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. 2025 Oct 16:1-16.
doi: 10.1080/03007995.2025.2574465. Online ahead of print.

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

Joel Raskin  1 , Anita H Clayton  2 , Susan G Kornstein  3 , George I Papakostas  4   5 , Yuki Prescott  1 , Kelly Abernathy  1 , John Hall  1 , Michael Ackermann  1 , William Wargin  1 , Greg Rigdon  1 , Valerie Arnold  6 , Roberta Ball  7 , Elan Cohen  8 , Donald J Garcia Jr  9 , Mark DiBuono  10 , Michael Downing  11 , Otto Dueno  12 , Beal Essink  13 , Corinna Gamez  14 , Haig Goenjian  15 , Michael Greenbaum  16 , Paul Gross  17 , Willis Holloway  18 , John Mark Joyce  19 , George Konis  20 , Jelena Kunovac  21 , Mark Lerman  22 , Elia Acevedo-Diaz  23 , Mustafa Rawaf  24 , Leon Rosenberg  25 , Lara Shirikjian  26 , Rishi Kakar  27 , Felipe Suplicy  28 , Drissana Tran  29 , Nick Vatakis  30 , Judith Joseph  31 , James Knutson  32 , Kurian Abraham  33 , Lawrence Ginsberg  34 , Gregory Mattingly  35 , Eric Chavez  36 , Saundra Maass-Robinson  37 , Andrew Sedillo  38 , Benny Barnhart  39
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Free article

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

Joel Raskin et al. Curr Med Res Opin. .
Free article

Abstract

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.

Keywords: Forvisirvat; Major Depressive Disorder; Sirtuin 6 activator.

Plain language summary

Forvisirvat increases the amount of Sirtuin 6 in people who take it. Sirtuin 6 may impact depression. In healthy people, forvisirvat had no bad side effects. We looked at how well forvisirvat worked and how safe it was for adults with major depressive disorder (MDD).About half the people in this study took forvisirvat and half took placebo (capsules that looked the same but did not contain medicine). The Montgomery Asberg Depression Rating Scale (MADRS) is a way to test how depressed people feel. We used it to test if forvisirvat helped people with MDD. We decided that 4 weeks after starting drug would be the best time to test if forvisirvat was working.About seven of ten people in the study were White. About two-thirds were women. No one had bad side effects. Overall, at 4 weeks the average change in MADRS score was not different between the people who took forvisirvat and those who took placebo. We did a post-hoc analysis (a different way of looking at data from what was originally planned). This is a way to explore new ideas, but not to prove anything. We asked if forvisirvat acted differently in women and men. We found that it did. Women improved more at 4 weeks with forvisirvat than with placebo. Men did not. We saw the same kind of results with other tests of depression included in the study. We are doing another study (NCT06254612) to see whether forvisirvat really does work better in women than in men.

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