Alto Neuroscience, Inc. (“Alto”) (NYSE: ANRO) today highlighted the publication in Nature Medicine of PRIME-PRAXOL, an independent, randomized, double-blind, placebo-controlled trial of the dopamine agonist pramipexole in patients with mood disorders and clinically significant anhedonia. The study was conducted and independently funded by investigators at Lund University, Sweden.
Adults with elevated baseline anhedonia symptoms with a diagnosis of major depressive disorder, dysthymia (chronic low mood, but not meeting MDD diagnostic criteria), or bipolar depression were randomized to flexible-dose pramipexole or placebo, added to ongoing treatment, for nine weeks, followed by a six-month open-label extension period. On the primary endpoint, pramipexole reduced anhedonia significantly more than placebo on the Snaith–Hamilton Pleasure Scale (mean difference −4.04; 95% CI −6.89 to −1.18; p=0.006; Hedges’ g=0.62 – Hedges’ g is a standardized measure of treatment effect similar to Cohen’s D), with significant improvements on independent measures of anhedonia (DARS; p=0.008) and apathy (AES-S; p<0.001) with improvements maintained through a six-month open-label treatment period.
Importantly, the publication also included a post-hoc analysis which found that a diagnosis of MDD, compared to the milder affective condition of dysthymia, showed a significant association with a greater change in SHAPS at week 9 in a regression analysis (p=0.038). In an analysis not published in the Nature Medicine piece, 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).
“Anhedonia is among the most disabling yet poorly addressed dimensions of depression, and it is the domain dopaminergic mechanisms are perhaps best positioned to address,” said Amit Etkin, M.D., Ph.D., founder and chief executive officer of Alto Neuroscience. “These Nature Medicine results add independent, peer-reviewed high-profile evidence — alongside PAX-D in The Lancet Psychiatry — for the effects of pramipexole, the active dopaminergic component of ALTO-207. Notably, the high nausea rate in this trial illustrates the precise tolerability limitation ALTO-207 is engineered to overcome — aiming to unlock this promising mechanism for a broader patient population. We are very encouraged by the results from this trial, further strengthening the scientific foundation for ALTO-207 as we advance our potentially pivotal Phase 2b trial in treatment-resistant depression.”
Consistent with prior studies, adverse events were common in the pramipexole arm despite a slow titration schedule — including nausea in roughly 60% of participants, along with sleep disturbance, dizziness, fatigue, and anxiety — reflecting the dose-limiting tolerability that has long constrained pramipexole’s use. ALTO-207 pairs pramipexole with the antiemetic ondansetron specifically aimed at mitigating these effects and enabling faster titration to therapeutic doses.
“Conventional antidepressants have little effect on the brain’s reward systems, leaving depressed patients with anhedonia having marked symptoms. With this study, the Lund group adds to the other recent work demonstrating that pramipexole greatly reduces this anhedonic burden,” said Alan Schatzberg, MD, Kenneth T. Norris Professor of Psychiatry and Behavioral Sciences at Stanford University School of Medicine. “What stands out in this study is the consistency of the findings — pramipexole improved both the consummatory and motivational dimensions of anhedonia, on multiple independent scales, and with good durability. Matching a dopaminergic treatment to patients defined by anhedonia, and potentially related reward-circuit dysfunction, is the kind of mechanism-led approach the field needs.”
The published findings across the PRIME-PRAXOL study are consistent with the broader evidence supporting ALTO-207, including PAX-D (Cohen’s d=0.87 versus placebo at 12 weeks in treatment-resistant depression) and a meta-analysis of pramipexole in depression (Hedges’ g=0.64).
About ALTO-207
ALTO-207 is a fixed-dose combination of pramipexole, a dopamine D3-preferring D3/D2 agonist, approved for the treatment of Parkinson’s disease with demonstrated antidepressant effect, and ondansetron, an antiemetic, selective 5-HT3 receptor antagonist. As a fixed-dose combination, ALTO-207 is designed to enable rapid titration and higher dosing by mitigating the dose-limiting adverse events typically experienced with pramipexole. ALTO-207 is being developed to address the significant unmet need for patients with treatment resistant depression.
In a randomized, placebo-controlled Phase 2a clinical trial evaluating ALTO-207 in 32 patients with depression ALTO-207 met primary and secondary endpoints demonstrating significantly greater improvements on MADRS compared to placebo. Patients randomized to receive ALTO-207 reached a mean dose of 4.1mg per day. ALTO-207 was well tolerated in the maintenance period of the study with an adverse event rate similar to placebo.
About Alto Neuroscience
Alto Neuroscience is a clinical-stage biopharmaceutical company with a mission to redefine psychiatry by leveraging neurobiology to develop personalized and highly effective treatment options. Alto’s Precision Psychiatry Platform™ measures brain biomarkers by analyzing EEG activity, neurocognitive assessments, wearable data, and other factors to better identify which patients are more likely to respond to Alto product candidates. Alto’s clinical-stage pipeline includes novel drug candidates in bipolar depression, major depressive disorder, treatment resistant depression, schizophrenia, and other mental health conditions. For more information, visit www.altoneuroscience.com or follow Alto on X.
Forward-Looking Statements
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