The FDA’s recent limited approval of two new monoclonal-antibody-based cholesterol drugs makes comments made by biotech industry guru G. Stephen Burrill in 2013 appear almost prescient. He said, “As the industry migrates away from an era of the one-size-fits-all blockbuster, the biotechnology industry’s strength at developing innovative therapies that meet unmet medical needs and target the molecular mechanisms of diseases gives it an upper hand in creating value.”1
Indeed, where statins work by partially inhibiting cholesterol production, a new class of monoclonal antibody drugs called PCSK9 inhibitors reduces the PCSK9 protein in the liver, allowing the liver to remove more of the LDL cholesterol (LDL-C) circulating in the bloodstream. When a PCSK9 inhibitor is used in conjunction with statins, the LDL-C reductions can be very large—40% to 60%. Statins were developed by pharmaceutical companies. The new PCSK9 inhibitors were developed by biotech companies.
This figure was adapted from Lambert G, et al. “The PCSK9 decade” J Lipid Res 2012; 53:2515-2524 and appears in reference 2.
High levels of low-density lipoprotein, or LDL-C, have long been associated with increased risk of cardiovascular (CV) disease. In fact, as explained in the introductory remarks accompanying a recent FDA briefing document, “For more than two decades, FDA has used a reduction in LDL-C as a surrogate for CV risk reduction for several lipid-altering drugs to support traditional approval. Certainly, at least for statins, the validity of a reduction in LDL-C as a surrogate for reduced CV risk has been confirmed through numerous randomized controlled trials involving multiple drugs in the class and a variety of patient populations with varying degrees of baseline risk and LDL-C values.”2
Nevertheless, in 2013 the American College of Cardiology (ACC) and the American Heart Association (AHA) jointly released new guidelines intended to move the focus toward reducing the risk of CV disease and away from lowering LDL-C values. As noted in a report on the use of statins in the United States, “The new ACC-AHA guidelines substantially broadened the number of individuals for whom statins are recommended, primarily by broadening the eligible population to lower levels of cardiac risk.”3
The authors commented that, “Most newly eligible individuals in the guidelines are those who do not have a diagnosis of coronary artery disease. Benefits from statins … in terms of a reduction in adverse CV events and in mortality are controversial and at best small.”3 Basically, statins are being recommended for people who probably do not need them while at the same time, according to the report, millions of people with diagnosed CV disease are not taking statins.
Making further tools available
Two PCSK9 inhibitors were approved in 2015 by the FDA: Amgen’s Repatha (evolocumab) and Praluent (alirocumab) from Sanofi US and Regeneron Pharmaceuticals. According to an article that discussed the approval process for evolocumab, 11 of the 14 members of the FDA’s Endocrinologic and Metabolic Drugs Advisory Committee (EMDAC) thought that the benefits of lowering LDL-C outweighed the risks for patients with HeFH—a gene mutation that affects the LDL-C receptors in the liver. In contrast, all 14 members recommended use for patients with HoFH, a much rarer and less well-controlled condition.
The same article postulated that some of the members who were uncertain about approving the drug “… might have been more reassured if evolocumab was reviewed as part of the FDA’s accelerated approval program…. Instituted in 1992, the accelerated approval program was designed to approve drugs to treat serious conditions on the basis of a surrogate end point. As part of this pathway, pharmaceutical companies are required to complete phase 4 confirmatory studies, and if such trials turn out negative, the FDA has regulations in place to remove the drug from the market. In contrast, Amgen would not be required to show a positive effect on cardiovascular outcomes if evolocumab were approved on the basis of changes in LDL cholesterol.”4
Summary
The use of a reduction in LDL-C as a surrogate for CV risk reduction is both clearly stated and also questioned in references 2 and 4. However, because the FDA continues to support the use of statins based both on their capability to lower LDL-C levels and the corresponding reduction in CV disease risk, reference 2 concluded, “One clinical scenario that may seem practical for monotherapy is the use in patients who cannot tolerate statins.” In other words, PCSK9 inhibitors could be used as an alternative treatment by statin-intolerant patients.
Repatha and Praluent have only just started to be used, and long-term safety and efficacy studies have years to run. They have been restricted to only HeFH patients for Praluent or HeFH and HoFH patients for Repatha. No doubt, as the results of further PCSK9 and statin studies become known, the risk/benefit debate associated with cholesterol-lowing drugs will continue.
References
- “BioMarket Trends,” GEN, Sept. 1, 2013.
- “FDA Briefing Document,” Endocrinologic and Metabolic Drugs Advisory Committee (EMDAC), June 2015.
- Johansen, M., E., et al, “Cardiovascular Risk and Statin Use in the United States,” The Annals of Family Medicine, May/June 2014, Vol.12, No. 3, pp. 215-223.
- O’Riordan, M., “Approve PCSK9 Inhibitor Evolocumab, FDA Panel Recommends,” Medscape, June 10, 2015.