Corinne Hanotin

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.

OBJECTIVESnThe primary objective of this study was to evaluate the low-density lipoprotein cholesterol (LDL-C)-lowering efficacy of 5 SAR236553/REGN727 (SAR236553) dosing regimens versus placebo at week 12 in patients with LDL-C ≥100 mg/dl on stable atorvastatin therapy. Secondary objectives included evaluation of effects on other lipid parameters and the attainment of LDL-C treatment goals of <100 mg/dl (2.59 mmol/l) and <70 mg/dl (1.81 mmol/l).nnnBACKGROUNDnSerum proprotein convertase subtilisin kexin 9 (PCSK9) binds to low-density lipoprotein receptors, increasing serum LDL-C. SAR236553 is a fully human monoclonal antibody to PCSK9.nnnMETHODSnThis double-blind, parallel-group, placebo-controlled trial randomized 183 patients with LDL-C ≥100 mg/dl (2.59 mmol/l) on stable-dose atorvastatin 10, 20, or 40 mg for ≥6 weeks to: 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.nnnRESULTSnSAR236553 demonstrated a clear 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. LDL-C reduction with placebo at week 12 was 5%. SAR236553 also substantially reduced non-high-density lipoprotein cholesterol, apolipoprotein B, and lipoprotein(a). SAR236553 was generally well tolerated. One patient on SAR236553 experienced a serious adverse event of leukocytoclastic vasculitis.nnnCONCLUSIONSnWhen added to atorvastatin, PCSK9 inhibition with SAR236553 further reduces LDL-C by 40% to 72%. These additional reductions are both dose- and dosing frequency-dependent. (Efficacy and Safety Evaluation of SAR236553 [REGN727] in Patients With Primary Hypercholesterolemia and LDL-cholesterol on Stable Atorvastatin Therapy; NCT01288443).

Atorvastatin with or without an antibody to PCSK9 in primary hypercholesterolemia.

BACKGROUNDnSerum proprotein convertase subtilisin/kexin 9 (PCSK9) binds to low-density lipoprotein (LDL) receptors, increasing the degradation of LDL receptors and reducing the rate at which LDL cholesterol is removed from the circulation. REGN727/SAR236553 (designated here as SAR236553), a fully human PCSK9 monoclonal antibody, increases the recycling of LDL receptors and reduces LDL cholesterol levels.nnnMETHODSnWe performed a phase 2, multicenter, double-blind, placebo-controlled trial involving 92 patients who had LDL cholesterol levels of 100 mg per deciliter (2.6 mmol per liter) or higher after treatment with 10 mg of atorvastatin for at least 7 weeks. Patients were randomly assigned to receive 8 weeks of treatment with 80 mg of atorvastatin daily plus SAR236553 once every 2 weeks, 10 mg of atorvastatin daily plus SAR236553 once every 2 weeks, or 80 mg of atorvastatin daily plus placebo once every 2 weeks and were followed for an additional 8 weeks after treatment.nnnRESULTSnThe least-squares mean (±SE) percent reduction from baseline in LDL cholesterol was 73.2±3.5 with 80 mg of atorvastatin plus SAR236553, as compared with 17.3±3.5 with 80 mg of atorvastatin plus placebo (P<0.001) and 66.2±3.5 with 10 mg of atorvastatin plus SAR236553. All the patients who received SAR236553, as compared with 52% of those who received 80 mg of atorvastatin plus placebo, attained an LDL cholesterol level of less than 100 mg per deciliter, and at least 90% of the patients who received SAR236553, as compared with 17% who received 80 mg of atorvastatin plus placebo, attained LDL cholesterol levels of less than 70 mg per deciliter (1.8 mmol per liter).nnnCONCLUSIONSnIn a randomized trial involving patients with primary hypercholesterolemia, adding SAR236553 to either 10 mg of atorvastatin or 80 mg of atorvastatin resulted in a significantly greater reduction in LDL cholesterol than that attained with 80 mg of atorvastatin alone. (Funded by Sanofi and Regeneron Pharmaceuticals; ClinicalTrials.gov number, NCT01288469.).

Effect of alirocumab on specific lipoprotein non-high-density lipoprotein cholesterol and subfractions as measured by the vertical auto profile method: analysis of 3 randomized trials versus placebo.

BackgroundThe effect of alirocumab on potentially atherogenic lipoprotein subfractions was assessed in a post hoc analysis using the vertical auto profile (VAP) method.MethodsPatients from three Phase II studies with low-density lipoprotein cholesterol (LDL-C) ≥2.59 mmol/L (100 mg/dL) at baseline on stable statin therapy were randomised to receive subcutaneous alirocumab 50–150 mg every 2xa0weeks (Q2W) or 150–300 mg every 4xa0weeks (according to study) or placebo for 8–12xa0weeks. Samples from patients treated with alirocumab 150 mg Q2W (nu2009=u200974; dose common to all three trials) or placebo (nu2009=u200971) were analysed by VAP. Percent change in lipoprotein subfractions with alirocumab vs. placebo was analysed at Weeks 6, 8 or 12 using analysis of covariance.ResultsAlirocumab significantly reduced LDL-C and the cholesterol content of subfractions LDL1, LDL2 and LDL3+4. Significant reductions were also observed in triglycerides, apolipoproteins CII and CIII and the cholesterol content of very low-density, intermediate-density, and remnant lipoproteins.ConclusionAlirocumab achieved reductions across a spectrum of atherogenic lipoproteins in patients receiving background statin therapy.Trial registrationClinicaltrials.gov identifiers: NCT01288443, NCT01288469, NCT01266876

THE EFFECTS OF CO-ADMINISTERING A MONOCLONAL ANTIBODY TO PROPROTEIN CONVERTASE SUBTILISIN/KEXIN TYPE 9 SERINE PROTEASE, REGN727/SAR236553, WITH 10 AND 80 MG ATORVASTATIN COMPARED TO 80 MG ATORVASTATIN ALONE IN PATIENTS WITH PRIMARY HYPERCHOLESTEROLEMIA (NCT: 01288469)

Background: Low-density lipoprotein cholesterol (LDL-C) reduction significantly lowers cardiovascular risk in at-risk patients. Atorvastatin 80 mg/ day (A80) is a proven and highly efficacious LDL-C-lowering treatment. However, many patients do not achieve goals with maximal dose of statin. Proprotein convertase subtilisin/kexin 9 (PCSK9) binds to LDL receptors (LDLRs), increasing LDLR degradation and reducing the rate of LDL-C removal from the circulation. REGN727/SAR236553, a fully human monoclonal antibody, binds to PCSK9, enhances LDLR expression, and further reduces LDL-C levels in statin-treated patients. The primary objective of this study was to assess the LDL-C efficacy of high dose of A (A80) alone compared to both A 10 mg/day (A10) and A80 combined with subcutaneously (sc) administered REGN727/SAR236553.