Current and Emerging Treatment
Current and Emerging Treatments: A Look to PCSK9 and Others to Reduce CV Risk
Current guidelines for the management of hypercholesterolemia acknowledge that although most patients achieve sufficient reduction in low-density lipoprotein-cholesterol (LDL-C) levels with high-dose statin therapy, a proportion of patients may require the addition of a nonstatin lipid-lowering therapy.1-4 Such patients include those who have atherosclerotic cardiovascular disease (ASCVD) or are at high risk of developing it, patients with heterozygous familial hypercholesterolemia (FH), people with high baseline LDL-C levels, or individuals who cannot tolerate the statin doses necessary to achieve treatment goals. Proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibition has been generating a significant amount of interest in the cardiovascular (CV) community.5 These monoclonal antibodies (mAbs) increase the number of LDL-C receptors on liver cells, boosting LDL-C clearance from the blood.6-8
Clinical development with fully humanized mAbs has progressed very rapidly.9 The PCSK9 inhibitors evolocumab and alirocumab, which both have US Food and Drug Administration (FDA) approval, are administered as subcutaneous injections every 2 weeks or every 4 weeks.5 In the pivotal phase 3 trials of alirocumab10 and evolocumab,11 both mAbs induced significant decreases in LDL-C (from 45% to 70%) and in other atherogenic parameters (eg, non-high-density lipoprotein-cholesterol [HDL-C], apoB, and lipoprotein [a]) for patients with FH, for high-risk patients not controlled by maximally tolerated statin and other lipid-lowering therapies, for patients with statin intolerance, and also as monotherapy. Alirocumab and evolocumab appeared well tolerated in these phase 3 trials.5
At the time of its approval, alirocumab was indicated for use as adjunct to diet and maximally tolerated statin therapy for the treatment of adults with heterozygous FH or clinical ASCVD who require additional lowering of LDL-C. Evolocumab is indicated to reduce the risk of myocardial infarction (MI), stroke, and coronary revascularization in adults with established ASCVD. It is used as an adjunct to diet, alone or in combination with other lipid-lowering therapies (eg, statins, ezetimibe), for the treatment of adults with primary hyperlipidemia (including heterozygous FH) to reduce LDL-C levels. Evolocumab is also used as an adjunct to other LDL-lowering therapies (eg, statins, ezetimibe, LDL apheresis) in patients with homozygous FH who require additional lowering of LDL-C levels.
In April 2017, the FDA approved alirocumab to prevent heart attack, stroke, and unstable angina requiring hospitalization and as an adjunct to diet, alone or in combination with other lipid-lowering therapies (eg, statins, ezetimibe), for the treatment of adults with primary hyperlipidemia (including heterozygous FH) to reduce LDL-C.
FOURIER, a multinational phase 3, randomized, double-blind, placebo-controlled trial, was designed to evaluate whether treatment with evolocumab in combination with statin therapy reduces CV events compared with placebo plus statin therapy. The primary endpoint was the time to CV death, MI, stroke, hospitalization for unstable angina, or coronary revascularization. The key secondary endpoint was the time to CV death, MI, or stroke.12
The study enrolled eligible patients with high cholesterol (LDL-C ≥70 mg/dL or non-HDL-C ≥100 mg/dL) and clinically evident ASCVD at more than 1300 study locations around the world. Participants were randomized to receive subcutaneous evolocumab 140 mg every two weeks or 420 mg monthly plus an effective statin dose or a subcutaneous placebo every two weeks or monthly plus an effective statin dose. Optimized statin therapy was defined as at least atorvastatin 20 mg or equivalent daily with a recommendation for at least atorvastatin 40 mg or equivalent daily where approved. The study was event-driven and continued until at least 1630 patients experienced a key secondary endpoint.12
At 48 weeks, the least-squares mean percentage reduction in LDL-C levels with evolocumab, as compared with placebo, was 59%, from a median baseline value of 92 mg/dL (2.4 mmol/L) to 30 mg/dL (0.78 mmol/L (P<0.001). Relative to placebo, evolocumab treatment significantly reduced the risk of the primary endpoint (1344 patients [9.8%] vs 1563 patients [11.3%]; hazard ratio [HR] = 0.85; 95% confidence interval [CI], 0.79–0.92; P<0.001) and the key secondary endpoint (816 [5.9%] vs 1013 [7.4%]; HR = 0.80; 95% CI, 0.73–0.88; P<0.001). The results were consistent across key subgroups, including the subgroup of patients in the lowest quartile for baseline LDL-C levels (median, 74 mg/dL [1.9 mmol/L]). There was no significant difference in adverse events between the study groups, including individuals with new-onset diabetes and neurocognitive events. The only exception was injection-site reactions, which were more common with evolocumab (2.1% vs 1.6%).12
