Alto Neuroscience, Inc. Completes Phase 2 Enrollment for ALTO-101 in Cognitive Impairment Associated with Schizophrenia

Alto Neuroscience has completed enrollment in its Phase 2 proof-of-concept trial evaluating ALTO-101, a transdermal phosphodiesterase-4 (PDE4) inhibitor, for cognitive impairment associated with schizophrenia (CIAS). Topline data are expected following completion of dosing and analysis and will inform future development decisions.

The study (NCT06502964) enrolled 83 patients across 13 U.S. clinical sites.

Why This Matters: The CIAS Gap?

Cognitive impairment affects nearly all individuals with schizophrenia and is a major determinant of:

• Functional disability
• Employment limitations
• Social impairment
• Independent living challenges

There are currently no approved pharmacologic treatments for CIAS. Any therapy demonstrating clinically meaningful benefit would enter an entirely open regulatory landscape.

Trial Design: Biomarker-Forward Strategy

The Phase 2 study is:

• Randomized
• Double-blind
• Placebo-controlled
• Crossover in design

Participants receive:

• 10 days of ALTO-101 or placebo
• Washout period
• 10 days of alternate intervention

This within-subject comparison enhances statistical sensitivity, particularly for brain-based biomarkers.

Primary Endpoint

• Theta-band inter-trial coherence (ITC), measured via EEG during an auditory oddball task

Theta ITC has been consistently associated with cognitive performance in schizophrenia. The study is powered at 80% to detect a 0.3 Cohen’s d effect size on the primary endpoint.

Biomarker Validation: Replication as a Signal

Baseline analyses demonstrated:

• Significant association between reduced theta ITC and slower processing speed
• Replication of findings from three independent schizophrenia datasets

This strengthens:

• Translational validity of theta ITC
• Rationale for biomarker-driven patient enrichment
• Credibility of Alto’s Precision Psychiatry Platform

Unlike traditional psychiatry trials that rely primarily on symptom scales, Alto is anchoring development to neurophysiological measures.

Mechanistic Differentiation: PDE4 Inhibition + Transdermal Delivery

ALTO-101 is a small molecule PDE4 inhibitor delivered via a proprietary transdermal delivery system (TDS), developed with MEDRx.

Rationale:

• PDE4 inhibition enhances intracellular cAMP signaling
• Potential cognitive enhancement via synaptic plasticity mechanisms

Transdermal delivery aims to:

• Reduce gastrointestinal adverse effects common with oral PDE4 inhibitors
• Provide steady-state CNS exposure
• Improve tolerability and adherence

In Phase 1, ALTO-101 demonstrated:

• Human brain penetration
• CNS pharmacodynamic effects
• Favorable tolerability profile

The program has received Fast Track Designation from the U.S. FDA.

Strategic Positioning: Precision Psychiatry

Alto’s broader strategy centers on biomarker-driven patient selection, leveraging:

• EEG data
• Neurocognitive testing
• Wearable-derived signals
• Predictive analytics

For this study, patient selection was enriched based on magnitude of processing speed deficits, with baseline data confirming reduced theta ITC in enrolled participants.

This precision-enrichment model attempts to avoid a common failure mode in psychiatry trials: heterogeneous populations diluting treatment signal.

Competitive Context

CIAS has historically been a high-failure therapeutic area. Challenges include:

• Weak signal detection
• Poor biomarker translation
• Symptom scale limitations
• High placebo response

Alto’s differentiation lies in:

• Objective electrophysiological endpoints
• Short-duration crossover design
• Targeted patient enrichment

If positive, this could validate EEG biomarkers as viable endpoints in neuropsychiatric drug development.

Key Upcoming Catalyst

Topline Phase 2 data expected near the end of Q1 will determine:

• Whether ALTO-101 meaningfully modulates theta ITC
• Whether EEG improvements translate into cognitive gains
• Whether effect sizes justify Phase 3 investment

A positive signal would position ALTO-101 as:

• Potential first-in-class CIAS therapy
• A proof-of-concept for biomarker-driven psychiatry
• A partnership or licensing candidate

Strategic Takeaway

Enrollment completion for ALTO-101 marks a critical inflection point in:

• CIAS therapeutic development
• Biomarker-based psychiatric drug design
• Transdermal PDE4 modulation strategy

The decisive test now shifts from mechanistic plausibility to reproducible clinical signal. If the data align across EEG and cognitive endpoints, Alto may have opened a new path in an area long considered scientifically elusive.