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
Kastelein JJ, Ginsberg HN, Langslet G et al.,
Eur Heart J. 2015 Sep 1. pii: ehv370. [Epub ahead of print]
BackgroundHeterozygous familial hypercholesterolaemia (HeFH) has a prevalence of 1:200 to 1:500 in the general population . 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 . Inhibition of PCSK9 may further lower LDL-c levels .
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 . 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.
- 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.
ConclusionIn 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.
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