ODYSSEY OUTCOMES assessed the effect of alirocumab on the occurrence of major adverse CV events in patients who had experienced an acute coronary syndrome (ACS) before enrolling in the trial and who were already on intensive or maximally tolerated statin treatment. Patients were randomized to receive alirocumab (n = 9462) or a placebo (n = 9462) and were assessed for a median of 2.8 years, with some patients being treated for up to five years. Approximately 90% of patients were on high-intensity statins prior to randomization. The trial was designed to maintain patients’ LDL-C levels between 25–50 mg/dL (0.65–1.29 mmol/L), using two different doses of alirocumab (75 mg and 150 mg). Alirocumab-treated patients started the trial on 75 mg every two weeks and switched to 150 mg every two weeks if their LDL-C levels remained above 50 mg/dL (n = 2615). Some patients who switched to 150 mg returned to 75 mg if their LDL-C fell below 25 mg/dL (n = 805). Patients who experienced two consecutive LDL-C measurements below 15 mg/dL (0.39 mmol/L) while on the 75 mg dose (n = 730) stopped active alirocumab therapy for the remainder of the trial.13
Patients who received alirocumab in the ODYSSEY OUTCOMES trial experienced a 15% reduced risk for major CV events or unstable angina requiring hospitalization (HR = 0.85; 95% CI, 0.78–0.93; P=0.0003). Additionally, alirocumab-treated patients showed a 27% reduced risk of stroke, a 14% reduced risk of non-fatal heart attack, and a 39% reduced risk of unstable angina requiring hospitalization. Furthermore, these patients showed a 15% reduced risk of death from any cause (also called all-cause mortality; HR = 0.85; 95% CI, 0.73–0.98; nominal P=0.026).13
Adverse events were similar between the alirocumab and placebo groups, except for injection-site reactions (alirocumab 3.8%, placebo 2.1%). In ODYSSEY OUTCOMES, the adverse events that occurred in >5% of patients included non-cardiac chest pain (7.0% alirocumab, 6.8% placebo), nasopharyngitis (6.0% alirocumab, 5.6% placebo), and myalgia (5.6% alirocumab, 5.3% placebo).13
Agents under investigation
Agents in phase 3 studies for hypercholesterolemia (as of November 2019) include inclisiran (gene silencing), a small interfering ribonucleic acid (siRNA) to PCSK9, and bempedoic acid (ETC-1002), an adenosine triphosphate (ATP) citrate lyase (ACL) inhibitor.
- Jacobson TA, Ito MK, Maki KC, et al. National Lipid Association recommendations for patient-centered management of dyslipidemia: part 1–full report. J Clin Lipidol. 2015;9:129-169.
- Nordestgaard BG, Chapman MJ, Humphries SE, et al. Familial hypercholesterolaemia is underdiagnosed and undertreated in the general population: guidance for clinicians to prevent coronary heart disease: consensus statement of the European Atherosclerosis Society. Eur Heart J. 2013;34:3478-3490a.
- Reiner Z, Catapano AL, De Backer G, et al; European Association for Cardiovascular Prevention and Rehabilitation. ESC/EAS guidelines for the management of dyslipidaemias: the Task Force for the management of dyslipidaemias of the European Society of Cardiology (ESC) and the European Atherosclerosis Society (EAS). Eur Heart J. 2011;32:1769-1818.
- Stone NJ, Robinson JG, Lichtenstein AH, et al. 2013 ACC/AHA guideline on the treatment of blood cholesterol to reduce atherosclerotic cardiovascular risk in adults: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines. J Am Coll Cardiol. 2014;63:2889-2934.
- Farnier M. Alirocumab for the treatment of hyperlipidemia in high-risk patients: an updated review. Expert Rev Cardiovasc Ther. 2017;15:923-932.
- Zheng C, Khoo C, Furtado J, Sacks FM. Apolipoprotein C-III and the metabolic basis for hypertriglyceridemia and the dense low-density lipoprotein phenotype. Circulation. 2010;121:1722-1734.
- Dadu RT, Ballantyne CM. Lipid lowering with PCSK9 inhibitors. Nat Rev Cardiol. 2014;11:563-575.
- Farnier M. PCSK9: From discovery to therapeutic applications. Arch Cardiovasc Dis. 2014;107:58-66.
- Stein EA, Raal F. Reduction of low-density lipoprotein cholesterol by monoclonal antibody inhibition of PCSK9. Annu Rev Med. 2014;65:417-431.
- Farnier M. An evaluation of alirocumab for the treatment of hypercholesterolemia. Expert Rev Cardiovasc Ther. 2015;13:1307-1323.
- Langslet G, Emery M, Wasserman SM. Evolocumab (AMG 145) for primary hypercholesterolemia. Expert Rev Cardiovasc Ther. 2015;13:477-488.
- Sabatine MS, Giugliano RP, Keech AC, et al; FOURIER Steering Committee and Investigators. Evolocumab and clinical outcomes in patients with cardiovascular disease. N Engl J Med. 2017;376:1713-1722.
- Schwartz GG, Steg PG, Szarek M, et al; ODYSSEY OUTCOMES committees and investigators. Alirocumab and cardiovascular outcomes after acute coronary syndrome. N Engl J Med. 2018;379:2097-2107.