MONOCLONAL ANTIBODIES TO LOWER LDL

June 12, 2012 (Richmond, Virginia) — The phase 2 trial showing reductions in LDL as large as 72% with the new monoclonal antibody SAR236553/ REGN727 (Sanofi/Regeneron) has been published in the June 19/26, 2012 issue of the Journal of the American College of Cardiology [1]. The study was first presented in March at the American College of Cardiology meeting.

The antibody is directed against the proprotein convertase subtilisin/kexin type 9 (PCSK9) enzyme, which plays a pivotal role in LDL-receptor degradation.

The current phase 2 trial assessed five dose regimens of the antibody in 183 patients with LDL more than >100 mg/dL while also receiving atorvastatin at doses of 10 to 40 mg daily.

The best results were seen with a dose of 150 mg of the antibody given by injection every two weeks, which was associated with a 72% reduction in LDL. "This surpasses that achieved with almost any other lipid-lowering therapy," the authors, led by Dr James McKenney (Virginia Commonwealth University, Richmond), note.

In an accompanying editorial [2], Dr Robert Vogel (University of Colorado, Denver) says that this is a significant study, both because of the magnitude of LDL reduction achieved and the novel pathway used. He notes that statins increase the expression of PCSK9 in a negative feedback mechanism, which limits their effects. Therefore, blocking PCSK9 might be expected to increase the clearance of atherogenic lipoproteins and enhance the efficacy of statins.

Vogel believes PCSK9 inhibition could be used as an adjunct to statin therapy to get patients to LDL goals, but this would be contingent on large safety studies being conducted. Pointing out that it is not known whether an immune response to fully humanized PCSK9 antibody will develop after prolonged treatment, he says the one case of leukocytoclastic vasculitis in this study may or may not have been a consequence of therapy.

Sanofi and Regeneron recently announced that phase 3 studies with SAR236553/ REGN727 are due to start this month in patients with high unmet medical need, such as patients with familial hypercholesterolemia (FH) or elevated cardiovascular risk who cannot reach their LDL-cholesterol goals with current standard therapies.