Comprehensive safety analysis of PCSK9 antibody confirms positive benefit-risk profile

Pooled Safety Analysis of Evolocumab in Over 6000 Patients from Double-Blind and Open-label Extension Studies

Literature - Toth PP, Descamps O, Genest J, et al. - Circulation 2017; published online ahead of print


Evolocumab, a PCSK9 inhibitor, significantly reduces LDL-C levels compared with placebo or ezetimibe, in patients with hypercholesterolemia, including those with familial hypercholesterolemia or other high-risk profiles, as well as in statin-intolerant patients, with a favourable safety and tolerability profile [1-5].

In this pooled analysis of the PROFICIO development program, the safety and tolerability of evolocumab was evaluated in more than 6000 patients enrolled in the randomised placebo- or ezetimibe-controlled phase 2 and 3 trials and during the Year 1 standard-of-care (SoC)-controlled portion of the open-label-extension (OLE) trials. The median evolocumab exposures were 2.8 months (phase 2 and 3 trials) and 11.1 months (extension studies).

Main results

  • The overall AE rates were similar between evolocumab and control in the parent studies (51.1% vs 49.6%) and in the Year 1 SoC-controlled period of the OLE studies (70.0% vs 66.0%).
  • Serious AEs were also comparable between evolocumab and control, occurring in 2.8% and 2.1%, during the parent studies and in 7.8% and 7.8%, during the OLE studies.
  • Fatal adverse events occurred in 3 patients (0.08%) on evolocumab and in 1 patient (0.05%) in the control arm of the parent trials and in 4 patients (0.13%) in the evolocumab arm and 6 patients (0.40%) in the SoC arm of the OLE trials.
  • Nasopharyngitis was the most common AE among evolocumab-treated patients during both periods (5.9% in the parent studies and 9.4% in the OLE studies; rates in the control- and SoC-treated groups were 4.8% and 9.5%).
  • Injection-site reactions (ISR) were observed in 3.3% of evolocumab-treated patients and 3.0% of control-treated patients in the parent trials. In the OLE trials, 91.6% of evolocumab-associated ISRs were mild in severity and 8.4% were of moderate severity.
  • Hypersensitivity reactions were observed in 3.2% of evolocumab-treated patients and 2.4% of patients in the control arm of parent trials and in 5.7% of evolocumab-treated patients and 4.3% of SoC-treated patients in the OLE trials.
  • Muscle-related AEs were similar in overall frequency and type of event in the evolocumab, control, or SoC groups.
  • Neurocognitive-related AEs were similar with evolocumab (0.1%) and control (0.3%) in the blinded phase 2 and 3 parent trials. In the OLE studies, the rate of neurocognitive events was 0.6%, and consisted primarily of amnesia and memory impairment in both treatment groups.
  • Laboratory evaluations revealed that CK and liver enzyme elevations were infrequent and similar between groups.
  • No neutralising anti-evolocumab antibodies were detected in the parent or OLE studies.


A pooled analysis of data of more than 6000 patients confirmed the safety and tolerability of evolocumab, which was not associated with a significant risk for hepatotoxicity, muscle-related AEs, or neurocognitive events. These findings support the positive benefit-risk profile of evolocumab.


1. Koren MJ, Lundqvist P, Bolognese M, et al. Anti-PCSK9 monotherapy for hypercholesterolemia: the MENDEL-2 randomized, controlled phase III clinical trial of evolocumab. J Am Coll Cardiol. 2014;63:2531-2540.

2. Koren MJ, Scott R, Kim JB, et al. Efficacy, safety, and tolerability of a monoclonal antibody to proprotein convertase subtilisin/kexin type 9 as monotherapy in patients with hypercholesterolaemia (MENDEL): a randomised, double-blind, placebo-controlled, phase 2 study. Lancet. 2012;380:1995-2006.

3. Raal F, Scott R, Somaratne R, et al. Low density lipoprotein cholesterol-lowering effects of AMG 145, a monoclonal antibody to proprotein convertase subtilisin/kexin type 9 serine protease in patients with heterozygous familial hypercholesterolemia: the Reduction of LDL-C with PCSK9 Inhibition in Heterozygous Familial Hypercholesterolemia Disorder (RUTHERFORD) randomized trial. Circulation. 2012;126:2408-2417.

4. Raal FJ, Stein EA, Dufour R, et al. PCSK9 inhibition with evolocumab ( AMG 145) in heterozygous familial hypercholesterolaemia (RUTHERFORD-2): a randomised, double-blind, placebo-controlled trial. Lancet. 2015;385:331-340.

5. Robinson JG, Nedergaard BS, Rogers WJ, et al. Effect of evolocumab or ezetimibe added to moderate- or high-intensity statin therapy on LDL-C lowering in patients with hypercholesterolemia: the LAPLACE-2 randomized clinical trial. JAMA. 2014;311:1870-1882.

Find this article online at Circulation

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