CHICAGO--A novel monoclonal antibody lowered low density lipoprotein cholesterol (LDL-C) up to 72 percent in patients with primary hypercholesterolemia in a randomized, double-blind, placebo-controlled trial. The results were announced March 26 at the 61st annual American College of Cardiology scientific session and simultaneously published online in the Journal of the American College of Cardiology.
“This was a very sophisticated trial that gleaned a lot of information,” said co-author Dean J. Kereiakes, MD, medical director of The Christ Hospital Heart and Vascular Center in Cincinnati, in an interview. The study was designed to test the safety and efficacy of the human monoclonal antibody SAR236553/REGN727.
Like the statin atorvastatin, this novel therapy is designed to lower LDL-C. Previous research has shown that atorvastatin lowers LDL-C by enhancing the production of the hepatic receptor PCSK9. The monoclonal antibody strategy takes another approach: It binds to a protein involved in the degradation of the receptors.
Results from three Phase 1 proof-of-concept trials, published earlier this month, showed that the monoclonal antibody significantly reduced LDL-C in healthy volunteers and people with familial or nonfamilial hypercholesterolemia (N Eng J Med 2012;366:1108-1018). James M. McKenney, PharmD, president and CEO of National Clinical Research in Richmond, Va., and the study’s lead author, presented findings from the follow-up Phase 2 study at the ACC conference.
Phase 2 was designed to assess the effect of 12 weeks of the monoclonal antibody treatment in patients who also were receiving stable 10, 20 or 40 mg doses of atorvastatin. “We all have patients in the clinic who we’ve had difficulty getting sufficient lowering ability to satisfy our risk reduction approaches,” McKenney said. “This indicates a need for a new and different way of approaching LDL, and this drug may be the answer.”
The study enrolled 183 patients with LDL-C levels of 100 mg/dL or greater and randomized them either to placebo or the monoclonal antibody therapy in five dose regimes: either a 50, 100 or 150 mg dose taken subcutaneously every two weeks or a 200 or 300 mg dose taken subcutaneously every four weeks. All participants were on stable dose atorvastatin. The trial period covered a screening, 12 weeks of double-blind treatment and an eight-week follow-up.
“This allows you to see the dose-response,” Kereiakes said. “You can see if it is a progressive response or if it plateaus.”
Patients had a mean age of 57 years; 52 percent were women; 86 percent were white; 86 percent were on a lipid-lowering treatment; 45 percent were hypertensive; 20 percent smoked; 12 percent had type 2 diabetes; 5 percent had coronary artery disease; and 3 percent had peripheral vascular disease.
The monoclonal antibody lowered LDL-C levels in patients in every group and every regime. Patients who took the drug every two weeks with 50, 100 and 150 mg had a reduction of 40 percent, 64 percent and 72 percent, respectively. In the once a month group, at 200 and 300 mg, the response was 43 percent and 48 percent, respectively. The placebo group saw a reduction of 5 percent.
One patient developed diarrhea and a rash after the initial treatment and was diagnosed with leukocytoclastic vasculitis. The patient received steroids. Kereiakes suggested the patient had developed an immunity response to the human protein.
The 150 mg every two weeks regime achieved the most efficacious results, with 100 percent attainment of LDL-C levels of less than100 mg/dL at 12 weeks and less than 70 mg/dL at 12 weeks. By contrast, the placebo group achieved 16 percent and 3 percent, respectively. The attainment under the five treatment regimes ranged from 46 percent (200 mg once every four weeks) to 100 percent (150 mg every two weeks).
“Right now many patients do not meet the target LDL level of 70,” Kereiakes said in the interview. That places them at risk of MI, stroke or needing interventions such as PCI or CABG surgery, he added. “This is a valuable add-on to statins.”
“We recorded a robust dose-dependent reduction in LDL-C,” McKenney said. “The efficacy and safety findings of this study … do support further development of this product” and a larger clinical trial to evaluate the drug in a more diverse patient population who are on other therapies to assess efficacy and safety.
“It is my understanding that a robust Phase 3 program is being planned and has