ALTO-207, A FIXED-DOSE COMBINATION OF PRAMIPEXOLE AND ONDANSETRON, SUGGESTS EFFICACY IN TREATING MAJOR DEPRESSION: FINDINGS FROM A RANDOMIZED, DOUBLE-BLIND PHASE 2A TRIAL

Background

Major Depressive Disorder (MDD) is a common, debilitating psychiatric disorder that is a leading cause of global burden. Despite evidence that efficacious treatments exist, the majority of individuals with MDD have an inadequate response to current standard-of-care treatments. Furthermore, approximately 30% fail to respond to multiple antidepressant treatments and are considered to have treatment-resistant depression (TRD). Pramipexole, a dopamine D3-preferring D3/D2 agonist, has demonstrated medium to large treatment effects in MDD and in TRD across multiple studies, yet requires slow titration due to dose-limiting nausea and vomiting. These side effects often lead to discontinuation of treatment or subtherapeutic doses. CTC-501 (now known as ALTO-207) is a fixed-dose combination of pramipexole and ondansetron, a 5-HT3 antagonist anti-emetic. In a Phase 1 study, ALTO-207 increased maximum tolerated doses and plasma concentrations by at least 2.5-fold using a ~5× faster titration than the pramipexole titration in the approved label, with 60% tolerating the study maximum dose of 6mg. It is unknown, however, whether this combination of compounds would be efficacious in treating depressive symptoms.

Methods

A Phase 2a proof-of-concept randomized trial was conducted in 32 adults with MDD (1:1 randomization) over 8 weeks to assess the safety and efficacy of the combination. Analyses used mixed models for repeated measures (MMRM) on score change from baseline.

Results

Baseline MADRS was 28.5 (SD 5.2). Compared with placebo, CTC-501 resulted in large improvements in MADRS scores (week 8 d=1.10, p=0.025). CGI-S showed a similar pattern (week 8 d=1.00, p=0.04). Effect sizes were ≥0.58 beginning at week 2. CTC-501 reached a mean of 4.1 mg/day of pramipexole within 8 days, which was subsequently well tolerated throughout maintenance with no discontinuation due to adverse events. After an initial titration schedule modification, 77% of CTC-501 subjects reached the study maximum of 5 mg/d pramipexole. Comparison of antidepressant effect sizes across randomized trials of pramipexole and CTC-501 further suggest a dose-response relationship with this Phase 2a study achieving the highest pramipexole dose to date.

Conclusions

CTC-501 (now ALTO-207) is a novel fixed-dose combination of pramipexole and ondansetron that allows for rapid titration to achieve doses of pramipexole that are generally not achieved in practice but are associated with greater efficacy. This combination demonstrated large effect sizes in reducing both depression severity as well as global illness severity, beginning as early as week 2 of treatment.