By William 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 the first in class injectable proprotein convertase subtilisin kexin type 9 (PCSK9) inhibitor for the treatment of hypercholesterolemia inadequately controlled on standard therapy. Alirocumab is a fully humanized monoclonal antibody produced in Chinese hamster ovary cell culture that targets PCSK9. It is marketed by Regeneron and Sanofi-Aventis as Praluent.
INDICATIONS
Alirocumab is indicated as adjunct to diet and maximally tolerated statin therapy for the treatment of adults with heterozygous familial hypercholesterolemia or clinical atherosclerotic cardiovascular disease (CVD) who require additional lowering of LDL-cholesterol (LDL-C).1
DOSAGE
The initial recommended dose is 75 mg given subcutaneously once every 2 weeks. The dose may be increased to 150 mg every 2 weeks if the response is inadequate.1 Response to treatments should be assessed 4 to 8 weeks after initiation or titration.
Alirocumab is available as 75 mg/mL or 150 mg/mL single-dose pens or syringes.
POTENTIAL ADVANTAGES
Alirocumab provides a new mechanism of action for lowering cholesterol in patients who have not achieved adequate lowering on maximum dose of statins.
POTENTIAL DISADVANTAGES
It remains to be established whether alirocumab has any effect on CVD morbidity or mortality. The long-term safety of alirocumab is not known.
COMMENTS
LDL-C receptors function to remove LDL-C from blood. The density of these receptors is modulated by PCSK9.3 Inhibition of PCSK9 reduces the degradation of these receptors and preserves receptor recycling. As a result, there is greater density of receptors to bind and remove LDL-C. The efficacy of alirocumab was studied in five randomized, placebo-controlled trials in subjects who were receiving a maximally tolerated dose of a statin (with or without other lipid-lowering treatment).1 Two studies involved subjects primarily with clinical atherosclerotic CVD and three studies included subjects with heterozygous familial hypercholesterolemia (HeFH). All studies were at least 52 weeks in duration, with the primary endpoint (mean % change in LDL-C from baseline) checked at week 24. In study 1, patients mainly with CVD (69%) and mean baseline LDL-C of 122 mg/dL were randomized to alirocumab 150 mg every 2 weeks (n = 1553) or placebo (n = 788).1,2 At week 24, the mean difference in reduction of LDL-C between alirocumab and placebo was -58% (95% confidence interval [CI], -61% to -56%). The differences in total-C, non-HDLC, and ApoB were reductions of -36%, -50%, and -51%, respectively. Study two involved CVD subjects (84%) with a mean baseline LDL-C of 102 mg/dL. These subjects were randomized to alirocumab, 75 mg every 2 weeks with the option of titrating to 150 mg (n = 209) or placebo (n = 107). At week 24, the majority of subjects remained on 75 mg (83%). The difference in LDL-C was -43% (95% CI, -50% to -35%). In the two studies with HeFH subjects (45% also with CVD) and mean baseline LDL-C of 141 mg, patients were randomized to 75 mg with the option of titrating to 150 mg (n = 490) or placebo (n = 245). At week 24, 42% were titrated to 150 mg and the difference in LDL-C was -54% (95% CI, -59% to -50%). In the third study in HeFH subjects (50% with CVD) with a mean baseline LDL-C of 198 mg/dL, patients were randomized to alirocumab 150 mg (n = 72) or placebo (n = 35). The LDL-C difference at week 24 was -36% (95% CI, -49% to -24%). The effect was maintained at week 52 in all studies and for 78 weeks in study one.2 Similar reduction in total-C, non-HDL-C, and ApoB were seen across all studies.
The alirocumab group had a higher frequency of injection site reactions (7.2% vs 5.1%) and anti-drug antibodies (4.8% vs 0.6%). A post-hoc analysis suggests that rates of major CVD events (composite endpoint of death from coronary artery disease, non-fatal myocardial infarction (MI), fatal or nonfatal ischemic stroke, or unstable angina requiring hospitalization) were statistically lower in the alirocumab group.2 However, when all adjudicated CVD events were included (congestive heart failure requiring hospitalization and ischemic-driven coronary revascularization), the difference was not statistically significant. A meta-analysis of study level data from 24 randomized, controlled trials involving alirocumab and the other recently approved PCSK9 inhibitor evoluocumab (n = 10,159) suggested reduced all-cause mortality but no change in CVD mortality.4 The wholesale cost for alirocumab is $1120 for a 4-week supply (two doses).
CLINICAL IMPLICATIONS
Alirocumab provides additional lowering of LDL-C in patients who have not been able to achieve adequate control with a statin or other lipid-lowering treatments. The FDA recently approvated a second PCSK9 inhibitor, evolocmab. Preliminary evidence suggests potential benefit in CVD morbidity/mortality, but this will need to be validated for alirocumab in the ODYSSEY Outcomes study of more than 18,000 with recent hospitalizations for ACS.5 The trial started in October 2012 and is expected to be completed by December 2017. The primary endpoint is time from randomization to first occurrence of one of the following clinical events: coronary heart disease death, any non-fatal MI, fatal and non-fatal ischemic stroke, or unstable angina requiring hospitalization. Until the results are available, it is unknown whether alirocumab has an effect on cardiovascular morbidity or mortality.
REFERENCES
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Praluent Prescribing Information. Sanofi-Aventis and Regeneron Pharmaceutical. July 2015.
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Robinson JG, et al. Efficacy and safety of alirocumab in reducing lipids and cardiovascular events. N Engl J Med 2015;372:1489-1499.
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Lambert G, et al. The PCSK9 decade. J Lipid Res 2012;53:2515-2524.
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Navarese 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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ODYSSEY Outcomes. Available at https://clinicaltrials.gov/ct2/show/NCT01663402?term=alirocumab&rank=9. Accessed Sept. 2, 2015.
