Safe LDL-c lowering with PCSK9 antibody in heterozygous FH

ODYSSEY FH I and FH II: 78 week results with alirocumab treatment in 735 patients with heterozygous familial hypercholesterolaemia

Literature - Kastelein JJ et al., Eur Heart J. 2015

Kastelein JJ, Ginsberg HN, Langslet G et al.,
Eur Heart J. 2015 Sep 1. pii: ehv370. [Epub ahead of print]


Heterozygous familial hypercholesterolaemia (HeFH) has a prevalence of 1:200 to 1:500 in the general population [1]. Patients have elevated LDL-c levels. Elevated LDL-c levels since birth are associated with increased CV risk. The widespread use of statins has dampened the increased risk of CV events. Observational studies have shown, however, that about 80% of adult patients with HeFH did not achieve an LDL-c level of <2.5 mmol/L (~100 mg/dL) despite treatment of maximum doses of statins with or without ezetimibe [2,3], while <1.8 mmol/L (<70 mg/dL) is recommended for patients with HeFH and at high CV risk [1]. Inhibition of PCSK9 may further lower LDL-c levels [4].
ODYSSEY FH I and FH II 2 are phase III studies that evaluated the efficacy and safety of the PCSK9-antibody alirocumab in patients with HeFH over 78 weeks, who were not at goal for primary (<2.6 mmol/L) or secondary (<1.8 mmol/L) prevention according to guidelines [5]. Patients were receiving high-dose statin therapy (or lower doses when justified by an investigator), with or without other lipid-lowering therapy. 735 Patients were randomised (2:1) to self-administered alirocumab 75 mg Q2W or placebo.

Main results

  • Mean LDL-c levels decreased from 3.7 at baseline to 2.2 mmol/L after 78 weeks of treatment in FH I (51.8% reduction from baseline vs. placebo), and from 3.5 to 1.8 mmol/L in FH II (52.1% reduction from baseline vs. placebo). Reductions were stable throughout the studies.
  • In FH I, 59.8% of patients on alirocumab achieved LDL-c<1.8 mmol/L (vs. 0.8% at placebo), and 68.2% in FH II (vs. 1.2% on placebo) at week 24, irrespective of prior CV events.
  • Significant reductions as compared with placebo in apolipoprotein B, non-HDL-c, lipoprotein (a) and triglycerides, and increases in HDL-c and apolipoprotein A1 were seen after treatment with alirocumab in both FH I and II.
  • A significant interaction (P=0.0267) was seen between gender and percentage reduction in LDL-c in pooled data from FH I and FH II, with 60.1% seen for males and 50.6% for females.
  • The proportion of patients experiencing treatment emergent adverse events (TEAEs), serious AEs and TEAEs leading to discontinuation were similar between groups in both studies.
  • Injection site reactions were more frequent in patients treated with alirocumab vs. placebo in FH I (12.4 vs. 11.0%) and FH II (11.4 vs. 7.4%). Most were classified as mild, and none of the reactions led to study drug discontinuation.
  • Alanine transaminase levels >3 upper limit of normal were seen in 1.6 and 3.6% of alirocumab-treated patients in FH I and FH II respectively, as compared with 1.2% in both placebo groups.
  • Anti-drug antibody (ADA) responses were seen in 17 (5.5%) patients treated with alirocumab and one (0.6%) with placebo in FH I, and 14 (8.6%) and one (1.3%) respectively in FH II. 


In HeFH patients with inadequately controlled LDL-c levels, self-administered alirocumab yielded sustained LDL-c reduction over 78 weeks and was generally well tolerated. The majority of patients achieved LDL-c<1.8 mmol/L. Subgroup analyses revealed greater percentage reductions in LDL-c in males as compared with females, but the degree of LDL-c lowering was substantial in both sexes. The effect of alirocumab on CV outcomes is currently being assessed in the large ongoing ODYSSEY OUTCOMES trial.

Find this article online at Eur Heart J


1. Nordestgaard BG, Chapman MJ, Humphries SE et al., Familial hypercholesterolaemia is underdiagnosed and undertreated in the general population: guidance for clinicians to prevent coronary heart disease: consensus statement of the European Atherosclerosis Society. Eur Heart J 2013;34:3478–3490a.
2. 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.
3. Pijlman AH, Huijgen R, Verhagen SN et al. Evaluation of cholesterol lowering treatment of patients with familial hypercholesterolemia: a large cross-sectional study in The Netherlands. Atherosclerosis 2010;209:189–194.
4. Seidah NG, Awan Z, Chretien M, et al. PCSK9: a key modulator of cardiovascular health. Circ Res 2014;114:1022–1036.
5. Reiner Z, Catapano AL, De BG, et al. ESC/EAS guidelines for the management of dyslipidaemias: the Task Force for the management of dyslipidaemias of the European Society of Cardiology (ESC) and the European Atherosclerosis Society (EAS). Eur Heart J 2011;32:1769–1818.

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