New cholesterol lowering drugs on the horizon

By Dr. Ananya Mandal, MDMar 25 2012

Cholesterol lowering in a novel way is about to be revealed at an annual American College of Cardiology meeting in Chicago.

The new drugs in development by pharmaceutical makers are injectable medications that block a protein called PCSK9. These drugs have shown promise in early clinical trials for slashing bad LDL cholesterol further than widely used statins can alone. Their biggest advocates say PCSK9 blockers have the potential to be the next multibillion-dollar class of heart drugs.

Regeneron Pharmaceuticals on Monday will unveil full trial results, including safety findings - giving a fuller picture of its potential and how widely it might be prescribed if approved. The drug called REGN 727, as well as rival products from Amgen Inc, Merck & Co and other drugmakers are all near completion of their clinical studies.

Evan Stein and colleagues report the results published in the New England Journal of Medicine of two single-dose studies in which the drug, REGN727, was administered intravenously and subcutaneously to healthy subjects. In a third, randomized, placebo-controlled, dose-ranging trial, REGN727 was administered subcutaneously on days 1, 29, and 43 in adults with and without familial hypercholesterolemia (FH).

REGN727 was well tolerated and no subjects stopped taking the drug due to adverse events. Five patients had brief elevations in creatine kinase over three times the upper limit of normal. The drug had a powerful LDL-lowering effect: in the dose-ranging study in subjects already receiving atorvastatin

• the 50 mg dose caused a 39% reduction of LDL cholesterol to 77.5 mg/dl,
• the 100 mg dose caused a 53% reduction of LDL cholesterol to 61.3 mg/dl, and
• the 150 mg dose caused a  61% reduction of LDL cholesterol to 53.8 mg/dl.

Amgen on Sunday will present data from a study of its anti-PCSK9 medicine, called AMG145. Although it is an early-stage trial involving relatively few patients, there is still compelling effectiveness and safety data. “PCSK9 is one of the most exciting targets in cardiovascular drug development today,” Michael Severino, Amgen's chief medical officer, said in an interview.

Severino said a large number of patients - some studies suggest 40 to 50 percent - fail to reach their cholesterol-lowering goals despite being on statins, and that PCSK9 inhibitors could give them the needed extra push. Moreover, the drugs could help a much smaller group of patients who cannot tolerate statins, he said.

An estimated 9 million Americans are deemed at high or very high risk of heart-related problems, and could benefit most from PCSK9 drugs added to statins. And at least another 1 million could use them instead of statins.

“For 30 years there really hasn't been another drug therapy of important magnitude added to the benefit of statins,” said Dr. Jefferey Borer, head of cardiology for SUNY-Downstate Medical Center in New York. “Most doctors don't know about this approach, so I think there will be a tremendous amount of interest at the meeting and people will begin to talk about it.” But Borer cautioned that more safety data is needed for anti-PCSK9 drugs because so many people may use them. “We need many large trials.”

Dr. Robert Eckel, former president of the American Heart Association, said that if the drug indeed lives up to its promises, it could potentially benefit many patients he sees every day. “Despite the proven benefit of statins in reducing [cardiovascular] risk, additional LDL-C lowering therapies are needed for patients with several genetic disorders that cause high levels of LDL-C and those with statin intolerance.” These patients, he added, make up 40 percent of the patients treated at his clinic.

And Dr. Christopher Cannon, a professor of medicine at Brigham and Women's Hospital in Boston, called PCSK9 inhibitors a “very important new class of drug. It reduces a major risk factor [for heart disease] by nearly two-thirds.”

“It is an early study,” said Dr. Harlan Krumholz, a professor of medicine at Yale University, said. “It is information that can be used to mount a rationale for further study and investment. But for patients, it is far too early to tell.”

In an accompanying editorial, Stephen Young and Loren Fong write that “at this point, the status of PCSK9 therapeutics appears to be full speed ahead.” But they also express caution, noting that much work remains to be done. “In the end, evidence of long-term safety, along with data showing protection from coronary disease, will be needed to define the role of these agents in clinical practice. High-risk patients who have not reached their recommended cholesterol target and patients who cannot tolerate statins could benefit greatly. Patient selection will undoubtedly be influenced by cost–benefit considerations.”

Regeneron plans to begin a number of large late-stage trials of REGN 727 by mid-2012. Amgen, meanwhile, is gearing up for a series of mid-stage studies of its product that will involve almost 2,000 patients.