Abstract Body (Do not enter title and authors here): Introduction: VS-041 is a novel drug candidate for HFpEF that inhibits key MMPs implicated in cardiac fibroinflammation, and diastolic dysfunction. VS-041 also inhibits formation of endotrophin, a collagen 6α–derived peptide, associated with increased risk of poor outcomes (heart failure hospitalization or death) in HFpEF. We conducted a phase 1 single- and multiple-ascending dose (SAD/MAD) safety, tolerability and pharmacokinetics (PK) study, and measured suppression of MMP9 activity in clinical plasma samples to estimate target engagement by VS-041.
Methods: A randomized, double-blinded, placebo-controlled study enrolled 70 healthy participants. The study was comprised of two parts: both SAD and MAD were conducted with 8 participants (6 active, 2 placebo) per cohort. In the SAD, 5 cohorts received VS-041 orally as immediate release tablets at dosages ranging from 30 mg to 500 mg. In the MAD part, 4 cohorts received 50mg – 400mg once- or twice-daily dosing for 7 days. Safety evaluation included assessment of adverse events (AE), vital signs, ECGs, and clinical laboratory tests. Blood samples were collected for PK analysis. A novel ex-vivo MMP9 activity assay in human plasma was performed using fluorescein-labeled gelatin conjugate as a physiological and specific substrate for MMP9.
Results: VS-041 was well tolerated across the dose range tested. No serious adverse events or dose-limiting toxicities were observed. There were few treatment-emergent AEs, all classified as mild and unrelated to test article administration. There were no ECG changes. VS-041 demonstrated dose-dependent increases in exposure up to 400mg, and steady state was achieved within 2 days with no accumulation. Terminal half-life ranged between 6-9 hrs. Serum levels achieved were within target range of the estimated minimally efficacious dose. In the ex-vivo assay, the gelatinolytic activity of MMP9 in plasma was inhibited by VS-041 in a concentration-dependent manner. The exposure of VS-041 modeled at a dose of 200mg BID is predicted to be continuously above or at the IC₅₀ for MMP9 (~90nM).
Conclusions: VS-041 is safe and well tolerated at doses that effectively inhibit key MMPs implicated in cardiac pathophysiology, offering promising therapeutic potential for patients with HFpEF.