AMG-145 Anti-PCSK9 Monoclonal Antibody Treatment of Lipoprotein Disorders

The discovery in 2003 of the role of proprotein convertase/subtilisin kexin type 9 (PCSK9) in regulating LDL receptor recycling opened the possibility of an exciting new therapeutic target for reducing LDL cholesterol. Subsequent epidemiological and Mendelian randomization studies provided additional evidence for the beneficial relationship between loss-of-function mutations and reduced cardiovascular disease. An important finding in 2006 was that circulating (plasma), and not intrahepatic, PCSK9 bound to the LDL receptor, targeting it for degradation. This provided the therapeutic potential for PCSK9 inhibition with a monoclonal antibody (MAb). Subsequent development with AMG-145, a fully human MAb targeting PCSK9, has proceeded rapidly, entering first-in-human (phase I) trials in late 2010, completing a large phase II program in 2012 and starting phase III trials in 2013. Should the development of AMG-145 and PCSK9 MAbs result in approval for general use for LDL cholesterol reduction, the most likely, and logical, utilization of these agents, based on both the anticipated cost and the method of administration (subcutaneous injections every 2 or 4 weeks) is where there is currently a significant unmet medical need. This includes the estimated 5% to 10% of patients who cannot tolerate statins, or effective doses of statins, and patients, such as those with familial hypercholesterolemia, who, despite good tolerance of and response to current agents, have severe elevations in LDL cholesterol and are still unable to achieve optimal posttreatment LDL cholesterol levels.