Alto Neuroscience Inc. (ANRO) presented updated data on its lead depression program and pipeline outlook at the TD Cowen 6th Annual Novel Mechanisms in Neuropsychiatry Summit on Wednesday, emphasizing a fast-titration dosing approach designed to overcome tolerance issues seen in prior pramipexole trials.
Shares of Alto Neuroscience fell to $26.94, down 12.48% from the previous close of $30.78, during the session. The stock has traded between $3.77 and $37.48 over the past 52 weeks. The company reported a balance sheet current ratio of 14.85 and holds more cash than debt, according to figures presented at the event.
CEO and Founder Amit Etkin, who originated the pramipexole combination concept during his time at Stanford, outlined the Phase IIb study for ALTO-207 — a fixed-dose combination of pramipexole, a D3-preferring dopamine agonist, and ondansetron, a nausea-mitigating agent. The program is being developed for both adjunctive and monotherapy use in treatment-resistant depression and major depressive disorder.
Etkin cited real-world prescribing data from the NIH All of Us dataset showing that approximately 75% of clinicians titrate pramipexole at least one-and-a-half times slower than FDA-approved labeling, with the average time to reach a 1-milligram dose exceeding 18 months. The slower titration likely contributed to tolerability failures in earlier studies, including a Chase Therapeutics Phase II trial that used 4.1 milligrams of pramipexole and reported an eight-point delta on the Montgomery-Asberg Depression Rating Scale with a Cohen's d of 1.1.
To address the issue, the ALTO-207 Phase IIb trial employs a two-week titration period using a custom dosing pack taken twice daily — a schedule roughly five times faster than the standard labeling. The 178-patient, randomized 1:1 study will enroll patients with adjacent treatment-resistant depression who have experienced two to five prior treatment failures and remain on stable antidepressants. The target maintenance dose is 3.2 milligrams of pramipexole and 15 milligrams of ondansetron daily over an eight-week total treatment period.
The trial is powered at a Cohen's d of 0.45 with 80% statistical power, with significance beginning at approximately 0.3 Cohen's d at 50% power. Etkin set a target adverse-event discontinuation rate of 9%, benchmarked against Caplyta, and assumed an overall dropout rate of 15%. Impulse-control disorder risk was estimated at roughly 0.1% based on Swedish registry data. Additional monitoring includes EKG checks for QTc prolongation from ondansetron, constipation and somnolence tracking, and urine antidepressant verification, which showed near 100% compliance in prior studies.
Phase IIb top-line results are expected in the second half of 2025, with an FDA meeting planned for the fourth quarter to review blinded tolerability data and align on Phase III design. Phase III enrollment is targeted to begin in early 2027.
Alto also discussed ALTO-300, an agomelatine program tested as a 25-milligram adjunctive treatment for major depressive disorder with data expected in the first half of 2025. A third program, ALTO-100, a pro-neuroplasticity treatment aimed at increasing BDNF signaling for bipolar depression, is expected to report top-line data in mid-2027. TD Cowen analysts Ritu Baral and Athena Chin covered the presentation.
