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), an orally-administered epigenetic sirtuin 6 (SIRT6) activator with antidepressant effects in animal models, was well tolerated in three phase 1 trials. This phase 2 study, SP-624-201, evaluated the safety and efficacy of forvisirvat 20 mg daily for 4 weeks in participants with major depressive disorder (MDD).

METHODS

SP-624-201 (NCT04479852) was a double-blind, placebo-controlled study. Participants were adults who met DSM-5 criteria for moderate to severe MDD and who discontinued psychoactive medications or supplements including antidepressants and mood stabilizers. 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 317 treated patients, 224 (70.7%) were White and 211 (66.6%) were female. No significant difference in the primary endpoint was observed between treatment groups. However, post-hoc analysis found that women treated with forvisirvat experienced significant overall improvement whereas men did not. The difference between sexes was also consistent for secondary efficacy measures. 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 161 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 MDD (NCT06254612), to confirm these results, is ongoing.