SNF472 selectively inhibits pathological calcification by binding to hydroxyapatite crystals
Palma, Spain and San Diego, USA, 25 June 2020 – Sanifit, a clinical-stage biopharmaceutical company focused on developing treatments for calcification disorders, today announced that data examining the mechanism of action of SNF472, Sanifit’s lead compound in development, has been published in the British Journal of Pharmacology (BJP).
SNF472 is a novel calcification inhibitor for the treatment of cardiovascular calcification (CVC) and the related rare disease calcific uremic arteriolopathy (calciphylaxis) in patients undergoing hemodialysis. SNF472 is currently in a pivotal phase 3 trial for calciphylaxis.
In patients undergoing dialysis, vascular calcification occurs when calcium and phosphate aggregate into hydroxyapatite (HAP) crystals and deposit in arterial walls. HAP crystals block small arteries in skin and soft tissue. SNF472 binds with high affinity to HAP crystals, the final common pathway of CVC, and selectively inhibits their accumulation in arterial walls independently on the etiology of HAP formation.
The studies examined the binding features of SNF472 for HAP crystals across a variety of in vitro and in vivo models. The binding was found to be fast (80% within 5 minutes) and insurmountable. SNF472 inhibited HAP crystal formation with an EC50 of 3.8 µM, with complete inhibition at 30.4 µM. At the lowest concentration tested (1 µM) in vascular smooth muscle cells, SNF472 inhibited calcification by 67%, with complete inhibition from 30 µM. Interestingly, the mean plasma concentration in a phase 2 open-label study with SNF472 in patients with calciphylaxis was 28 µM after 12 weeks of treatment. Improvements in wound healing (primary endpoint), pain and quality of life (secondary endpoints) were observed. Similar concentrations significantly attenuated the progression of coronary artery calcification in a phase 2b double-blind, placebo-controlled phase 2b trial in patients on hemodialysis.
SNF472 showed no deleterious effects on bone mineralization in dogs after 9 months at 25 mg/kg (maximum concentration 384 µM) and the EC50 for in vitro calcium chelation is 539 µM. Full results can be accessed online here.
The data support continued clinical investigation of SNF472 for the treatment of vascular calcification and calciphylaxis in patients undergoing dialysis.
Joan Perelló, Chief Executive Officer of Sanifit, said: “We welcome the BJP’s publication of these data, which provide valuable insight into SNF472’s mechanism of action and its significant potential as an effective inhibitor of HAP crystallization in the cardiovascular system. With no current approved therapy for vascular calcification or calciphylaxis, which are associated with increased mortality and morbidity in patients undergoing dialysis, we look forward to advancing SNF472 in our clinical development for the patients in need.”
Figure 1: Graphical Abstract from paper: Perelló, J, Ferrer, MD, del Mar Pérez, M, et al. Mechanism of action of SNF472, a novel calcification inhibitor to treat vascular calcification and calciphylaxis. Br J Pharmacol. 2020 https://doi.org/10.1111/bph.15163