An experimental drug that acts in a novel way to lower cholesterol proved even more effective than statins and had few undesirable side effects, newly released data shows. The drug acts by modifying the way cholesterol levels are naturally controlled. A protein produced in the liver helps limit the amount of LDL, or “bad” cholesterol, that liver cells can remove from the bloodstream. The new drug, called REGN727, is a monoclonal antibody, made in a laboratory, that blocks the action of that protein.
“About 5 to 10 percent of people can’t tolerate statins at all, and more can’t tolerate higher doses,” said Dr. Evan A. Stein, director of the Metabolic and Atherosclerosis Research Center in Cincinnati and lead author of the drug trials. “It’s still early in development, but for them this is potentially a most promising alternative.” The drug will probably require regular injections.
The studies, sponsored by the pharmaceutical companies developing the drug, were published on Thursday in The New England Journal of Medicine. The study tested SAR236553/REGN727 (Sanofi and Regeneron), a monoclonal antibody that binds to PCSK9, blocking its effects and preventing the degradation of LDL receptors. PCSK9 is a serine protease synthesized in the liver. Upon entering the circulation, the drug binds to hepatic LDL receptors, leading to their breakdown. As a result, the liver loses some of its capacity to remove LDL cholesterol from circulation, which results in an increase in LDL-cholesterol levels. Researchers have previously shown that gain-of-function mutations in the Pcsk9 gene were linked to hypercholesterolemia and that loss-of-function mutations are associated with low LDL-cholesterol levels and a low prevalence of coronary heart disease events.
“The study shows that the drug has incredibly potent effect in lowering cholesterol,” said Dr. Mario J. Garcia, chief of cardiology at Montefiore Medical Center in New York City, who was not involved in the research. “Even though this is very exciting, and perhaps a real breakthrough, at this point it’s premature to conclude that this drug will increase survival or improve quality of life. Also, we don’t know whether the drug will continue to be effective over time — it’s an antibody, and there’s always the possibility that the body itself can become immune to its effect,” he said.
Dr. Stein and his colleagues recruited a large sample of people with high cholesterol. Some were being treated with statins or modified diet, while others were not being treated at all. Some had familial hypercholesterolemia, a common genetic disorder that causes extremely high cholesterol. The researchers conducted two single-dose studies, injecting a placebo or the drug at higher and lower doses into 72 healthy volunteers who were not taking other lipid-lowering drugs. All of them had LDL readings above 100 milligrams per deciliter, the upper limit of normal. They were periodically evaluated over the next four months.
A single dose of REGN727 reduced LDL cholesterol by as much as 65 percent compared with placebo, with higher doses producing reductions still evident two months later, the researchers found.
In a third trial, using multiple doses, the scientists tested 61 people with hypercholesterolemia. Most of the participants were taking Lipitor (atorvastatin), and 10 were being treated with diet modification only. Three times over a six-week period, patients received an injection of a placebo or the drug in varying doses; then they were monitored over the following two months. All those who were on Lipitor had LDL levels above 100 milligrams per deciliter, and those on a modified diet had levels above 130.
The multiple-dose groups saw reductions of 38 to 65 percent over placebo, and reductions were as large for those taking Lipitor as for those who were not. The drug apparently does not increase the effectiveness of statins, but instead provides an added and separate effect. There were few adverse events, and none serious enough to make anyone discontinue the trials.
Phase 2 studies, have not been published, but the results of two such trials were presented on Sunday and Monday at a meeting of the American College of Cardiology in Chicago. One included 183 patients already taking Lipitor. In this group, patients given REGN727 reduced LDL by an additional 40 to 70 percent compared with those on a placebo.
James M. McKenney, director of National Clinical Research, the firm conducting one of the trials, said that the addition of REGN727 caused no increase in side effects like muscle weakness or irregular liver function, sometimes seen with use of statins. If it proves successful in larger trials, the new drug may help shed light on “how beneficial very low levels of cholesterol are in reducing heart disease risk,” he said.
The researchers said a longer study is needed to establish the long-term safety of the SAR236553/REGN727 antibody, but results from this trial were promising, with only one adverse reaction reported.
Dr Rick Nishimura (Mayo Clinic, Rochester, MN), the moderator during the press conference, called the new compound a potential “game changer” but stressed that these are early days, indeed. “For anything to be effective, you have to look at clinical outcomes,” Nishimura told heartwire. “We've had a lot of things in the past that lower cholesterol and that everybody has been very excited about. When you actually look to see whether it prevents heart attacks in thousands of patients, that's where the rubber really hits the road. All this new stuff that's being presented, we're very excited about, but it's happened time and time again where new drugs come out to lower cholesterol, and you test them in a randomized trial for hard outcomes, and they might not be effective.”
Speaking with heartwire about the results, Dr Steven Nissen (Cleveland Clinic, OH) was excited about the findings but measured. “I think it's really promising, and yes, it's injectable, but it means that we can get virtually anybody to their LDL-cholesterol targets. I think the drugs are likely to turn out to be safe, and we already are seeing that they're very effective. There are a lot of people not at goal who are going to benefit. There are a lot of people who are statin intolerant who are going to benefit. It's a very promising class, but it's early. We need phase 3 data. The studies presented at this meeting are phase 1 and phase 2 studies.”