CardioExchange Archive

When added to low-dose atorvastatin, a much-discussed new monoclonal antibody to PCSK9 significantly lowers cholesterol more effectively than atorvastatin alone, according to a phase 2 study published in the New England Journal of Medicine. Earlier this year, in March, the findings of three phase 1 trials demonstrating the cholesterol-lowering effects of the drug in healthy volunteers and in people with familial or nonfamilial hypercholesterolemia were also published in NEJM.

In the new trial, Eli Roth and colleagues studied 92 patients with LDL levels of 100 mg/dL or higher despite taking atorvastatin 10 mg. Patients were randomized to 8 weeks of treatment with 80 mg atorvastatin plus the PCSK9 inhibitor SAR236553, 10 mg atorvastatin plus SAR236553, or 80 mg atorvastatin plus placebo. SAR236553 was administered as an injection once every 2 weeks.

PCSK9 inhibition significantly improved LDL reduction. LDL decreases from baseline were as follows:

• atorvastatin 80 mg + SAR236553: 73.2%
• atorvastatin 10 mg + SAR236553: 66.2%
• atorvastatin 80 mg + placebo: 17.3%

The investigators reported that 100% of patients in the two groups that received SAR236553 achieved target LDL levels of less than 100 mg/dL, compared with only 52% who received atorvastatin plus placebo.

The results, write the authors, suggest that SAR236553 “may benefit patients in whom LDL cholesterol has not been reduced to recommended levels, either because of an inadequate lipid-lowering response with high-dose statins alone or because of unacceptable side effects with high-dose statins.”

James Stein told CardioExchange:

“These results are very promising. What we need now are larger studies of SAR236553 with a longer duration, to determine its safety and tolerability. If it is safe and effectively lowers total and LDL cholesterol over long periods of time, it would be expected to reduce cardiovascular disease risk, but of course outcomes studies eventually will be needed to prove that.”

In July the companies developing SAR236553, Sanofi and Regeneron, announced a large phase 3 program for the drug, including an 18,000-patient outcomes trial. Next Monday, at the American Heart Association scientific sessions, the results of two more phase 2 studies of SAR236553 will be presented, as well as a study with another PCSK9 monoclonal antibody from Pfizer, RN316 (PF-04950615).