Dr. Amy Simon, Senior Director of Clinical Research at Alnylam discusses the Phase I clinical study of ALN-PCS, an RNAi therapeutic targeting PCSK9 for the treatment of severe hypercholesterolemia.

Dr. Simon begins the discussion by providing some context around why a new therapeutic targeting this disease area is so important.  Severe hypercholesterolemia is characterized by very high levels of LDL cholesterol, or bad cholesterol, in the blood.  As Dr. Simon describes in the podcast, people with severe hypercholesterolemia cannot regulate their levels of cholesterol with lifestyle changes, and therefore have an elevated risk of developing this cardiovascular disease.

PCSK9 is a disease gene expressed in the liver that plays a key role in the regulation of LDL receptors.  High levels of PCSK9 lead to a reduced level of LDL receptors, allowing higher levels of LDL cholesterol to be present.  “By targeting the PCSK9 mRNA,” she detailed, “we will deplete PCSK9 expression on the liver and thereby lead to increased LDL receptor levels on the liver, with a subsequent lowering of LDL cholesterol.”

The Phase I trial is designed as a randomized, single-blind, placebo-controlled, single ascending dose study with approximately 32 healthy volunteers with elevated LDL cholesterol.  “In this Phase I study, our main initial objectives are to just demonstrate safety and tolerability of ALN-PCS in subjects of elevated baseline cholesterol, or LDL cholesterol,” Dr. Simon noted.  “In addition, we’re also hoping to have an opportunity to assess preliminary proof of concept based on measurements in blood based on both PCSK9 and LDL cholesterol.”