Arrivo focuses on major depressive disorder in women following initial positive results

Arrivo BioVentures has discovered that its SIRT6 activator, SP-624, significantly reduces symptoms of major depressive disorder (MDD) exclusively in women. This finding emerged from a Phase IIa trial (NCT04479852), as reported by CEO Steve Butts. SP-624's efficacy was measured using the Montgomery-Asberg Depression Rating Scale (MADRS) score, revealing substantial symptom reduction in female patients, while no significant effect was observed in males.

Following the promising results of the Phase IIa trial, Arrivo BioVentures, headquartered in Morrisville, North Carolina, initiated further investigations. On October 10, 2024, the company announced the enrollment of the first participant in a Phase I trial (NCT06570369) for the same indication. Concurrently, Arrivo is conducting a Phase IIb trial (NCT06254612) focused on evaluating the drug’s effectiveness specifically in women. The first patient for this trial was dosed in April 2024.

Explaining the gender disparity in response to SP-624, Butts referred to research indicating that gene expression profiles associated with MDD vary between men and women. A 2018 meta-analysis published in Biological Psychiatry examined the gene expression differences in men and women with MDD, revealing that out of 706 and 882 genes differentially expressed in men and women respectively, only 21 genes were commonly altered in the same direction across both sexes.

Butts highlighted the novelty of their approach by stating, "Our drug is the first epigenetic mechanism being tested in depression that can really test that theory." He further emphasized that this is the first instance of using a SIRT6 activator in depression patients.

SP-624, developed by Sirtsei Pharmaceuticals—a subsidiary of Arrivo—targets Sirtuin 6 (SIRT6). This NAD-dependent enzyme impacts gene expression, metabolism, and repair processes linked to MDD. Activation of SIRT6 is believed to alleviate depressive symptoms.

The prevalence of MDD exhibits notable gender differences, with females being twice as likely to suffer from the disorder compared to males, according to a GlobalData analysis. This analysis spanned the eight major markets: the US, France, Germany, Italy, Spain, the UK, Japan, and Canada. The MDD market in these regions is projected to grow to $9.6 billion by 2029.

Despite the higher prevalence of MDD in women and the unique genetic profile associated with it, no treatments are specifically approved for women. The clinical development space oriented towards female patients has faced challenges. However, recent years have seen the approval of drugs like Johnson & Johnson Innovation Medicines’ Spravato (esketamine) and Axsome Therapeutics’ Auvelity (dextromethorphan-bupropion) for MDD. Additionally, Johnson & Johnson reported positive results from a Phase III study of seltorexant, which improved depressive symptoms according to the MADRS scale.

Not all attempts at new treatments have been successful. Sage Therapeutics experienced a significant setback in September 2023 when the US Food and Drug Administration (FDA) rejected their MDD drug, Zurzuvae (zuranolone). Following this, the company had to cut 40% of its workforce. Subsequently, on October 17, 2024, Sage Therapeutics announced another round of layoffs, reducing 55% of its remaining R&D staff to support the ongoing launch of Zurzuvae for postpartum depression (PPD), for which the drug is approved.

SP-624 represents a potentially groundbreaking approach to treating depression in women by targeting the specific genetic mechanisms that differentiate female MDD from its male counterpart.