Reduction of LDL-C levels with AMG-145, a monoclonal antibody against PCSK9, in heterozygous familial hypercholesterolemia: the RUTHERFORD study

Evaluation of: Raal F, Scott R, Somaratne R et al. Low-density lipoprotein cholesterol-lowering effects of AMG 145, a monoclonal antibody to proprotein convertase subtilisin/kexin type 9 serine protease in patients with heterozygous familial hypercholesterolemia: the Reduction of LDL-C with PCSK9 Inhibition in Heterozygous Familial Hypercholesterolemia Disorder (RUTHERFORD) randomized trial. Circulation 126(20), 2408-2417 (2012). Familial hypercholesterolemia (FH) is a genetic disorder mainly caused by mutations in the LDL receptor gene. The heterozygous FH (heFH) condition is inherited in an autosomal dominant pattern and is characterized by very high levels of LDL cholesterol (LDL-C) and cardiovascular risk. Although statins reduce LDL-C levels and risk in heFH, many of these patients do not reach the current treatment goal for LDL-C below 100 mg/dl (2.5 mmol/l). Moreover, statins increase the plasma levels of PCSK9, a liver-secreted protein that binds to the LDL receptor, which prevent its recycling to the cell surface and ultimately lead to its degradation in lysosomes. Monoclonal antibodies (mAbs) against PCSK9 to reduce LDL-C levels are under clinical development by several pharmaceutical companies and have shown convincing results with regards to efficacy and safety in Phase I and II studies. Recently, the RUTHERFORD study in heFH patients who were not at goal despite maximally tolerated lipid-lowering therapy has shown that the AMG-145((R)) mAb (Amgen, CA, USA) significantly reduces LDL-C levels by 55% and allows 89% of patients to reach an LDL-C <100 mg/dl. These findings, along with similar data with the REGN727((R)) mAb (Regeneron Pharmaceuticals, NY, USA) highlight the beneficial effects of anti-PCSK9 mAbs in patients with heFH.