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

Sirtsei Pharmaceuticals is developing forvisirvat, a first-in-human SIRT6 activator with an epigenetic mechanism of action (MoA), for the treatment of MDD. SIRT6 is a NAD+ dependent enzyme. SIRT6-deficient mice have a shortened lifespan and phenotypes associated with age-related impairments, cancer, and metabolic disorders. SIRT6 overexpression in mice protects against metabolic pathologies and increases lifespan. SIRT6 has an epigenetic MoA that includes reduced inflammation, enhanced mitochondrial health, metabolic homeostasis and DNA repair. Each of these may play a role in neurodegeneration, metabolic disorders, and psychiatric disorders such as MDD. Both in vitro and animal studies support forvisirvat’s role in MDD. It activates SIRT6 deacetylation of histones preventing transcription of DNA. Forvisirvat reduces lipopolysaccharide (LPS)-induced inflammatory cytokines, silences gene pathways responsible for neuroinflammation including the NFκB pathway. It enhances neuroplasticity as evidenced by long-term potentiation assay in vitro and in vivo and prevents cognitive deficits induced by scopolamine (anticholinergic) or phencyclidine (NMDA antagonist) in the novel object recognition test. Forvisirvat works in multiple depression models including LPS-and ACTH-treated mice, olfactory bulbectomized rats and in a model of treatment-resistant depression (forced swim test in Wystar-Kyoto rats). Four phase 1 trials of single oral doses up to 80mg, and 20 and 40mg for 10 days demonstrated forvisirvat was well tolerated and reached target plasma concentrations in healthy adults, supporting progression of 20 mg daily into a Phase 2 study. A Phase 2 study evaluated the safety and efficacy of forvisirvat 20 mg daily vs placebo for 4 weeks in participants with MDD. No significant difference in the primary endpoint was observed between treatment groups. However, post-hoc analyses found that women treated with forvisirvat experienced consistent significant overall improvement on the primary and secondary efficacy measures whereas men showed no effect on any scale. Safety was comparable to placebo. A Phase 1 quantitative EEG study using brain network analytics (BNA) is ongoing. The first cohort in healthy adults is complete and showed that 20 mg once daily was centrally active and changed BNA profiles relative to placebo after 1 day and 2 weeks of daily treatment. Observed post-dose increases across high-frequency bands support improved cognition, while reduction in delta power support potential antidepressant effects. Evoked response potentials showed improved decision-making speed and context updating and reversing functions, often impaired in MDD. Enrollment of a second cohort of adults with MDD is underway. A phase 2b-3 study is nearing completion. This study is nearly identical in design to the previous Phase 2 study but with a larger n and includes a cognitive test. It seeks to confirm the results from the prior study, with the primary efficacy endpoint in agreement with the FDA pre-specified in females only. Efficacy and tolerability remain challenges to successful MDD treatment. Forvisirvat, a novel SIRT6 activator with effects in preclinical models of depression and cognition, is associated with several mechanisms implicated in MDD. A Phase 2 study suggested efficacy in females, a Phase 2b-3 study is ongoing in an attempt to confirm these findings.