In patients with primary hypercholesterolemia, adding SAR236553 to either 10 mg of atorvastatin or 80 mg of atorvastatin resulted in a significantly greater reduction in low-density lipoprotein (LDL) cholesterol than that attained with 80 mg of atorvastatin alone, according to a Phase 2, randomized trial.

Serum proprotein convertase subtilisin/kexin 9 (PCSK9) binds to LDL receptors, increasing the degradation of LDL receptors and reducing the rate at which LDL cholesterol is removed from the circulation, according to the study authors. A fully human monoclonal antibody that binds to PCSK9 can lower LDL cholesterol levels in patients with hypercholesterolemia—both those who are being treated with statins and those who are not (N Engl J Med 2012;366:1108-1018).

The purpose of this study, published Oct. 31 in the New England Journal of Medicine, was to compare the effects of SAR236553 coadministered with high-dose or low-dose atorvastatin, as compared with high-dose atorvastatin alone, in patients with LDL cholesterol levels of 100 mg per deciliter or higher. The preliminary results of this study were presented at the 2012 American College of Cardiology scientific sessions.

For this multicenter, double-blind, placebo-controlled trial, Eli M. Roth, MD, medical director of Sterling Research Group in Cincinnati, and colleagues enrolled 92 patients who had LDL levels of 100 mg per deciliter (2.6 mmol per liter) or higher after treatment with 10 mg of atorvastatin for at least seven weeks.

They randomly assigned patients to receive eight weeks of treatment with 80 mg of atorvastatin daily plus SAR236553 once every two weeks, 10 mg of atorvastatin daily plus SAR236553 once every two weeks or 80 mg of atorvastatin daily plus placebo once every two weeks. The patients were followed for an additional eight weeks after treatment.

After eight weeks of treatment, the least-squares mean percent reduction from baseline in LDL cholesterol was 73.2 with 80 mg of atorvastatin plus SAR236553, as compared with 17.3 with 80 mg of atorvastatin plus placebo and 66.2 with 10 mg of atorvastatin plus SAR236553, Roth and colleagues wrote.

The researchers reported that all the patients who received SAR236553 attained an LDL level of less than 100 mg per deciliter, as compared with 52 percent of those who received 80 mg of atorvastatin plus placebo. Also, at least 90 percent of the patients who received SAR236553 attained LDL levels of less than 70 mg per deciliter (1.8 mmol per liter), as compared with 17 percent who received 80 mg of atorvastatin plus placebo.

There were no specific safety issues identified, they wrote, adding that larger studies will be necessary to assess the potential risk of adverse effects of the drug.

While the trial results are “preliminary,” the study authors wrote that they suggest that administration of SAR236553 with statins may benefit patients in whom LDL cholesterol has not been reduced to recommended levels. However, they acknowledged that the mechanism underlying this effect is unknown.  

“We found a consistent and fairly robust reduction of nearly one-third in the median lipoprotein(a) level when SAR236553 was added to either 80 mg of atorvastatin or 10 mg of atorvastatin,” Roth et al concluded. “The results of this small study of shorter duration warrant further investigation in large, longer-term studies.”

Sanofi and Regeneron Pharmaceuticals funded the trial.