Angiopoietin-like 3 antibody halves LDL-c levels in patients with refractory hypercholesterolemia

Evinacumab in patients with refractory hypercholesterolemia

Literature - Rosenson RS, Burgess LJ, Ebenbichler CF, et al. - N Engl J Med. 2020;383:2307-2319. doi: 10.1056/NEJMoa2031049. Epub 2020 Nov 15.

Introduction and methods

Patients with refractory hypercholesterolemia with or without heterozygous familial hypercholesterolemia (HeFH) have elevated levels of LDL-c despite treatment with a maximum tolerated statin, ezetimibe, and PCSK9 inhibitor. These patients have a high risk for ASCVD.

Functional analyses conducted in a phase 2 proof-of-concept study showed that evinacumab, a human monoclonal antibody directed against angiopoietin-like 3 (ANGPTL3), was effective in lowering the LDL-c concentration independent of the LDL receptor [1-3]. The phase 3 ELIPSE homozygous FH trial has previously shown that evinacumab reduced LDL-c concentrations by ~50% in patients with familiar homozygous hypercholesterolemia [4]. In both trials, evinacumab was given intravenously (IV) at a dose of 15 mg/kg bodyweight over a period of 60 minutes every 4 weeks. However, subcutaneous (SC) administration of evinacumab can be more convenient for patients.

This trial evaluated the efficacy and safety of SC and IV administration of evinacumab compared to placebo in patients with refractory hypercholesterolemia receiving polytherapy for high LDL-c plasma levels.

The trial was a randomized, double-blind, placebo-controlled phase 2 trial. Patients (18-80 years) with primary hypercholesterolemia, defined as heterozygous or non-heterozygous familial hypercholesterolemia, with clinical ASCVD were included in the study. The hypercholesterolemia was refractory to treatment of a maximum tolerated statin and PCSK9 inhibitor, with or without ezetimibe. Refractory hypercholesterolemia was defined as LDL-c levels ≥70 mg/dL (≥1.81 mmol/L) with clinical ASCVD or LDL-c ≥100 mg/dL (≥2.59 mmol/L) without clinical ASCVD. Patients were randomly assigned to SC evinacumab treatment of 450 mg weekly (n=40), 300 mg weekly (n=43), 300 mg every 2 weeks (n=39), or placebo weekly (1:1:1:1) (n=41) or IV evinacumab treatment of 15 mg/kg bodyweight every 4 weeks (n=39), 5 mg/kg bodyweight every 4 weeks (n=36), or placebo every 4 weeks (1:1:1) (n=34). Randomization was stratified according to the presence or absence of familial hypercholesterolemia (2:1) and receipt or nonreceipt to high intensity statin. The primary endpoint was the percent change from baseline in LDL-c concentration at week 16 with evinacumab compared to placebo. Secondary outcomes included lipid levels.

Main results

  • SC evinacumab resulted in a reduction of LDL-c at 16 weeks with a least-squares mean difference of 56.0% (95% CI: 38.3%-73.7%, P<0.001) in the group with 450 mg/week and 52.9% (95% CI: 35.1%-70.7%, P<0.001) in the group receiving 300 mg/week compared to LDL-c concentrations in the placebo group. Patients injected with 300 mg/2 weeks evinacumab had an LDL-c reduction with a least-square mean difference of 38.5% (95% CI: 20.6%-56.5%, P<0.001). The reduction in LDL-c levels was observed in the second week of the trial and was consistent through week 16.
  • IV administration of evinacumab 15 mg/kg/4 weeks at week 16 reduced LDL-c concentrations with least-squares mean difference of 50.5% (95% CI: 32.6%-68.4%, P<0.001) and 24.2% (95% CI: 5.7%-42.6%) in the group with 5 mg/kg/4 weeks compared to placebo. These reduced levels were observed at week 2 and maintained throughout the duration of the trial.
  • HDL-c levels were 27.9%, 30.3%, and 19.5% decreased in patients with SC treatment of evinacumab at a dose of 450 mg/week, 300 mg/week, and 300 mg/2 weeks, respectively, compared to a 1.7% reduction in patients receiving placebo.
  • The reduction in HDL-c after IV administration of evinacumab was 31.4% in the 15 mg/kg bodyweight group and 14.9% in the 5 mg/kg bodyweight group compared to 1.9% reduction in the placebo group.
  • Serious adverse events occurred in 3-16% of patients across the trial groups. There were no significant differences observed between the SC and IV treated groups for serious adverse events, adverse events resulting in treatment discontinuation or adverse events of special interest.

Conclusion

This phase 2 trial showed that ANGPTL3 inhibition by evinacumab in patients with refractory hypercholesterolemia, including heterozygous familial hypercholesterolemia, significantly reduced LDL-c concentrations with ~50% at maximum dose. LDL-c reduction with evinacumab at maximum dose was similar in SC and IV treated patients.

References

1. Gaudet D, Gipe DA, Pordy R, et al. ANGPTL3 inhibition in homozygous familial hypercholesterolemia. N Engl J Med 2017; 377: 296-7.

2. Banerjee P, Chan K-C, Tarabocchia M, et al. Functional analysis of LDLR (low-density lipoprotein receptor) variants in patient lymphocytes to assess the effect of evinacumab in homozygous familial hypercholesterolemia patients with a spectrum of LDLR activity. Arterioscler Thromb Vasc Biol 2019; 39: 2248-60.

3. Gusarova V, Alexa CA, Wang Y, et al. ANGPTL3 blockade with a human monoclonal antibody reduces plasma lipids in dyslipidemic mice and monkeys. J Lipid Res 2015; 56: 1308-17.

4. Raal FJ, Rosenson RS, Reeskamp LF, et al. Evinacumab for homozygous familial hypercholesterolemia. N Engl J Med 2020; 383: 711-20.

Find this article online at N Eng J Med

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