Three members of the FDA’s Endocrinologic and Metabolic Drugs Advisory Committee explained their decision to approve two proprotein convertase subtilisin kexin type 9 (PCSK9) inhibitors this summer.

Brendan M. Everett, MD, MPH; Robert J. Smith, MD; and William R. Hiatt, MD, wrote about the approvals of alirocumab (Praluent, Regeneron Pharmaceuticals and Amgen) and evolocumab (Repatha, Amgen) in the New England Journal of Medicine on Oct. 21.

They explained that alirocumab lowered low-density lipoprotein (LDL) cholesterol by 39 percent to 62 percent compared with placebo, while evolocumab decreased LDL cholesterol by 47 percent to 56 percent compared with placebo. Meanwhile, approximately 37 percent of patients receiving evolocumab and 24 percent of patients receiving alirocumab had LDL cholesterol levels below 25 mg per deciliter on two consecutive measurements.

The injectable medications are intended for adults with primary hypercholesterolemia, mixed dyslipidemia and those unable to take statins. Patients with homozygous familial hypercholesterolemia were also included in the evolocumab studies.

Everett, Smith and Hiatt wrote that the committee did not receive efficacy data on cardiovascular outcomes, although preliminary adverse events with evolocumab were encouraging.

“During the meeting, the FDA noted that if a medication is approved through this traditional pathway on the basis of a surrogate end point, the FDA can subsequently mandate postmarketing safety studies but cannot require postmarketing studies of benefits, such as cardiovascular event reduction,” they wrote. Thus, the principal issue before the advisory committee was whether the observed LDL cholesterol reduction provided sufficient evidence to substitute for demonstration of clinical cardio- vascular benefit.”

Although the IMPROVE-IT study showed reducing LDL cholesterol also decreased cardiovascular risk, the FDA advisory committee members said the hypothesis is not supported with other trials that included non-statin medications that lower LDL cholesterol.

They noted that using LDL cholesterol reduction as a surrogate end point before outcomes trials had been completed has benefits and risks. The benefits include demonstrating a statistically significant benefit while exposing few patients to the novel medication and evaluating new medications in patients with uncommon disorders such as homozygous familial hypercholesterolemia for which trials with a clinical end point would not be feasible.

The FDA advisory committee approved alirocumab by a 13 to 3 vote and approved evolocumab by an 11 to 4 vote.

“Many committee members, including those who supported approval, emphatically stated that LDL cholesterol levels were not a reliable surrogate for cardiovascular benefit and acknowledged that approval could lead to wide-spread use before definitive efficacy and adequate safety data are available,” they wrote. “This concern may be somewhat mitigated by the high cost and requirement for parenteral administration of PCSK9 inhibitors. Establishing evidence of improved cardiovascular outcomes is key to evaluating medications from any new drug class intended to reduce such risk. As substantially as alirocumab and evolocumab reduce LDL cholesterol, definitive evidence of reduced cardiovascular event rates is essential. Ongoing trials designed to provide such evidence should elucidate the medications’ true clinical benefits and possible risks.”