PCSK9 Inhibitors Edge Closer to FDA Approval

Two investigational proprotein convertase subtilisin kexin 9 (PCSK9) inhibitors received votes in support of approval this week from the FDA’s Endocrinologic and Metabolic Drugs Advisory Committee.

The two injectable biologic agents are alirocumab (Praluent, from Regeneron and Sanofi), which received the panel’s approval on Tuesday, and evolocumab (Repatha, from Amgen), which received it on Wednesday.

The FDA usually, but not always, follows the recommendations of its advisory committees. Final approval decisions for both PCSK9 inhibitors are expected from the agency this summer.

‘A breakthrough in how we treat cholesterol’

Steven Nissen, MD, Chairman of Cardiovascular Medicine at Cleveland Clinic, who has been involved in research investigating the PCSK9 inhibitors, calls them very powerful, noting that they reduce LDL cholesterol (LDL-C) levels by 50 to 70 percent in clinical trials.

“This is a breakthrough in how we treat cholesterol,” he says. “The PCSK9 inhibitors are probably the most important new class of drugs we have seen in cardiology in quite a long time. They are going to generate a lot of interest and excitement, and for good reason.”

Dr. Nissen says alirocumab and evolocumab are very similar to one another. The biggest difference is in their recommended dosing schedules — one can be given every two weeks or every four weeks, while the other is given every two weeks.

“I don’t think there is an advantage of one over the other,” he says.

A new option for difficult-to-treat patients

The new agents work by inhibiting the PCSK9 protein from degrading LDL receptors in the liver, thereby increasing LDL-C clearance and lowering circulating levels of LDL-C.

Dr. Nissen notes that PCSK9 inhibitors will not replace statins but will rather be used in addition to them.

“It wouldn’t makes sense to withhold drugs that have been shown to have a major benefit in morbidity and mortality in order to give these new drugs,” he says. “PCSK9 inhibitors are for patients who cannot tolerate statins or who cannot take enough of them to get their LDL cholesterol down to optimal levels. These drugs will be very valuable for those difficult-to-treat patients.”

Another PCSK9 agent in the pipeline

Cleveland Clinic has been involved in many clinical trials of various PCSK9 inhibitors during their development. For example, Dr. Nissen is leading a 1,000-patient study of evolocumab to learn if it can actually remove plaque from the coronary arteries. That study is expected to be completed sometime next year.

He also is on the steering committee for a trial of a third PCSK9 inhibitor, bococizumab, being developed by Pfizer. That agent is expected to be filed for FDA approval later this year.

Results of outcomes studies eagerly awaited

While it’s established that alirocumab and evolocumab are highly effective in reducing cholesterol, Dr. Nissen notes that their impact on clinical outcomes remains to be demonstrated.

“Clinical outcome trials to determine whether or not they reduce the risk of the things we really care about — like myocardial infarction, stroke and death — have not yet been completed, but those studies are ongoing,” he says. “However, many people expect these agents to have a favorable effect on those endpoints as well.”