Safety and Efficacy of a Monoclonal Antibody to Proprotein Convertase Subtilisin/Kexin Type 9 Serine Protease, SAR236553/REGN727, in Patients With Primary Hypercholesterolemia Receiving Ongoing Stable Atorvastatin Therapy
What is the effect of proprotein convertase subtilisin/kexin 9 (PCSK9) inhibition on levels of low-density lipoprotein cholesterol (LDL-C) in patients on atorvastatin therapy?
This double-blind, placebo-controlled trial randomized 183 patients with LDL-C ≥100 mg/dl on stable-dose atorvastatin to either subcutaneous placebo every 2 weeks (Q2W); SAR236553 50, 100, or 150 mg Q2W; or SAR236553 200 or 300 mg every 4 weeks (Q4W) alternating with placebo for a total treatment period of 12 weeks.
SAR236553 demonstrated a dose-response relationship with respect to percentage LDL-C lowering for both Q2W and Q4W administration: 40%, 64%, and 72% with 50, 100, and 150 mg Q2W, respectively, and 43% and 48% with 200 and 300 mg Q4W. SAR236553 also reduced non-high-density lipoprotein cholesterol, apolipoprotein B (ApoB), and lipoprotein(a). One patient on SAR236553 experienced a serious adverse event of leukocytoclastic vasculitis.
When added to atorvastatin, PCSK9 inhibition with SAR236553 further reduces LDL-C by 40-72%. These additional reductions are both dose- and dosing frequency-dependent.
PCSK9 is a serine protease involved in LDL receptor degradation. Reduced function mutations of PCSK9 lead to reduced LDL levels and protection from coronary artery disease. Recent studies have indicated that treatment with a monoclonal antibody to PCSK9 leads to highly significant reductions in LDL-C. This phase 2 trial confirms efficacy of this approach towards all ApoB containing lipoproteins, and demonstrates that greater efficacy is achieved with a Q2W subcutaneous dosing strategy. Additional trials are now needed to determine incremental benefit of SAR236553 towards coronary artery disease, as well as long-term safety.
Keywords: Coronary Artery Disease, Lipoprotein(a), Receptors, LDL, Heptanoic Acids, Serine Proteases, Subtilisin, Hypercholesterolemia, Proprotein Convertases, Pyrroles, Cholesterol, Biological Markers
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