SP647FIRST-TIME-IN-HUMAN PHASE 1 CLINICAL TRIAL IN HEALTHY VOLUNTEERS WITH SNF472, A NOVEL INHIBITOR OF VASCULAR CALCIFICATION

Introduction: SNF472, an intravenous formulation of phytate, is being developed for the prevention of vascular calcification in patients with end-stage renal failure on hemodialysis. It acts by preventing the formation and growth of hydroxyapatite crystals. Extensive non-clinical investigations have shown adequate evidence of efficacy and safety to warrant a first study in humans. Methods: A double-blind, randomized, single ascending dose study was performed in two cohorts of eight healthy male volunteers. Single ascending doses of 0.5, 5, 9 and 12 mg/kg of SNF 472 were administered by a four hour infusion in a leap-frog design. Apart from standard safety parameters and pharmacokinetics, a potential biomarker of calcification that assesses the potential for the formation of hydroxyapatite crystals ex vivo, by artificially increasing the calcium phosphorus product of blood samples from the subjects ex vivo, was used to assess pharmacodynamics. Results: The only adverse event of note was mild dose dependent local venous irritation. This is not anticipated to be an issue in the target population as SNF472 will be administered into the tubing delivering blood to the dialysis column. At a dose of 0.5 mg/kg SNF472 plasma concentrations were below the limit of detection. At the 5, 9 and 12 mg/kg doses, mean maximum plasma concentrations above the anticipated EC50 (5µM) were achieved. With the 12 mg/kg dose concentrations were 10-fold more than the EC50. In terms of the biomarker, the doses of 5, 9 and 12 mg/kg were on a plateau and reduced hydroxyapatite crystal formation by 80%. Conclusions: The findings support continuation of the development program, the next steps being a single dose and multiple dose studies in hemodialysis patients.