Improvement in wound healing, pain, and quality of life after 12 weeks of SNF472 treatment: a phase 2 open-label study of patients with calciphylaxis.

BACKGROUND: Calciphylaxis in end-stage renal disease is characterized by painful necrotic skin ulcers and high mortality. There are no approved therapies. SNF472, an intravenous formulation of myo-inositol hexaphosphate, inhibits the formation and growth of hydroxyapatite crystals, the final common pathway in the pathogenesis of vascular calcification. METHODS: In this open-label, single-arm study, calciphylaxis patients on thrice-weekly hemodialysis and standard care, received intravenous SNF472 3 times per week for 12 weeks. The primary endpoint was wound healing assessed using the quantitative Bates-Jensen Wound Assessment Tool (BWAT). Pain visual analog scale (VAS), quality of life (wound-QoL), and qualitative wound image review were secondary endpoints. Quantitative changes from baseline were analyzed by paired t-tests using multiple imputation to account for missing observations. RESULTS: Fourteen patients received SNF472. Improvements from baseline to week 12 were observed for mean BWAT score (- 8.1; P < 0.001), pain VAS (- 23.6 mm; P = 0.015) and wound-QoL global score (- 0.90; P = 0.003). Of the 9 patients with ulcerated lesions at baseline who completed treatment, wound image review showed improvement for 7. SNF472 was well tolerated with no serious treatment-related adverse events. The most common adverse events were infections which occur frequently in patients on hemodialysis. None of these were considered as treatment-related. CONCLUSIONS: SNF472 was well-tolerated and improvements from baseline to week 12 in wound healing, pain, and quality of life were observed. A randomized, double-blind, placebo-controlled trial is planned to evaluate SNF472 in patients with calciphylaxis.

A phase 1b randomized, placebo-controlled clinical trial with SNF472 in haemodialysis patients.

AIMS: SNF472 is a calcification inhibitor that is being studied as a novel treatment for calciphylaxis and cardiovascular calcification (CVC). A first study showed acceptable safety and tolerability in a single ascending dose administration in healthy volunteers and a single dose administration in haemodialysis (HD) patients. This study aimed to assess the safety, tolerability, and pharmacokinetics/pharmacodynamics relationship of intravenous SNF472 in HD patients in a multiple ascending dose administration trial with 5 doses tested for 1 week (3 administrations) and 1 dose tested for 4 weeks (12 administrations). METHODS: This double blind, randomized, placebo-controlled Phase 1b study investigated the safety, tolerability, pharmacokinetics and pharmacodynamics of SNF472 after repeated administrations to HD patients for up to 28 days. A pharmacodynamic assessment was performed to evaluate the potential for SNF472 to inhibit hydroxyapatite (HAP) formation. Patients were grouped into 2 cohorts, receiving multiple ascending doses for 1 week (1 to 20 mg/kg, Cohort 1) and 1 dose of 10 mg/kg for 4 weeks (Cohort 2) of intravenous SNF472. RESULTS: Physical status, body weight, cardiorespiratory function, body temperature and laboratory parameters were in the normal range. No clinically relevant effects on heart rate or blood pressure were observed. No abnormal electrocardiogram or QTcB period were reported. The peak plasma concentration (7.6, 16.1, 46.0 and 66.9 µg/mL for 3, 5, 12.5 and 20 mg/kg, respectively) was observed at the end of the 4-hour infusion and thereafter concentrations declined rapidly with half-life between 32 and 65 min. SNF472 at 10 mg/kg inhibited dose dependently HAP crystallization in plasma samples after 28 days of treatment (78% inhibition, P < .001). CONCLUSIONS: SNF472 is safe and well tolerated in HD patients after 2 schemes: multiple ascending doses for 1 week and after repeated dosing of 10 mg/kg for 4 weeks. In both schemes, SNF472 inhibits the induction of HAP crystallization. These results provide support for the use of SNF472 as a novel treatment for CVC in end-stage renal disease.

Characterization of SNF472 pharmacokinetics and efficacy in uremic and non-uremic rats models of cardiovascular calcification.

End-stage renal disease is strongly associated with progressive cardiovascular calcification (CVC) and there is currently no therapy targeted to treat CVC. SNF472 is an experimental formulation under development for treatment of soft tissue calcification. We have investigated the pharmacokinetics of SNF472 administration in rats and its inhibitory effects on CVC. SNF472 was studied in three rat models: (1) prevention of vitamin D3-induced CVC with an intravenous SNF472 bolus of 1 mg/kg SNF472, (2) inhibition of progression of vitamin D3-induced CVC with a subcutaneous SNF472 bolus of 10 or 60 mg/kg SNF472, starting after calcification induction, (3) CVC in adenine-induced uremic rats treated with 50 mg/kg SNF472 via i.v. 4h -infusion. Uremic rats presented lower plasma levels of SNF472 than control animals after i.v. infusion. CVC in non-uremic rats was inhibited by 60-70% after treatment with SNF472 and progression of cardiac calcification completely blocked. Development of CVC in uremic rats was inhibited by up to 80% following i.v. infusion of SNF472. SNF472 inhibits the development and progression of CVC in uremic and non-uremic rats in the same range of SNF472 plasma levels but using in each case the required dose to obtain those levels. These results collectively support the development of SNF472 as a novel therapeutic option for treatment of CVC in humans.