PCSK9 Inhibitors

Approximately 73.5 million adults in the United States have a high level of low-density lipoprotein cholesterol (LDL-C). LDL-C is known as “bad” cholesterol, and a high LDL-C level contributes to cardiovascular disease. The use of HMG-CoA reductase inhibitors (statins), diet, and exercise can help to lower cholesterol, but many patients require additional help.

Proprotein convertase subtilisin kexin type 9 (PCSK9) inhibitors are a new class of medications used as add-on therapy to decrease the LDL-C level. The 2 currently approved PCSK9 inhibitors are alirocumab (Praluent by Sanofi) and evolocumab (Repatha by Amgen), approved in July and August 2015, respectively. Another PCSK9 inhibitor, bococizumab (Pfizer), will likely be presented to the FDA in 2016. In addition, Alnylam Pharmaceuticals/The Medicines Company and Eli Lilly have agents in phase 2 trials.^1-3

Therapeutic Use, Dosing, and Administration

Alirocumab and evolocumab are FDA-approved to lower LDL-C levels for heterozygous familial hypercholesterolemia, homozygous familial hypercholesterolemia (evolocumab only), or clinical atherosclerotic cardiovascular disease in patients who require additional lowering of LDL-C. Although these agents effectively lower LDL-C levels, the impact on heart attacks, strokes, and mortality has not been established. These agents should be used in addition to diet and maximally tolerated statin therapy.

Alirocumab and evolocumab are administered by subcutaneous injection every 2 weeks; evolocumab may also be administered every 4 weeks. Most patients obtain sufficient LDL-C reduction using alirocumab 75 mg. However, if more LDL-C lowering is desired, the alirocumab dosage may be increased to 150 mg. Evolocumab may be dosed as either 140 mg every 2 weeks or 420 mg once monthly. Both agents should be stored in the refrigerator but warmed to room temperature before injection, although evolocumab may also be stored at room temperature in the original carton for 30 days. Because these agents are self-administered, patients should receive training on injection technique. Injection sites include the abdomen, thigh, or upper arm, and should be rotated each time.^2,4,5

Pharmacology

Low-density lipoprotein receptors (LDLRs) on hepatocytes are responsible for clearing LDL from the body. PCSK9 is a protein that binds LDLRs to promote their degradation. Alirocumab and evolocumab are antibodies that inhibit PCSK9 and thus prevent LDLR degradation. This action will increase the number of LDLRs and subsequently increase the clearance of LDL, ultimately lowering LDL-C levels.

Alirocumab and evolocumab demonstrate similar pharmacokinetics. Both agents are moderately absorbed (72%-85%) and demonstrate long half-lives (11-20 days). Their volume of distribution is small: 0.04 to 0.05 L/kg for alirocumab, and 3.3 L/kg for evolocumab. Both agents are believed to undergo proteolytic degradation.^2,4,5

Comparative Efficacy

Head-to-head trials have not been conducted with alirocumab and evolocumab, but each has been compared with placebo. The ODYSSEY COMBO I study was a multicenter, randomized, double-blind trial that evaluated alirocumab as add-on therapy to treat patients on statins. Patients were at least 18 years of age (mean: 63 years), were receiving maximally tolerated statin (with or without other therapies), and had either an LDL-C level >70 mg/dL and established cardiovascular disease or an LDL-C level >100 mg/dL with coronary heart disease risk-equivalents. Patients received either alirocumab 75 mg subcutaneously every 2 weeks, followed by 150 mg every 2 weeks after 12 weeks if the LDL-C level was >70 mg/mL (205 patients), or matching placebo (106 patients). The baseline mean LDL-C level was 100.3 mg/dL + 29.7 mg/dL and 104.6 mg/dL + 32.3 mg/dL in the respective groups. The mean percentage change in LDL from baseline to week 24 (primary endpoint) was —48.2% (95% CI, –52.0% to –44.4%) in the alirocumab group and –2.3% (95% CI, –7.6% to 3.1%) in the placebo group (P <.0001).

