Alto Neuroscience (ANRO) investor relations material

ALTO-207 clinical development and rationale

• Focus on treatment-resistant depression (TRD) with a hypodopaminergic phenotype, targeting dopamine modulation, especially via D3 receptor agonism using pramipexole.

• Pramipexole shows strong efficacy in TRD, but dose-limiting nausea and vomiting restrict its use; a co-formulation with ondansetron enables higher, faster dosing.

• PAX-D study demonstrated a robust, sustained effect (Cohen's d ~0.9) over 48 weeks in TRD, with significant improvements in depression and anhedonia.

• Combination therapy allows rapid titration to higher doses, improving generalizability and tolerability compared to pramipexole alone.

• Broad IP portfolio covers composition, method of treatment, modified release, titration schedule, and biomarker-identified populations.

Planned studies and regulatory strategy

• Phase IIb trial to start, reading out in H2 2027; phase III planned for early 2027, pending FDA alignment.

• Phase IIb: 1:1 randomization, titration to 3.2 mg pramipexole and 15 mg ondansetron BID, 8-week duration, 178 patients.

• Study powered for 80% at Cohen's d 0.45; phase IIb intended as part of registration package.

• FDA requested 13-week tox study and ondansetron dose-ranging phase I for open-label extension and dose optimization.

Clinical trial execution and risk mitigation

• In-house operations team enables rigorous patient selection, requiring medical and pharmacy records to ensure real-world compliance.

• Sponsor eligibility review and AI tools assess patient data, reducing risk of professional patients and improving trial quality.

• Preference for internal trial management over CROs for greater control and data quality.