By William T. Elliott, MD, FACP, and James Chan, PharmD, PhD
Dr. Elliott is Chair, Formulary Committee, Northern California Kaiser Permanente; and Assistant Professor of Medicine, University of California, San Francisco. Dr. Chan is Pharmacy Quality and Outcomes Manager, Kaiser Permanente, Oakland, CA
Drs. Elliott and Chan report no financial relationships relevant to this field of study.
The FDA has approved a second parenteral proprotein convertase subtilisin kexin type 9 (PCSK9) inhibitor to treat hypercholesterolemia inadequately treated with standard lipid-lowering therapy. The first agent in this class, alirocumab (Praluent), was approved in July. Similar to alirocumab, evolocumab is a human monoclonal antibody produced in Chinese hamster ovary cells. Evolocumab is marketed by Amgen as Repatha.
INDICATIONS
Evolocumab is indicated as an adjunct to diet and maximally tolerated statin therapy for the treatment of heterozygous familial hypercholesterolemia (HeFH) or clinical atherosclerotic cardiovascular disease (CVD) in patients who require additional lowering of LDL-C.1 It is also indicated for homozygous familial hypercholesterolemia (HoFH) in patients who require additional lowering of LDL-C inadequately lowered with standard therapy, including LDL-apheresis.
DOSAGE
The recommended dose for HeFH or CVD is 140 mg subcutaneously every other week or 420 mg once monthly. For HoFH, the recommended dose is 420 mg once monthly.1 Those with HoFH should have LDL-C levels checked 4 to 8 weeks after initiation of therapy.1 Evolocumab is available in 140 mg/mL prefilled syringes and in a SureClick autoinjector.
POTENTIAL ADVANTAGES
Evolocumab offers a second PCSK9 inhibitor to lower LDL-C. It is approved for monthly administration, while alirocumab is approved for once every 2 weeks administration.
POTENTIAL DISADVANTAGES
Effect on mortality and morbidity remains to be determined. Long-term safety (e.g., cognitive function) also remains to be determined.
COMMENTS
Evolocumab has been evaluated in numerous Phase 2 and Phase 3 studies.2,3 Four studies are representative of the efficacy of the drug, two in subjects with primary hypercholesterolemia and CVD (one 12-week study and one 52-week study), one in HeFH subjects, and one with HoFH subjects.1 In subjects with primary hyperlipidemia with CVD, evolocumab 140 mg every 2 weeks was compared to 420 mg once a month, or placebo when added on to atorvastatin 80 mg, rosuvastatin 40 mg, or simvastatin 40 mg. The mean baseline LDL-C was 108 mg/dL. At 12 weeks, the mean differences in change in LDL-C from baseline were -71% (95% confidence interval [CI], -81% to -61%) for 140 mg once every 2 weeks and -63% (95% CI,-76% to -50%) for 420 mg monthly. Differences for non-HDL-C, ApoB, and total cholesterol were -58%, -55%, -42% and -52%, -49%, -36%, respectively. Effects in LDL-C were maintained for at least 52 weeks.1,4 In the study with HeFH patients on statins with or without other lipid-lowering drugs, mean differences in LDL-C were -61% and -60% for the two doses, respectively. Changes in other lipid levels were similar. In the study with HoFH patients who were not on lipid-apheresis therapy, the 12-week mean difference was -31% for LDL-C. Differences in non-HDL-C, ApoB, and total-C were -28%, -21%, and -25%, respectively. In an open-label, randomized trial, 4465 subjects who completed one of 12 Phase 2 or 3 studies were randomized to 140 mg once every two weeks, 420 mg monthly, or standard therapy alone.3 The primary endpoint was the incidence of adverse events. The secondary endpoint was the change in LDL-C and a prespecified exploratory outcome of the incidence of adjudicated cardiovascular events (death, or coronary events, including myocardial infarction [MI], unstable angina requiring hospitalization, or coronary revascularization), cerebrovascular events (stroke or transient ischemic attack), and heart failure requiring hospitalization. The drug was generally well tolerated, with the frequency of nasopharyngitis, upper respiratory tract infections, influenza, injection site reaction, and neurocognitive events numerically higher with evolocumab. Change in LDL-C was maintained over 48 weeks. Subjects in the evolocumab group had a significantly lower incidence of CV events at 1 year (0.95% vs 2.18%; P = 0.003). The wholesale cost for evolocumab is $1084 for a 4-week treatment (2 doses) and $1627 for a monthly administration.
CLINICAL IMPLICATIONS
Evolocumab is the second PCSK9 inhibitor to be approved after alirocumab. There are currently no direct comparisons between the two drugs. Evolocumab has an advantage over alirocumab in that it may be given monthly. Both drugs showed preliminary evidence of reduction in CV events, but this needs confirmation in a prospective trial. Similar to alirocumab, a large trial evaluating the impact of additional LDL-C lowering and CV events is in progress. The trial is a 5-year study (with the primary outcome of time to CV death, MI, hospitalization for unstable angina, stroke, or coronary revascularization) in more than 27,000 participants with a history of clinically evident CVD and who are at high risk of a recurrent event.5 This study is expected to be completed in February 2018 and will provide definitive assessment of the CV benefit of evolocumab. A subset of this study will also evaluate the effect of the drug on cognitive function.
REFERENCES
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Repatha Prescribing Information. Amgen Inc, August 2015.
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Navareas EP, et al. Effects of proprotein convertase subtilisin/kexin type 9 antibodies in adults with hypercholesterolemia: A systematic review and meta-analysis. Ann Intern Med 2015;163:40-51.
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Sabatine MS, et al. Efficacy and safety of evolocumab in reducing lipids and cardiovascular events. N Engl J Med 2015;372:1500-1509.
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Blom DJ, et al. A 52-week placebo-controlled trial of evolocumab in hyperlipidemia. N Engl J Med 2014;370:1809-1819.
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https://clinicaltrials.gov/ct2/show/NCT01764633?term=evolocumab+fourier&rank=1. Accessed Sept. 20, 2015.
