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New Monoclonal Antibody Lowers LDL: Biologic Wows for Lipid Lowering
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By Crystal Phend, Senior Staff Writer, MedPage Today
Published: March 26, 2012
CHICAGO -- A novel monoclonal antibody when added to statin therapy substantially cuts LDL cholesterol levels beyond reductions achieved with statin therapy alone, a phase II study found.
Subcutaneous injection every two weeks dropped LDL by 40% to 72% more than placebo across the doses tested among patients uncontrolled on their background regimen of atorvastatin (Lipitor), James M. McKenney, PharmD, of National Clinical Research in Richmond, Va., reported here at the American College of Cardiology meeting and simultaneously in the Journal of the American College of Cardiology.
Action Points
· A novel monoclonal antibody when added to statin therapy substantially cuts LDL cholesterol levels beyond reductions achieved with statin therapy alone.
· The agent, dubbed REGN727 or SAR236553 for now, is the furthest along in a new class of biologics that boost liver absorption of cholesterol by blocking serum proprotein convertase subtilisin kexin 9 (PCSK9).
"If the drug continues to show this kind of efficacy and especially if it shows safety, it could be a new era in the treatment of lipid disorders," McKenney said at a press conference after the late-breaking clinical trial session.
"This is a wow," said conference co-chair Rick A. Nishimura, MD, of the Mayo Clinic in Rochester, Minn., calling the monoclonal antibody a potential game changer at the press conference.
The agent, dubbed REGN727 or SAR236553 for now, is the furthest along in a new class of biologics that boost liver absorption of cholesterol by blocking serum proprotein convertase subtilisin kexin 9 (PCSK9).
That protein is produced largely in the liver, where it binds to hepatic LDL receptors to mark them for degradation, and thus reduces the capacity of the liver to remove LDL from circulation.
In the phase II trial, the LDL reductions seen among the 183 patients with LDL levels of 100 mg/dL or above at baseline atop their regimen of atorvastatin were (all P<0.0001):
· 5.1% with placebo
· 39.6% with 50 mg of the PCSK9 inhibitor every two weeks
· 64.2% with 100 mg of the monoclonal antibody every two weeks
· 72.4% with 150 mg of the agent every two weeks
· 43.2% with 200 mg of the PCSK9 inhibitor every four weeks
· 47.7% with 300 mg of the agent every four weeks
These reductions appeared additive to the the typically 40% to 50% reductions these patients typically achieve with statin treatment, McKenney noted.
The vast majority of patients randomized to the PCSK9 inhibitor on any schedule or dose got their LDL levels under control to less than 100 mg/dL, with rates ranging from 89% with the lowest monthly dose to 100% with the highest biweekly dose.
The proportion who got to goal with LDL levels under 70 mg/dL over the 12 weeks of treatment ranged from 47% with the lowest biweekly dose to 100% with the highest biweekly dose.
"It's great to finally be able to treat virtually 100% of patients and get them down to optimal levels, levels we never dreamed of getting patients to 10 years ago," co-author Evan A. Stein, MD, PhD, of the Metabolic and Atherosclerosis Research Center in Cincinnati, told MedPage Today.
There are still many patients who can't get to the more aggressive goals for LDL lowering with statins alone, not to mention the patients who don't tolerate statin therapy, said Steve Nissen, MD, from the Cleveland Clinic, who called the agent exciting in an interview.
Sequestering away extra cholesterol in the cells shouldn't be a problem, Stein explained, because cells compensate by reducing their own endogenous production of this lipid, which is used in cell walls and important tasks like production of vitamin D, steroid hormones, and bile.
Safety in the phase II trial largely looked the same as in the series of phase I trials with the same PSCK9 inhibitor. Stein reported those findings in the New England Journal of Medicine last week.
Liver enzymes and kidney function markers weren't elevated above the normal range in any patients on the monoclonal antibody in the phase II trial.
Muscle pain or weakness occurred in one or two patients in every dose and placebo group, each with 30 or 31 patients.
Treatment emergent serious adverse events weren't dose-dependent, and only one was thought related to the study drug.
That patient developed diarrhea followed by a rash on his limbs and trunk nine days after his first injection, diagnosed as leukocytoclastic vasculitis, which rapidly resolved with prednisone treatment. There was no organ involvement and no anti-drug antibodies seen before or after the event.
That event isn't likely to be a hurdle to development of the monoclonal antibody, which is entering phase III testing now, McKenney said.
Nissen said he was comfortable that there weren't any emergent safety issues.
But because there is some risk of immunity with an agent like this, it will be important to see further data on that risk, noted study discussant Karol E. Watson, MD, of the University of California Los Angeles.
"There's no question we need longer-term outcome studies," she said at the session
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