Potential of Proprotein Convertase Subtilisin/Kexin Type 9 Based Therapeutics

The link between proprotein convertase subtilisin/kexin type 9 (PCSK9) and cholesterol metabolism was established only in 2003 when genetic mapping and positional cloning in patients with autosomal dominant hypercholesterolemia in which linkage to the loci coding for the LDL receptor and apolipoprotein B had been excluded identified the genetic defect missense as mutations in PCSK9, a protein/enzyme previously unknown to be related to lipid metabolism. Laboratory-based investigations confirmed that these were gain-of-function mutations. Further studies in cohorts with low LDL cholesterol (LDLc) levels from large epidemiological cardiovascular studies reported that loss-of-function mutations in PCSK9 were associated with protection from cardiovascular disease. An additional critical observation provided evidence that the interaction of PCSK9 and the LDL receptor was through circulating, not intracellular, PCSK9, which bound to the receptor, and then mediated the recycling of the LDL receptor. These findings established PSCK9 as a potential therapeutic target and resulted in biopharmaceutical companies developing interventions designed to lower LDLc levels. Clinical development programs for monoclonal antibodies against PCSK9 have advanced rapidly with completion of comprehensive phase 1 and 2 trials with both REGN727/SAR236553 (REGN727) and AMG 145, clearly demonstrating substantial reductions in LDLc levels in patients receiving diet alone, low, moderate, and high doses of statins, or statin combined with ezetimibe, and both heterozygous familial hypercholesterolemia and nonfamilial hypercholesterolemia subjects. Concomitant and parallel reductions in the levels of apolipoprotein B and its related lipoproteins, and small but significant increases in HDL cholesterol levels were seen as anticipated. An unanticipated and robust decrease in lipoprotein(a) levels was also noted. Although these trials have been relatively short term, no significant safety issues or target organs of interest have emerged. Larger and much longer phase 3 trials are now in progress to assess the long-term tolerability, safety, and impact on cardiovascular disease events of these very effective LDLc lowering compounds.