Phase 2b/3 Trial Evaluates Forvisirvat in Major Depressive Disorder

A large phase 2b/3 clinical trial evaluating the investigational agent Forvisirvat (SP-624) in major depressive disorder (MDD) is nearing completion, according to Joel Raskin, MD, chief medical officer of Arrivo Bioventures. Raskin discussed the program with Psychiatric Times at the 2026 American Society of Clinical Psychopharmacology (ASCP) Annual Meeting in Miami, Florida.

The ongoing study is evaluating Forvisirvat, an oral investigational antidepressant and first-in-class Sirtuin 6 (SIRT6) activator, as monotherapy in approximately 500 patients with MDD.

The study compares 20 mg of once-daily Forvisirvat with placebo over a 4-week treatment period, followed by a 2-week blinded off-drug phase designed to assess persistence of treatment effects, Raskin explained.

“We’re doing that because we saw in our previous study and in animal models that a single dose can actually have long-term effects, probably through the epigenetic mechanism of action,” he said. This strategy allows the investigators to further explore that phenomenon.

Focusing on Female Patients

Raskin explained that the trial’s outcome measures were developed in consultation with the US Food and Drug Administration and leveraged data from a previous phase 2 study in which the primary endpoint was not met overall, but post hoc analyses suggested potential benefit in women. Thus, investigators are curious about the specific efficacy in women specifically and then overall in women and men.

“Our primary outcome measure is the MADRS scale in females,” Raskin said. “And the second objective will be males and females, the entire group.”

He noted that the study was structured as a potential registration-quality trial. “This [strategy] is really to allow us potentially to have a regulatory quality study, a registration trial,” Raskin said.

Previous Trial Insights

According to Raskin, the earlier study demonstrated a separation from placebo over time in female participants receiving Forvisirvat.

“In the first cut post hoc, we found that females had a very dramatic effect, a very statistically significant effect on the Montgomery-Asberg scale at week 3, but was already separating towards week 2,” he told Psychiatric Times.

Raskin added that the observed benefit appeared to persist into the blinded off-drug phase.

“It maintained that effect for the off-drug one-week phase at that time, whereas placebo started returning to baseline like we would expect,” he said.

The investigators also observed statistically significant findings across multiple outcome measures in women.

“What was interesting in that trial was that 5 out of the 6 outcome measures that we looked at were statistically significant in females,” Raskin said.

By contrast, male participants did not appear to show a treatment signal.

“Males had absolutely no effect,” he said. “Drug and placebo right on top of one another.”

Researchers Explore Sex Differences in Depression Biology

The findings prompted investigators to further explore possible biologic explanations for sex-specific antidepressant effects.

“The question became, as we looked at it, was the female effect a true effect?” Raskin said. “And we think so based on that widening separation over time, a low placebo response in the females, and that maintenance of effect on the blinded phase.”

Raskin said the research team subsequently began reviewing literature on biologic sex differences in depression and treatment response. “We know that men and women are different,” he said. “However, in all research, they’re lumped together.”

These limitations start with preclinical models, he added. “When one looks at animal studies, there are always male mice. No one has studied the female mice.”

The investigators looked to the research for male-female differences, and were inspired by work by Marianne Seney, PhD, from the University of Pittsburgh that examined postmortem brain tissue from individuals with depression.

“She took the male and female brains and did RNA seq and found that 1027 genes moved in opposite directions in male and female brains,” Raskin said. “Fifty-two of those were statistically significant.”

According to Raskin, some of the implicated genes involved pathways related to neuroinflammation and mitochondrial function, both areas linked to SIRT6 activity.

Neuroinflammation and Estrogen Effects May Influence Response

Raskin said their current hypothesis centers on inflammatory and hormonal differences in depression between women and men.

“We know that women have more of a chronic inflammation pattern to depression than men,” he said, noting that Forvisirvat has demonstrated gene-silencing effects on the NF-kappa B inflammatory pathway. He also referenced emerging findings related to the estrogen effect they have seen.

“The hypothesis that led to our current trial was that females will have a preferential benefit to Forvisirvat,” Raskin said. “But we have to confirm that, and we have males in the trial as well, and we shall see.”

Dr Raskin is a psychiatrist and the chief medical officer of Arrivo BioVentures LLC.

Reference
1. Raskin J, Forvisirvat (SP-624), a First-In-Human SIRT6 Activator with an Epigenetic Mechanism of Action, Currently in a Phase 2b-3 Study for the Treatment of Major Depressive Disorder. Poster presented at the 2026 American Society of Clinical Psychopharmacology Annual Meeting; May 26-29, 2026; Miami, FL.