Evolocumab was evaluated in a multicenter, 52-week, placebo-controlled trial with adults aged 18 to 75 years. During a 4- to 12-week run-in period, patients were assigned to a lipid-lowering regimen based on LDL-C level, previous statin use, and cardiovascular risk, as per the Adult Treatment Panel III of the National Cholesterol Education Program. Regimens included diet alone, diet with 10 mg atorvastatin daily, diet with 80 mg atorvastatin daily, or diet with 80 mg atorvastatin and 10 mg ezetimibe daily. For all 4 groups, patients with LDL levels at least 75 mg/dL and no greater than a fasting triglyceride level of 400 mg/dL were randomized to receive 420 mg evolucumab or placebo subcutaneously every 4 weeks for 48 weeks. The mean LDL-C level at baseline was 104.0 + 21.6 mg/dL for all patients receiving placebo versus 104.2 + 22.1 mg/dL for all patients receiving evolocumab. The least-squares mean percentage change in LDL from baseline in the evolocumab group (taking into account the change in placebo group) was 57.5 + 1.6% at week 12 and 57.0 + 2.1% at week 52 (P <.001). Evolocumab significantly reduced LDL-C levels in each run-in period group versus placebo (P <.001 for all comparisons), with the mean reduction ranging from 48.5% to 61.6%.

Clinical outcomes, including cardiovascular morbidity and mortality, are not currently known. However, trials for these agents, including bococizumab, are underway, with the first expected to be completed in October 2017.^6-8

Adverse Reactions

PCSK9 inhibitors are generally well tolerated, with adverse reactions occurring at rates similar to those for placebo. The most common adverse reactions related to alirocumab and evolocumab, respectively, include nasopharyngitis (11.3%, 10.5%), injection site reactions (7.2%, 5.7%), influenza (5.7%, 7.5%), and upper respiratory tract infection/sinusitis (3.0%, 9.3%). Discontinue use if hypersensitivity occurs.^2,4,5

Drug Interactions

Alirocumab and evolocumab have not been found to induce or inhibit any transporters or enzymes; therefore, drug interactions are not expected.^2,4,5

Safety Issues

Evolocumab may be confused with elotuzumab.

Conclusion

PCSK9 inhibitors have shown efficacy in lowering LDL-C levels and may be a viable option for patients requiring LDL lowering in addition to statin therapy, diet, and exercise. Future trials may help to further elucidate the role of PCSK9 inhibitors on cardiovascular morbidity and mortality.

Jennifer L. Cruz, PharmD, BCPS, is an assistant professor of clinical education at UNC Eshelman School of Pharmacy. Katherine Summers is a PharmD candidate at UNC Eshelman School of Pharmacy.

References

• Cholesterol: high cholesterol facts. Centers for Disease Control and Prevention website. cdc.gov/cholesterol/facts.htm. Updated March 17, 2015. Accessed February 26, 2016.
• Facts & Comparisons eAnswers website. online.factsandcomparisons.com. Updated October 2015. Accessed February 2016.
• Clinical trials.gov website. clinicaltrials.gov. US National Library of Medicine. Accessed March 9, 2016.
• Praluent [package insert]. Bridgewater, NJ: Sanofi-Aventis; 2015.
• Repatha [package insert]. Thousand Oaks, CA: Amgen Inc; 2015.
• Kereiakes DJ, Robinson JG, Cannon CP, et al. Efficacy and safety of the proprotein convertase subtilisin/kexin type 9 inhibitor alirocumab among high cardiovascular risk patients on maximally tolerated statin therapy: the ODYSSEY COMBO I study. Am Heart J. 2015;169(6):906-915. doi: 10.1016/j.ahj.2015.03.004.
• Blom DJ, Hala T, Bolognese M, et al; DESCARTES Investigators. A 52-week placebo-controlled trial of evolocumab in hyperlipidemia. N Engl J Med. 2014;370(19):1809-1819. doi: 10.1056/NEJMoa1316222.
• Mathon J. PCSK9 race: Amgen, Sanofi, and Regeneron first out of the gate, but Pfizer poised to make up lost ground. Informa Business Intelligence website. citeline.com/pcsk9-race-amgen-sanofi-regeneron-first-gate-pfizer-poised-make-lost-ground. Published August 31, 2015. Accessed March 9, 2016.