The term cardiovascular disease covers a broad array of health problems. Everyone tends to think of heart attacks or hypertension when it is brought up. However, there are less publicized diseases that also fall under the cardiovascular disease moniker.
Cardiovascular calcification (CVC) is a disease whose name sort of explains itself. Usually seen in dialysis patients, it is characterized by the hardening of blood vessels, particularly the walls of the aortic valve. A more severe form is calciphylaxis, characterized by the obstruction of smaller blood vessels in the body.
This calcification is a severe problem for dialysis patients with end-stage kidney disease. During dialysis, a type of crystal called hydroxyapatite is formed out of calcium and phosphates. This crystal collects in blood vessels and causes blood vessels to harden, and can even obstruct smaller blood vessels such as in calciphylaxis. This got a team of scientists in Spain wondering, could they target these crystal formations and prevent the calcification?
The team, composed of scientists from Sanifit Therapeutics and colleges in Spain and the United States, wanted to investigate a hydroxyapatite crystal inhibitor named SNF472 to treat cardiovascular calcification. Several studies have tried to target pathways leading to the formation of the crystals, but SNF472 would bind to the crystal itself and prevent the formation of larger crystals.
In an open-labeled phase 2 trial, SNF472 proved successful in preventing pain and initiating a degree of wound healing in 14 calciphylaxis patients. In a double-blind, randomized phase2b trial that used SNF472 to treat patients undergoing hemodialysis for a year, it was found that the treatment prevented calcification compared to controls. This new study intended to examine the results more carefully to reveal how effective SNF472 was at preventing calcification.
The team began by setting up a rat model to test SNF472’s effectiveness independently. The rats were treated with Vitamin D, which induced calcification of the heart and aorta. Treatment with SNF472 reduced calcification by up to 80% in both the aorta and the heart and max dosage, with minimum dosage still eliciting a 44% reduction. The team also developed a test to determine if SNF472 prevented the formation of hydroxyapatite crystals, which it did in a dose-dependent manner.
Analysis of patient serum from the open-label trial showed the median SNF472 concentration and activity maintained somewhat maintained in the blood (though the numbers varied with each patient). The randomized trial also showed that higher doses correlated with higher crystal inhibition rates.
This study identified that SNF472 could inhibit cardiovascular calcification in a dose-dependent manner. By examining serum samples, the team was able to see SNF472 levels and how they correlated with lower calcification readings. These data support the claim that SNF472 could help patients at risk for cardiovascular calcification during dialysis.
The study concludes, “In conclusion, in this report we used our previously validated PD assay for calcium phosphate crystallization to show that SNF472 substantially and consistently inhibits calcium phosphate crystallization with repeated dosing, and that this PD effect correlates with reduction in CVC progression in rats and in clinical effect in patients with ESKD on hemodialysis.”
Sources: Nature Scientific Reports, Mayo Clinic
