The following are key points to remember from this perspective on the benefits of reducing low-density lipoprotein cholesterol (LDL-C) with PCSK9 inhibitors:

1. The Food and Drug Administration (FDA) approved the two injectable proprotein convertase subtilisin-kexin type 9 (PCSK9) inhibitor drugs on the basis of demonstrated marked reduction in LDL-C compared to placebo: 39-62% with alirocumab and 47-56% with evolocumab. Each are fully humanized monoclonal antibodies that inactivate PCSK9, which by doing so prevents degradation of LDL-receptors and promotes hepatic clearance of LDL-C.
2. Observational data that loss of function mutations with PCSK9 is associated with a reduction in cardiovascular (CV) events provided strong encouragement to the development of selective antibodies as an adjunct to statin therapy, which also enhances LDL-receptor activity.
3. In clinical trials, each agent decreased the LDL-C to <25 mg/dl in a significant percentage of patients (24-37%), most of whom were on statins. This raised concerns to the FDA including neurocognitive, gastrointestinal, and metabolic.
4. The potential target populations for the PCSK9 antibody therapy were those with primary hypercholesterolemia, mixed hyperlipidemia including diabetes, and statin intolerance. The primary issue for the FDA was whether to approve the drug on the basis of the surrogate endpoint of LDL-C, which could mandate post-marketing studies of safety, but could not require post-marketing studies of CV event reduction and overall outcome.
5. The FDA used LDL-C as a surrogate for outcome for statins and ezetimibe. The concern for an increased cancer risk in a trial of ezetimibe placed the surrogate endpoint in question. This was resolved for ezetimibe by the IMPROVE-IT trial, which demonstrated the benefit of adding ezetimibe to simvastatin for reducing CV events with no increase in cancer risk. However, other recent trials of lipid-lowering drugs have not shown a CV event reduction benefit despite significant reduction in LDL-C including estrogens, fenofibrate, torcetrapib, and niacin-laropiprant.
6. The benefits of using the LDL-C surrogate include smaller study cohorts over relatively short periods of time for safety and lower costs for development. However, this was at the expense of not knowing the long-term safety of uncommon, but important adverse events (e.g., neurocognitive) and the potential for increase in mortality as with torcetrapib, the CTEP inhibitor that lowered the LDL-C by 27% and increased the HDL-C by >50%.
7. The use of the PCSK9 antibody for statin-intolerant patients was most attractive, but with the potential that too often they would be used in lieu of statins and that statin intolerance is overdiagnosed (70% of patients considered statin-intolerant tolerated 20 mg of atorvastatin for 24 weeks in a blinded study of alirocumab).
8. Both drugs were FDA approved by a wide margin because of the potential value to a very high-risk cohort until the large outcome trials were completed. Committee members were emphatic that LDL-C was not a reliable surrogate for CV benefit and concerned that approval could lead to widespread use before definitive efficacy and safety data were available. Whether that concern would be mitigated by the high cost and requirement of an injection was not known.

Keywords: Antibodies, Monoclonal, Biomarkers, Cholesterol, Cholesterol, LDL, Diabetes Mellitus, Dyslipidemias, Hydroxymethylglutaryl-CoA Reductase Inhibitors, Hypercholesterolemia, Lipoproteins, LDL, Primary Prevention, Proprotein Convertases, Receptors, LDL, Simvastatin, Subtilisins

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