お知らせ • Apr 23
Alto Neuroscience Initiates Phase 2b Trial Of ALTO-207 In Treatment-Resistant Depression
Alto Neuroscience, Inc. initiated a Phase 2b randomized, placebo-controlled trial of ALTO-207 in treatment-resistant depression (TRD), a program designed to replicate the strongly positive PAX-D study results and support a streamlined path to registration. TRD is estimated to affect up to 7 million adults in the United States, representing patients who do not respond adequately to current antidepressant therapies. The Phase 2b trial design is informed by the PAX-D study, a randomized, placebo-controlled trial published in The Lancet Psychiatry (July 2025), which demonstrated a Cohen’s d effect size of 0.87 for pramipexole augmentation in TRD — substantially exceeding the effect sizes observed with currently approved therapies. ALTO-207, a fixed-dose combination of pramipexole and ondansetron, with a novel, modified-release formulation, is designed to mitigate pramipexole-associated nausea, thus enabling improved tolerability, more rapid titration, and higher dosing. The combination is further supported by results from a prior Phase 2a trial of ALTO-207, which demonstrated statistically significant improvement on MADRS (Cohen’s d = 1.1) with a favorable tolerability profile at a higher mean dose of pramipexole. The Phase 2b trial will enroll approximately 178 adults with treatment-resistant depression who have experienced two to five prior treatment failures during their current episode of depression and remain on a stable background antidepressant. Participants will be randomized 1:1 to receive ALTO-207 or placebo over an eight-week treatment period. ALTO-207 will be titrated up to a target dose of 3.2 mg pramipexole and 15 mg ondansetron per day. The trial will be conducted at sites in the United States and United Kingdom, including National Health Service (NHS) sites that participated in the PAX-D study. The primary endpoint is change from baseline in MADRS, consistent with FDA guidance for depression trials. Topline data are expected in the second half of 2027. 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. Treatment-resistant depression (TRD) is a serious form of major depressive disorder (MDD), typically defined as inadequate response to at least two prior antidepressant treatments of adequate dose and duration. Despite the availability of multiple therapies, approximately one-third of patients with MDD do not achieve sufficient symptom relief with standard treatments. MDD affects approximately 21 million adults in the United States each year, suggesting that an estimated 6–7 million individuals may suffer from TRD. Patients with TRD often experience persistent, recurrent symptoms, increased risk of hospitalization and suicide, and significant impairment in daily functioning. TRD represents a substantial unmet medical need and a disproportionate share of the overall economic burden of depression, driven by higher healthcare utilization, reduced productivity, and long-term disability. Current treatment approaches are frequently characterized by a trial-and-error process, delayed onset of action, substantial side effect burden, and limited rates of sustained response.