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,” said Amit Etkin, M.D., Ph.D., founder and chief executive officer of Alto Neuroscience. “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.”
The primary endpoint in the study is theta-band inter-trial coherence (ITC), an EEG measure strongly correlated with cognitive performance, measured during an auditory oddball paradigm. Additional EEG endpoints include resting-state theta power, mismatch negativity, and auditory steady-state response. Cognitive performance will be assessed using select domains of the MATRICS Consensus Cognitive Battery (MCCB) and a computerized measure of processing speed. The study is 80% powered to detect a 0.3 Cohen’s d effect size on the primary outcome measure.
Scientific Rationale and Baseline Findings
Baseline analyses from all screened participants demonstrated a statistically significant association between reduced theta ITC and slower processing speed. These findings replicate prior prospectively analyzed schizophrenia datasets and support the relevance of theta ITC as a translational biomarker for cognitive impairment in CIAS, reinforcing the scientific rationale for the ALTO-101 program.
Alto employed a patient selection strategy based on magnitude of processing speed deficits, and an initial baseline assessment reveals clear enrichment for reduced Theta ITC and cognitive performance in participants enrolled in the trial.
ALTO-101 is administered via a novel, proprietary transdermal delivery system (TDS) developed in collaboration with MEDRx. The TDS formulation is intended to mitigate the gastrointestinal adverse effects commonly associated with oral PDE4 inhibitors, while maintaining central nervous system target engagement.
About ALTO-101
ALTO-101 is a novel small molecule PDE4 inhibitor being developed for cognitive impairment associated with schizophrenia – an indication for which ALTO-101 has been granted Fast Track Designation by the U.S. FDA. Through a proprietary transdermal delivery system, ALTO-101 is designed to provide steady state concentrations to improve drug safety, tolerability, and pharmacokinetics. The proprietary transdermal delivery system for ALTO-101 has been developed in partnership with MEDRx. In Phase 1 clinical trials, ALTO-101 demonstrated human brain penetration, robust CNS-relevant pharmacodynamic effects, and was well tolerated across therapeutically relevant dose ranges.
About Cognitive Impairment Associated with Schizophrenia (CIAS)
Cognitive impairment is a core and disabling feature of schizophrenia, affecting areas such as memory, attention, processing speed, and executive function. These deficits are a primary determinant of poor functional outcomes for patients, impacting their ability to work, maintain social relationships, and live independently. Currently, there are no approved treatments for CIAS, representing a significant unmet medical need for the millions of people living with schizophrenia worldwide.
About Alto Neuroscience
Alto Neuroscience is a clinical-stage biopharmaceutical company with a mission to redefine psychiatry by leveraging neurobiology to develop personalized and highly effective treatment options. Alto’s Precision Psychiatry Platform™ measures brain biomarkers by analyzing EEG activity, neurocognitive assessments, wearable data, and other factors to better identify which patients are more likely to respond to Alto product candidates. Alto’s clinical-stage pipeline includes novel drug candidates in bipolar depression, major depressive disorder, treatment resistant depression (TRD), and schizophrenia, and other mental health conditions.
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