Alto Neuroscience, Inc. announced positive results from its healthy volunteer Phase 1 study of ALTO-101, a novel PDE4 inhibitor in development for cognitive impairment associated with schizophrenia (CIAS). Results from the study demonstrated favorable tolerability and improved pharmacokinetics of ALTO-101 when administered via a transdermal delivery system (TDS) compared to oral administration. The TDS formulation is being developed in partnership with MEDRx.

The drug exposure levels achieved with the transdermal formulation were significantly greater than systemic exposure with oral administration while also reducing typical class-wide adverse events. The Company plans to initiate a proof-of-concept study evaluating ALTO-101 in patients with CIAS in the first half of 2024, with topline data expected in the second half of 2025. The company have now demonstrated transdermal administration of ALTO-101 results in significantly greater, stable drug concentration with a once-daily formulation that is well-tolerated.

The company believe the reduction in typical class-wide adverse events observed with ALTO-101 provides a significant point of differentiation compared to other PDE4 inhibitors currently available, or in development. The company look forward to advancing this product candidate for patients with CIAS who currently have few treatment options. The study was designed to evaluate the safety, tolerability, pharmacokinetics, and adhesion properties of a proprietary transdermal formulation of ALTO-101 compared to oral administration of ALTO-101 in healthy human volunteers.

It included a 2-way crossover design consisting of two dosing periods. 15teen adults between 40-64 years old were enrolled in the study. In period 1, participants received a single oral dose of 1 mg ALTO-101, following a 7-day washout period; in period 2, participants received continual transdermal dosing of 18 mg ALTO-101 for two days - patches were administered once-daily and worn for 24 hours.

Dizziness - 40% oral vs. 7.1% TDS; Nausea - 20% oral vs. 0% TDS; All adverse events reported in the study were mild in severity, and there were no reported serious adverse events.

No participants discontinued the study due to adverse events. The transdermal formulation demonstrated favorable adhesion properties and there were no application site reactions that led to patch removal or intolerance. Overall, the results from this Phase 1 study indicate a favorable profile for ALTO-101 with higher levels of drug exposure, expected to be within the necessary therapeutic range, and lower rates of adverse events.

The pharmacodynamic effects observed with orally administered ALTO-101, which were previously reported by the Company, inform the relevant therapeutic range believed to be required to achieve the desired pro-cognitive and clinical effects. Under the terms of the development agreement between Alto and MEDRx, upon this achievement of the desired pharmacokinetic profile for ALTO-101, MEDRx is eligible to receive a milestone payment of $1.5 million from Alto that is payable in a combination of cash and common stock of Alto Neuroscience. ALTO-101 is a novel small molecule PDE4 inhibitor being developed for cognitive impairment associated with schizophrenia, a disease state defined by negative and cognitive symptoms with no currently available targeted treatments.

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.