A Phase 2, multicenter, double-blind, randomized, placebo-controlled study of the safety and efficacy of forvisirvat (SP-624) in the treatment of adults with major depressive disorder.

Objective: Forvisirvat (SP-624) is an orally-administered epigenetic sirtuin 6 (SIRT6) activator with antidepressant effects in animal models that was well tolerated in three phase 1 trials in healthy adults. This phase 2 clinical study, SP-624-201, was designed to evaluate the safety and efficacy of forvisirvat 20 mg daily for 4 weeks in participants with major depressive disorder.

Methods: SP-624-201 (NCT04479852) was a double-blind, placebo-controlled study. Participants were adults who met DSM-5 criteria for moderate to severe major depressive disorder, as confirmed by the Mini International Neuropsychiatric Interview. Participants receiving psychoactive medications or psychoactive supplements including antidepressants and mood stabilizers, were required to discontinue these medications and wait at least five half-lives of the medications before receiving forvisirvat. Primary endpoint was change from baseline to Week 4 in Montgomery Asberg Depression Rating Scale score. Participants were randomized to forvisirvat 20 mg daily (N = 163) or placebo (N = 156).

Results: Of the 319 patients enrolled in the study, 319 (70.2%) were White and 211 (66.1%) were female. Mean age across subgroups ranged from 41.4 to 44.4 years. No significant difference in the primary endpoint was observed between treatment groups. However, the first post-hoc analysis conducted found that women treated with forvisirvat experienced significant overall improvement whereas men treated with forvisirvat did not. The difference between sexes was consistent for secondary efficacy measures as well. No serious adverse events were reported for forvisirvat-treated participants. The most frequent treatment-emergent event was headache (forvisirvat: 8.1%, placebo: 11.5%). Six of 163 forvisirvat-treated participants and 5 of 156 participants who received placebo discontinued due to adverse events.

Conclusions: The novel epigenetic mechanism of action of forvisirvat, favorable safety profile, and consistent post-hoc efficacy results in women observed in this study support further development of forvisirvat. A phase 2b/3 trial of forvisirvat in major depressive disorder (NCT06254612), to confirm these results, is ongoing.