Arrivo BioVentures’ SIRT6 activator SP-624 has been found to significantly reduce symptoms of major depressive disorder (MDD), but only in women.
Steve Butts, Arrivo CEO, stated that data from a Phase IIa trial (NCT04479852) showed SP-624 elicited a significant reduction in MDD symptoms, as measured by the Montgomery-Asberg Depression Rating Scale (MADRS) score. However, reduction was only evident among female patients; for males, no statistically significant difference could be found.
Following this trial, the Morrisville, North Carolina-based biotech announced it enrolled its first subject in a Phase I trial (NCT06570369) of the drug for this indication in a 10 October 2024 release. In parallel, Arrivo is running a Phase IIb trial (NCT06254612) specifically focussed on evaluating the drug’s efficacy in female patients as the primary endpoint, which dosed the first patient in April 2024.
To explain the disparity, Butts pointed to research indicating gene expression profiles associated with MDD differ between the sexes. A 2018 meta-analysis published in Biological Psychiatry found that of 706 and 882 genes differentially expressed in men and women with MDD, respectively, only 21 genes in common changed in the same direction—were either up- or downregulated for both sexes.
“Our drug is the first epigenetic mechanism being tested in depression that can really test that theory”, claims Butts, adding, “this is the first time that a SIRT6 activator has ever been used in a patient with depression.”
SP-624 is a small molecule developed by Sirtsei Pharmaceuticals, a subsidiary of Arrivo, which targets Sirtuin 6 (SIRT6). An NAD-dependent enzyme, SIRT6 modulates gene expression, metabolism, and repair associated with MDD, the activation of which is thought to alleviate depression.
Beyond mechanistic differences, MDD also presents at different incidence rates between sexes. As per GlobalData analysis, the prevalence of MDD among females was double that of men in across the eight major markets (the US, France, Germany, Italy, Spain, the UK, Japan and Canada) 2023. The MDD market is expected to become $9.6bn in size in 2029 in those same eight markets, as per a GlobalData report.
GlobalData is the parent company of Pharmaceutical Technology
There are so far no marketed therapies indicated exclusively to treat MDD in women, despite its prevalence and distinct genetic profile, and development in the female-oriented clinical space has met resistance. However, in recent years, drugs like Johnson and & Johnson Innovation Medicines’ (J&J) Spravato (esketamine) and Axsome Therapeutics’ Auvelity (dextromethorphan-bupropion) have been approved to treat MDD. J&J also saw some success in the MDD arena earlier this year when its Phase III study with seltorexant improved depressive symptoms in patients as per the MADRS scale.
However, not all have been successful. Sage Therapeutics axed 40% of its staff in September 2023 following the rejection of their drug Zurzuvae (zuranolone) for MDD by the US Food and Drug Administration (FDA). The drug is approved to treat postpartum depression (PPD). Earlier this month (17 October 2024), the company fired 55% of the remaining R&D staff to support the drug’s ongoing launch for PPD.
