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

Abstract

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.

Keywords: SNF472; cardiovascular calcification; haemodialysis; hydroxyapatite; myo-inositol hexaphosphate; renal disease.

Figure 1

Flowchart of distribution of patients in Cohort 1 A, and Cohort 2 B

Figure 2

Pharmacokinetic profile of intravenous SNF472 in haemodialysis patients in a multiple ascending dose. A, Plasma SNF472 levels at Day 1. B, SNF472 plasma C_max at Day 1 and Day 5. Results represent mean ± standard deviation

Figure 3

Intravenous administration of SNF472 inhibits hydroxyapatite crystallization in dialysis patient plasma ex vivo. A, Dose/pharmacodynamics relationship. Four parameter log dose (mg/kg) response modelling of the inhibition of induction of hydroxyapatite crystallization in plasma samples from dialysis patients administered increasing doses of SNF472 or placebo over 5 days. Solid line represents the dose–response curve calculated from the individual data points. Dashed lines represent the 90% confidence interval. B, Pharmacokinetics/pharmacodynamics relationship.

Figure 4

Inhibition of hydroxyapatite (HAP) crystallization following repeated dosing of 10 mg/kg SNF472 through the entire study period. A, Time‐course of crystallization inhibition in active patients over the 4‐week period. Solid line connects the means of every day. B, Global inhibition of crystallization throughout the study period. Results represent the mean ± standard deviation. Data were analysed by a Student t test. (*) indicates significant differences vs placebo, p ≤ .001