The Long-Term Efficacy and Safety of Evinacumab in Patients With Homozygous Familial Hypercholesterolemia

Frederick J Raal; Robert S Rosenson; Laurens F Reeskamp; John J P Kastelein; Paolo Rubba; P Barton Duell; Masahiro Koseki; Erik Stroes; Shazia Ali; Poulabi Banerjee; Kuo-Chen Chan; Nagwa Khilla; Jennifer McGinniss; Robert Pordy; Yi Zhang; Daniel Gaudet

doi:10.1016/j.jacadv.2023.100648

The Long-Term Efficacy and Safety of Evinacumab in Patients With Homozygous Familial Hypercholesterolemia

JACC Adv. 2023 Oct 11;2(9):100648. doi: 10.1016/j.jacadv.2023.100648. eCollection 2023 Nov.

Authors

Affiliations

¹ Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, South Africa.
² Cardiometabolics Unit, Zena and Michael A Wiener Cardiovascular Institute, Marie-Josee and Henry R. Kravis Center for Cardiovascular Health, Icahn School of Medicine at Mount Sinai, New York, New York, USA.
³ Department of Vascular Medicine, University of Amsterdam, Amsterdam, The Netherlands.
⁴ Department of Internal Medicine and Surgery, Federico II University, Naples, Italy.
⁵ Knight Cardiovascular Institute and Division of Endocrinology, Diabetes and Clinical Nutrition, Oregon Health & Science University, Portland, Oregon, USA.
⁶ Division of Cardiovascular Medicine, Department of Medicine, Osaka University Graduate School of Medicine, Osaka, Japan.
⁷ Amsterdam Cardiovascular Sciences, Amsterdam, The Netherlands.
⁸ Regeneron Pharmaceuticals, Inc, Tarrytown, New York, USA.
⁹ Clinical Lipidology and Rare Lipid Disorders Unit, Department of Medicine, Université de Montréal Community Gene Medicine Center, Lipid Clinic Chicoutimi Hospital and ECOGENE-21 Clinical and Translational Research Center, Chicoutimi, Quebec, Canada.

Abstract

Background: Homozygous familial hypercholesterolemia (HoFH) is characterized by early-onset atherosclerotic cardiovascular disease due to the high low-density lipoprotein cholesterol (LDL-C) burden. Patients with null-null low-density lipoprotein receptor (LDLR) variants respond poorly, if at all, to statins and proprotein convertase subtilisin/kexin type 9 inhibitors, which act by upregulating LDLR expression. The 24-week double-blind treatment period (DBTP) of the phase 3 ELIPSE HoFH (Evinacumab Lipid Studies in Patients with Homozygous Familial hypercholesterolemia; NCT03399786) study demonstrated significant LDL-C reductions in patients with HoFH; LDL-C reductions were also observed in those with null-null LDLR mutations.

Objectives: The purpose of this study was to evaluate longer-term efficacy and safety of evinacumab in patients with HoFH from the ELIPSE HoFH study.

Methods: Patients with HoFH on stable lipid-lowering therapies (LLTs) ± lipoprotein apheresis and screening LDL-C ≥70 mg/dL who completed the DBTP entered the 24-week open-label treatment period (OLTP) and received intravenous evinacumab 15 mg/kg every 4 weeks. OLTP results were summarized descriptively.

Results: A total of 64 patients completed the DBTP and received open-label evinacumab. Despite multiple LLTs, the mean baseline LDL-C at DBTP entry was 250.5 ± 162.3 mg/dL. From baseline to week 48 (end of OLTP), evinacumab reduced mean LDL-C by 46.3% (mean reduction, 134.3 ± 117.3 mg/dL), with similar mean LDL-C reductions for patients with null-null (47.2%) and non-null variants (45.9%). Adverse events occurred in 47 (73.4%) patients; 4 (6.3%) patients experienced adverse events considered evinacumab-related (drug hypersensitivity, infusion-related reaction and asthenia, generalized pruritis, and muscle spasms).

Conclusions: In patients with HoFH, evinacumab demonstrated substantial and sustained LDL-C reduction regardless of LDLR function, and was generally well tolerated.

Keywords: angiopoietin-like protein 3; clinical trial; evinacumab; homozygous familial hypercholesterolemia; lipids; lipoprotein.