Patients with heterozygous familial hypercholesterolemia benefit from PCSK9-antibody

Efficacy and safety of the proprotein convertase subtilisin/kexin type 9 monoclonal antibody alirocumab vs placebo with heterozygous familial hypercholesterolemia

Literature - Kastelein JJP, Hovingh GH, Langslet G et al. - J Clin Lipidol, 2017, DOI:


Only approximately 20% of patients with heterozygous familial hypercholesterolemia (HeFH) reach their LDL-C goal of ≤100 mg/dL when treated with statins, ezetimibe, and/or bile acid sequestrants [1,2]. On the other hand, the PCSK9 inhibitor alirocumab resulted in significant LDL-C reductions, both as monotherapy and in combination with statin therapy, in a variety of patient populations in the phase III ODYSSEY program [3-5].

In this analysis of four 78-week placebo-controlled ODYSSEY studies (FH I, FH II, long term and high FH), the LDL-C-lowering efficacy and safety of alirocumab Q2W were evaluated in 1257 HeFH patients on maximally tolerated dose of statins and other lipid-lowering therapies. Patients of the FH I and FH II trials received 75 mg Q2W or 150 mg Q2W and at week 12, some patients increased their dose from 75 to 150 mg Q2W if LDL-c was still ≥70 mg/dL at week 8. Patients of the long term and high FH received 150 mg Q2W from the start.

Main results

  • At week 12, before any dose increase, the mean percent change in LDL-C from baseline was -43.6% for patients on alirocumab 75 mg Q2W and -57.1% for those on 150 mg Q2W (placebo: 15.4% and 11.1%, respectively; all P < 0.0001 vs placebo).
  • At week 12, 41.8% of patients on alirocumab 75 mg had their dose increased to 150 mg (75/150 mg) in a blinded manner.
  • The mean percent change in LDL-C from baseline to week 24 was -48.8% for patients on alirocumab 75/150 mg (placebo: 17.1%) and -55.0% for those on alirocumab 150 mg Q2W (placebo: 11.3%; all P < 0.0001).
  • The on-treatment least squares (LS) mean LDL-C levels were reduced to 69.1 and 75.6 mg/dL at week 24 in the alirocumab 75/150 mg and 150 mg groups, respectively. For weeks 24 to 78, LS mean LDL-C levels were 69.1-75.6 mg/dL (75/150 mg group) and 72.2-82.3 mg/dL (150 mg group).
  • At week 24, most patients receiving alirocumab 75/150 mg (75.3%) or 150 mg (64.5%) achieved LDL-C levels of<70 or <100 mg/dL, depending on their CV risk (all P < 0.0001 vs placebo).
  • Alirocumab 75/150 mg or 150 mg significantly reduced Apo B, non–HDL-C, total cholesterol, Lp(a), and fasting triglycerides levels vs placebo (all P < 0.0001), and significantly increased the HDL-C and Apo A1 levels vs placebo.
  • In a multivariate analysis of two studies, the difference between LDL-C levels at baseline and the treatment goal, was the best predictor for the necessary dose adjustment from 75 mg to 150 mg at week 12 (P < 0.0001). Other predictors included a higher BMI and not taking other lipid-lowering treatments except statins.
  • The rates of treatment-emergent adverse events were similar in alirocumab (80.5%) and placebo-treated patients (83.0%).


In four studies with HeFH patients, alirocumab resulted in significant LDL-C-lowering in most patients who were receiving the maximally tolerated dose of a statin, with or without other lipid-lowering therapies.


1. Huijgen R, Kindt I, Verhoeven SB, et al. Two years after molecular diagnosis of familial hypercholesterolemia: majority on cholesterol lowering treatment but a minority reaches treatment goal. PLoS One. 2010;5:e9220.

2. Beliard S, Carreau V, Carrie A, et al. Improvement in LDL cholesterol levels of patients with familial hypercholesterolemia: can we do better? Analysis of results obtained during the past two decades in 1669 French subjects. Atherosclerosis. 2014;234:136–141.

3. Koren MJ, Roth EM, McKenney JM, et al. Safety and efficacy of alirocumab 150 mg every 2 weeks, a fully human proprotein convertase subtilisin/kexin type 9 monoclonal antibody: A Phase II pooled analysis. Postgrad Med. 2015;127:125–132.

4. Roth EM, Taskinen MR, Ginsberg HN, et al. Monotherapy with the PCSK9 inhibitor alirocumab versus ezetimibe in patients with hypercholesterolemia: results of a 24 week, double-blind, randomized Phase 3 trial. Int J Cardiol. 2014;176:55–61.

5. Cannon CP, Cariou B, Blom D, et al. Efficacy and safety of alirocumab in high cardiovascular risk patients with inadequately controlled hypercholesterolaemia on maximally tolerated doses of statins: the ODYSSEY COMBO II randomized controlled trial. Eur Heart J.2015;36:1186–1194.

Find this article online at J Clin Lipidol

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