Alto Neuroscience, Inc. highlighted a publication in Nature Medicine detailing the results of PRIME-PRAXOL, an independent, randomized, double-blind, placebo-controlled trial of pramipexole in patients with mood disorders and clinically significant anhedonia. The study, conducted by investigators at Lund University, demonstrated that pramipexole significantly reduced anhedonia compared to placebo. The findings reinforce the dopaminergic mechanism underlying ALTO-207, Alto Neuroscience's fixed-dose combination therapy currently in a potentially pivotal Phase 2b trial for treatment-resistant depression, with data expected in 2H 2027.

The trial randomized adults with elevated baseline anhedonia symptoms and diagnoses of major depressive disorder, dysthymia, or bipolar depression to flexible-dose pramipexole or placebo for nine weeks, followed by a six-month open-label extension. On the primary endpoint, pramipexole reduced anhedonia significantly more than placebo on the Snaith–Hamilton Pleasure Scale (SHAPS). The study reported a mean difference of −4.04 (95% CI −6.89 to −1.18; p=0.006) with a Hedges' g of 0.62. Significant improvements were also observed on independent measures of anhedonia (DARS; p=0.008) and apathy (AES-S; p<0.001), with improvements maintained through the six-month open-label treatment period.

A post-hoc analysis found that a diagnosis of major depressive disorder (MDD), compared to dysthymia, showed a significant association with greater change in SHAPS at week 9 (p=0.038). In a separate analysis, the MDD subgroup demonstrated a significantly larger effect on SHAPS at week 9 (Hedges' g=0.99) and a significant effect on the Hamilton Depression Rating Scale (HDRS-6) (Hedges' g=0.64).

Adverse events were common in the pramipexole arm, including nausea in roughly 60% of participants, along with sleep disturbance, dizziness, fatigue, and anxiety. These side effects reflect the dose-limiting tolerability that has constrained pramipexole's use. ALTO-207 pairs pramipexole with the antiemetic ondansetron to mitigate these effects and enable faster titration to therapeutic doses.

Key Trial Findings

About ALTO-207

ALTO-207 is a fixed-dose combination of pramipexole, a dopamine D3-preferring D3/D2 agonist, and ondansetron, an antiemetic. The combination is designed to enable rapid titration and higher dosing by mitigating dose-limiting adverse events. In a randomized, placebo-controlled Phase 2a clinical trial evaluating ALTO-207 in 32 patients with depression, the therapy met primary and secondary endpoints, demonstrating significantly greater improvements on the MADRS compared to placebo. Patients reached a mean dose of 4.1mg per day, and the therapy was well tolerated with an adverse event rate similar to placebo.