PCSK9 Inhibitors: Good News on Evolocumab

The eagerly awaited results of a trial of the safety and efficacy of the experimental cholesterol lowering drug evolocumab (Amgen) show it is so safe and effective that the question now shifts to whether a few years from now, millions of people will be taking it.

Evolocumab reduced LDL cholesterol by 61% over 12 weeks and showed evidence of reducing cardiovascular events. Results presented today at the American College of Cardiology meeting in San Diego, CA also showed it was half as likely as standard care to be associated with serious adverse events.

“The reduction in LDL was profound,” said lead investigator Marc Sabatine, MD, chairman of the TIMI study and a senior physician in the Division of Cardiovascular Medicine at Brigham and Women’s Hospital in Boston. That suggests “that if we can drive a patient’s LDL cholesterol down a large amount to a very low level we may start to see a benefit sooner than would be expected with a more modest intervention.”

The drug inhibits proptein convertase subtilisin-kexin type 9 (PCSK9) one of three such experimental PCSK9 inhibitor drugs now in trials. The drug’s mechanism is similar to that of statins. It increases LDL receptor activity on the hepatocyte surface.

Evolucumab in earlier trials showed it reduced LDL cholesterol by 61% from a median of 120 mg/DL to 48 mg/DL.

Evolocumab has not yet been approved by the US Food and Drug Administration (FDA.) Those include death, heart attacks, stroke, being hospitalized for a heart problem, or needing a cardiovascular intervention.

The rate of such events at 1 year was 0.95% in the evolocumab patients vs. 2.18 % in patients receiving standard care such as moderate or high-intensity statin therapy.

The results presented today were published simultaneously in the New England Journal of Medicine.

With colleagues, Sabatine studied a total of 4,465 patients who were in one of 12 phase II of phase III trials of the drug’s cholesterol-lowering properties. These patients were then enrolled in a 1-year extension study to investigate evolocumab’s long-term safety, LDL-lowering and cardiovascular outcomes.

The patients got either evolocumab, either every 2 weeks or 4 weeks plus standard care, or standard care alone.

As for the drug’s future, should it get FDA approval, Sabatine said he sees it as an adjunct to statin therapy, particularly for patients who still have higher cholesterol than desired after taking statins. It would also be indicated for patients who do not tolerate statins, he said.

Another frontier is the concept of setting new lower standards for a healthy level of LDL cholesterol, Sabatine added, and using it as a preventive measure. That could include starting drug therapy earlier, he said.

“We haven’t yet seen the floor for LDL levels,” he said, noting that “hunter-gatherer populations have levels of 40 mg/DL. “ Patients in the study had LDL levels as high as 120 mg/DL.

Other issues Sabatine addressed at a news conference after the presentation to the meeting’s attendees included a somewhat high rate of injection site reactions. The drug is delivered by a subcutaneous injection, which some patients might find bothersome, he agreed. “A lot of companies are working on the mode of delivery,” he said, to make it easier on patients.

Price could be a big factor. Sabatine said he had no information on what the drug might eventually cost, or whether Medicare and other insurers would be receptive to paying for it.

Other studies underway involving evolocumab include a trial of 27,500 patients enrolled in a trial of the drug’s impact on cardiovascular outcomes. Results are expected in 2 017.

According to the US Centers for Disease Control and Prevention, about 1 in 3 US adults has high LDL cholesterol. The condition is a major risk factor for cardiovascular disease, the leading cause of death worldwide.