Lomitapide and Mipomersen
Two First-in-Class Drugs for Reducing Low-Density Lipoprotein Cholesterol in Patients With Homozygous Familial Hypercholesterolemia
Low-density lipoproteins (LDLs) are a proven causal risk factor for the development of atherosclerotic cardiovascular disease. Plasma levels of LDL cholesterol (LDL-C) and its major protein, apolipoprotein B (apoB), are positively associated with incident cardiovascular events.1 Individuals with genetic conditions of extremely high LDL-C develop premature cardiovascular disease; conversely, those with genetically low LDL-C are protected from cardiovascular disease. Interventions that reduce LDL-C, including statins and bile acid sequestrants, are proven to reduce cardiovascular risk.2 Indeed, therapy to reduce LDL-C is a cornerstone of the treatment and primary prevention of atherosclerotic cardiovascular disease.
Despite the commercial availability of 3 major classes of LDL-lowering drugs (statins, bile acid sequestrants, and a cholesterol absorption inhibitor), a substantial unmet need has remained with regard to LDL-lowering treatment. Some patients are intolerant of statins because of myalgias. Others have genetic conditions that substantially elevate their LDL-C and make it challenging to achieve desirable LDL-C levels even with combination therapy. Perhaps the single best example of a genetic condition in which patients frequently fail to achieve acceptable LDL-C levels despite aggressive therapy is familial hypercholesterolemia (FH).3,4 This condition, classically caused by loss-of-function mutations in the LDL receptor,5 is associated with substantially elevated LDL-C and premature atherosclerotic cardiovascular disease. Patients with heterozygous FH typically have untreated LDL-C levels in the range of 200 to 400 mg/dL, and many cannot achieve desirable LDL-C levels on available combination therapy. Patients with 2 mutant LDL receptor alleles have homozygous FH (hoFH) with LDL-C levels usually >400 mg/dL and cannot achieve desirable LDL-C levels on available therapy. There are other causes of autosomal-dominant hypercholesterolemia4 resulting from mutations in the receptor-binding region of apoB (the ligand for the LDL receptor) and gain-of-function mutations in PCSK9 (a protein that targets the LDL receptor for degradation), …