Two novel lipid-lowering drugs should be approved by the U.S. Food and Drug Administration (FDA) according to the agency’s Endocrinologic and Metabolic Drugs Advisory Committee which met on June 9 and 10 to discuss the safety and efficacy of Sanofi and Regeneron Phermaceuticals’ alirocumab and Amgen's evolocumab for reducing low-density lipoprotein cholesterol (LDL-C). The drugs, if approved, would be the first in a new class of drugs known as proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors and would offer the more than 70 million patients with high LDL-C an alternative treatment option to statins, which are associated with numerous side effects. The pharmaceutical companies are seeking approval of the drugs, which are both injectable and administered subcutaneously, for use in patients with high LDL-C who are not benefiting from statins; people who are high risk due to a previous myocardial infarction or those with diabetes for which statins are not effective; and patients with high LDL-C who are statin-intolerant.

PCSK9 is a protein that controls LDL-C levels in the blood by regulating LDL receptor metabolism. Since a 2006 study first suggested that impaired PCSK9 activity might lower cardiovascular events, numerous clinical trials have been underway to study PCSK9 inhibitors. The results of two trials looking at evolocumab and alirocumab were presented at ACC.15. Results from the OSLER-1 AND -2 Trial showed the use of evolocumab plus standard therapy dramatically lowered LDL-C. The study found patients receiving evolocumab saw their cholesterol drop 61 percent, from a median of 120 mg per deciliter to 48 milligrams per deciliter. Reductions were sustained through the median 11-month follow-up period. Study investigators also noted evidence of reduction in the rate of cardiovascular events among patients in the evolocumab group. The ODYSSEY LONG TERM trial found that among patients with heterozygous familial hypercholesterolemia or high cardiovascular risk, alirocumab resulted in a large reduction in LDL-C compared with placebo, which was maintained, although slightly attenuated at 78 weeks. Alirocumab appeared to be generally well-tolerated and was associated with low cardiovascular events.

While results showing the drugs’ effectiveness at lowering LDL-C are promising for the new agents, definitive evidence showing the effectiveness of the drugs for reducing myocardial infarction and death won’t be available until 2017 when large clinical trials are completed.

“At this point in time, the data linking LDL reduction with reduced cardiovascular risk are quite strong,” said Deepak L. Bhatt, MD, MPH, FACC, a member of ACC’s Board of Trustees. “The older epidemiologic data, the statin studies, the Mendelian randomization studies, and most recently data for ezetimibe all support this link. PCSK9 inhibitors are extremely effective at reducing LDL cholesterol. Early signals from LDL-lowering trials of two of the PCSK9 inhibitors suggest there may be a reduction in cardiovascular events. The ongoing cardiovascular outcome trials should close the loop on this exciting class of compounds and will hopefully demonstrate their ability to translate LDL reduction into lower cardiovascular event rates. Until those data are available, the PCSK9 inhibitors should serve a useful role in the high risk categories of patients in which they will likely be approved.”

The FDA will ultimately decide the fate of the drugs in the coming months.

Keywords: Advisory Committees, Anticholesteremic Agents, Azetidines, Cardiovascular Diseases, Cholesterol, Cholesterol, LDL, Diabetes Mellitus, Dyslipidemias, Follow-Up Studies, Hydroxymethylglutaryl-CoA Reductase Inhibitors, Hyperlipoproteinemia Type II, Lipoproteins, LDL, Myocardial Infarction, Pharmaceutical Preparations, Proprotein Convertases, Receptors, LDL, Research Personnel, Risk Factors, Subtilisins, United States Food and Drug Administration

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