Sustained efficacy and safety of PCSK9 antibody in HoFH and severe HeFH

Long-Term Evolocumab in Patients With Familial Hypercholesterolemia

Literature - Santos RD, Stein EA, Hovingh GK et al., - J Am Coll Cardiol. 2020; 75(6). DOI: 10.1016/j.jacc.2019.12.020

Introduction and methods

A contemporary registry of patients with heterozygous familial hypercholesterolemia (HeFH) demonstrated that less than 5% of these patients reach the LDL-c target of<70 mg/dL (1.8 mmol/L), despite treatment with maximally tolerated statins plus ezetimibe [1]. An even smaller proportion of homozygous FH (HoFH) patients attains the target of LDL-c <100 mg/dL (2.6 mmol/L). Additional lipid-lowering agents exist, such as lomitapide or mipomersen, but they are associated with tolerability and safety concerns [2,3]. Moreover, these agents have not been approved for use in a pediatric population, which limits their use in HoFH patients, who are at risk from birth. Lipoprotein apheresis can reduce LDL-c levels in these patients, but the effects are transient and the procedure invasive, time-intensive and costly and not available in many countries.

The PCSK9 antibody evolocumab has been approved as an adjunct to diet and maximally tolerated statin therapy in patients with HoFH or HeFH. Interim results on evolocumab treatment in the TAUSSIG study in subjects with HoFH after a mean follow-up of 1.7 years have been published [4]. This article presents the extended safety and efficacy data in subjects with HoFH or severe FH who received open-label evolocumab treatment, with or without apheresis.

Patients were diagnosed based on genotype or clinical criteria (history of untreated LDL-c >500 mg/dL [13 mmol/L] plus xanthoma before the age of 10 years or evidence of HeFH in both parents). Eligible patients were at least 12 years old. They were receiving stable lipid-lowering therapy for at least 4 weeks, with either:

  • baseline LDL-c ≥130 mg/dL (3.4 mmol/L)
  • baseline LDL-c ≥100 mg/dL with a diagnosis of coronary heart disease or risk equivalent
  • undergoing biweekly lipoprotein apheresis

Apheresis status at baseline determined the initial dosing of evolocumab; with patients undergoing apheresis receiving 420 mg Q2W just after apheresis. Patients not on apheresis received evolocumab 420 mg QM. Dosing could be changed at week 12 or 24, at the clinician’s discretion. Patients who showed <5% reduction in LDL-c with maximally suppressed serum free PCSK9 levels, could be withdrawn from the study at week 12 or 24.

The primary objective was to investigate the safety and tolerability of long-term evolocumab treatment, and the secondary to quantify the lipid-lowering efficacy. The study was terminated early, before the planned final assessment at week 260, because the sponsor judged that sufficient information on long-term safety and efficacy in this population had been gathered. Lab results are analysed through week 216.

Main results

  • 106 Of 300 (35%) enrolled patients were diagnosed with HoFH, of whom 14 were younger than 18 years. Median duration of evolocumab treatment was 4.1 years (range: 0.2 to 5.0). At enrolment, 32.1% of HoFH patients received apheresis treatment, among whom 4 of the 14 adolescents. 13.9% of HeFH patients underwent regular apheresis treatment.
  • HoFH and HeFH showed a similar pattern of treatment-emergent adverse events (TEAEs). The most common AEs, with overall frequency ≥10%, were nasopharyngitis, influenza, upper respiratory tract infection, headache, myalgia and diarrhea. This pattern was similar to that observed in previous evolocumab trials.
  • 11 Patients (3.7%) discontinued evolocumab due to TEAE. Injection-site reactions did not lead to treatment discontinuation.
  • Safety findings were similar in those receiving and those not on apheresis, except that injection-site reactions were more common in patients on apheresis (29.4% vs. 5.6% in HoFH [QM] and 18.5% vs. 10.2% in HeFH [Q2W]).
  • 10 HoFH patients showed LDL-c reduction <5% at weeks 12 and 24.
  • HoFH patients showed a mean (SD) LDL-c reduction of 21.2% (25.0) at week 12 and 24.0% (41.3) at week 216. Mean absolute changes were -59.8 (75.3) mg/dL and -74.9 (124.5) mg/dL, respectively. HeFH patients showed a mean (SD) LDL-c reduction of 54.9% (17.4) at week 12 and 47.2% (27.9) at week 216. Mean absolute changes were -104.4 (42.4) mg/dL and -90.6 (61.9) mg/dL, respectively.
  • The annualized event rate of adjudicated CV events was 2.7% (2.8% for HoFH, 2.6% for HeFH).
  • LDL-c reductions were similar for those receiving apheresis and those not receiving it. 3 of 34 HoFH patients could discontinue apheresis, as well as 13 of 27 HeFH patients. 10 Out of 16 patients who stopped apheresis treatment, did so within 90 days after initiation of evolocumab.


This open-label study in patients with HoFH or severe HeFH showed that evolocumab was well-tolerated over a median duration of 4.1 years, the longest follow-up for a PCSK9 inhibitor in this patient population to date. Evolocumab effectively reduced LDL-c, and the effects were maintained during the study period.


1. Perez de Isla L, Alonso R, Watts GF, et al. Attainment of LDL-cholesterol treatment goals in patients with familial hypercholesterolemia: 5- year SAFEHEART registry follow-up. J Am Coll Cardiol 2016;67:1278–85.

2. Cuchel M, Meagher EA, du Toit Theron H, et al. Efficacy and safety of a microsomal triglyceride transfer protein inhibitor in patients with homo- zygous familial hypercholesterolaemia: a single- arm, open-label, phase 3 study. Lancet 2013;381: 40–6.

3. Raal FJ, Santos RD, Blom DJ, et al. Mipo- mersen, an apolipoprotein B synthesis inhibitor, for lowering of LDL cholesterol concentrations in patients with homozygous familial hyper- cholesterolaemia: a randomised, double-blind, placebo-controlled 998–1006.

4. Raal FJ, Hovingh GK, Blom D, et al. Long-term treatment with evolocumab added to conven- tional drug therapy, with or without apheresis, in patients with homozygous familial hyper- cholesterolaemia: an interim subset analysis of the open-label TAUSSIG study. Lancet Diabetes Endocrinol 2017;5:280–90.

Find this article at J Am Coll Cardiol

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