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

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.

Graphical abstract

Figure 1

LDL Metabolism and Mechanism of ANGPTL3 Inhibition in Patients With HoFH LDL metabolism in (A) patients with HoFH, and (B) mechanism of ANGPTL3 inhibition in patients with HoFH. ANGPTL3 regulates lipoprotein metabolism via inhibition of LPL and EL. LPL is a key enzyme responsible for the catabolism of TGs, converting VLDL into IDL, and further to LDL. In patients with HoFH, that have near or absent LDLR function, hepatic uptake of LDL is impaired resulting in elevated LDL-C. Inhibition of ANGPTL3 by evinacumab leads to extensive remodeling of VLDL, generating lipid-depleted remnant particles, which accelerates their removal from circulation via remnant receptors. This in turn leads to depletion of the LDL precursor pool, thus reducing LDL-C levels. Endothelial lipase is the key mediator of this LDLR-independent pathway. ANGPTL3 = angiopoietin-like 3; EL = endothelial lipase; FFA = free fatty acid; HoFH = homozygous familial hypercholesterolemia; IDL = intermediate-density lipoprotein; LDL = low-density lipoprotein; LDL-C = low-density lipoprotein cholesterol; LDLR = low-density lipoprotein receptor; LPL = lipoprotein lipase; mAb = monoclonal antibody; PL = phospholipase; TG = triglyceride; VLDL = very low-density lipoprotein.

Figure 2

Mean Percent Change in Calculated LDL-C From Baseline Over Time B = baseline; DB = double-blind; DBTP = double-blind treatment period; IV = intravenous; LDL-C = low-density lipoprotein cholesterol; OLTP = open-label treatment period; Q4W = every 4 weeks; SE = standard error.

Figure 3

Percent Change in Lipid Parameters From Baseline to Week 48 Box indicates interquartile range; horizontal line indicates median; vertical line indicates minimum and maximum values. ApoB = apolipoprotein B; DB = double-blind; HDL-C = high-density lipoprotein cholesterol; IV = intravenous; Lp(a) = lipoprotein(a); OLTP = open-label treatment period; Q4W = every 4 weeks; TG = triglyceride.

Figure 4

Proportion of Patients With HoFH Achieving LDL-C Goals Proportion of patients with HoFH achieving LDL-C goals at (A) week 24 (the end of the DBTP) and (B) week 48 (the end of the OLTP). ASCVD = atherosclerotic cardiovascular disease; DB = double-blind; HoFH = homozygous familial hypercholesterolemia; IV = intravenous; LDL-C = low-density lipoprotein cholesterol; OLTP = open-label treatment period; Q4W = every 4 weeks.

Figure 5

Proportion of Patients Who Met Criteria for Lipoprotein Apheresis at Baseline, Week 24, and Week 48 According to US FDA (2019) and Per-Protocol EU Apheresis Criteria DB = double-blind; DBTP = double-blind treatment period; FDA = Food and Drug Administration; IV = intravenous; LDL-C = low-density lipoprotein cholesterol; OLTP = open-label treatment period; Q4W = every 4 weeks.

Central Illustration

ELIPSE HoFH Study: Efficacy and Safety of Evinacumab in Patients With Homozygous Familial Hypercholesterolemia ^aMean percent change reported for ApoB, non-HDL-C, HDL-C, and total cholesterol. Median percent change reported for triglycerides and Lp(a). ApoB = apolipoprotein B; B = baseline; DB = double-blind; DBTP = double-blind treatment period; HDL-C = high-density lipoprotein cholesterol; HoFH = homozygous familial hypercholesteremia; IV = intravenous; LDL-C = low-density lipoprotein cholesterol; Lp(a) = lipoprotein(a); LLT = lipid-lowering therapy; OLTP = open-label treatment period; Q4W = every 4 weeks.