In the clinic, PCSK9 inhibition is rapidly gaining traction as it is backed by studies showing dramatic reductions in circulating cholesterol. In preliminary phase 2 data reported last November at the American Heart Association's annual scientific sessions, Regeneron's fully human PCSK9-blocking antibody achieved a 65% mean drop in LDL levels in individuals with familial hypercholesterolemia after just three treatments at the high dose. In a second trial enrolling 90 individuals with non-familial hypercholesterolemia, those treated with statins and anti-PCSK9, saw LDL levels plummet a further 65% on top of the statin benefit. Regeneron developed the PCSK9 mAb in partnership with Paris-based Sanofi, using Regeneron's VelocImmune mice, in which their murine variable chain regions have been removed and replaced with human heavy- and light-chain counterparts. Amgen of Thousand Oaks, California, has reported similarly dramatic LDL reductions for its antibody in phase 1, and Alnylam Pharmaceuticals in Cambridge, Massachusetts, reported in January that its lipid nanoparticle siRNA therapeutic in phase 1 led to a mean reduction in LDL of 39% after a single dose.
PCSK9 is a secreted protease that degrades LDL receptors in the liver. This limits receptor-mediated LDL cholesterol clearance from the bloodstream. As a drug target, PCSK9 boasts an impressive track record of genetic validation. In 2003, a group in France identified gain-of-function missense mutations in PCSK9 that led to hypercholesterolemia and premature coronary artery disease in families. Overexpressing PCSK9 in mice led to a dramatic reduction in LDL receptor number and soaring LDL cholesterol in blood. The field really took off in 2006 when heart disease researcher Helen Hobbs, at the University of Texas Southwestern in Dallas, reported that two common PCSK9 loss-of-function mutations were associated with a mean 28% reduction in plasma LDL and an 88% reduction in coronary heart disease. Other mutations conferred somewhat smaller benefits (New Engl. J. Med. 354, 1264–1272, 2006). Two individuals lacking both functioning PCSK9 alleles have been reported, with miniscule LDL levels of 14 mg/dl and 16 mg/dl, respectively; neither individual has any apparent health problems.
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