Coverage Policy Manual
Policy #: 2016011
Category: Pharmacy
Initiated: April 2016
Last Review: April 2018
  PCSK9 INHIBITORS (Evolocumab) (Alirocumab)

The proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors are a novel class of medications to treat hypercholesterolemia. PCSK9 is a regulatory serine protease that increases circulating levels of low-density lipid cholesterol (LDL-C). PCSK9 binding leads to a degradation of LDL receptors and a corresponding inhibition of LDL-C breakdown.  By inhibiting the binding of PCSK9 to LDL receptors, the PCSK9 inhibitors have been shown in clinical trials to induce potent lowering of LDL-C.
In July 2015, the U.S. FDA approved alirocumab (Praluent) injection, the first PCSK9 inhibitor approved for the use in addition to diet and maximally tolerated statin therapy in adult patients with heterozygous familial hypercholesterolemia (HeFH) or patients with clinical atherosclerotic cardiovascular disease such as heart attacks or strokes, who require additional lowering of LDL cholesterol.
In August 2015, the FDA approved a second PCSK9 inhibitor, evolocumab (Repatha™), as an adjunct to diet and maximally tolerated statin therapy for the treatment of adults with heterozygous familial hypercholesterolemia (HeFH) or clinical atherosclerotic cardiovascular disease (ASCVD), who require additional lowering of low-density lipoprotein cholesterol (LDL-C).
Evolocumab (Repatha™) is also indicated as an adjunct to diet and other LDL-lowering therapies (e.g. statins, ezetimibe, LDL apheresis) in patients with homozygous familial hypercholesterolemia (HoFH) who require additional lowering of LDL-C.   

The use of evolocumab and alirocumab is not covered under the medical benefit.  
The use of PCSK9 Inhibitors is addressed under the pharmacy benefit.  

Evolocumab (Repatha)
Koren and colleagues (2014) reported on the results of the MENDEL-2, a randomized controlled, phase III monotherapy trial to compare biweekly and monthly evolocumab with placebo and oral ezetimibe in those with hypercholesterolemia.  The trial included 614 participants with LDL-C levels ≥ 100 and < 190 mg/dl and a 10-year Framingham coronary heart disease risk score of ≤ 10%.  Participants were randomized to receive evolocumab (n=306), ezetimibe (n=154) or placebo (n=155).  At 12 weeks, LDL-C levels had decreased from baseline by an average of 57.0% (95% CI, -59.5% to -54.6%) with biweekly evolocumab versus 0.1% (95% CI, -3.2% to 3.4%) with placebo and 17.8% (95% CI, -21.0% to -14.5%) with ezetimibe (p<0.001).  All individuals in the evolocumab group realized a reduction in baseline LDL-C levels as compared to approximately 92% of the ezetimibe group.  Treatment-emergent adverse event rates were comparable between all groups, 44% for each group.  These adverse events lead to study treatment discontinuation in 7 (2.3%) in the evolocumab group, 5 (3.2%) of the ezetimibe group and 6 (3.9%) of the placebo group.
The randomized controlled, double-blinded GAUSS-2 trial of 307 participants reported by Stroes and colleagues (2014) assessed the effectiveness and safety of evolocumab against ezetimibe in individuals with hypercholesterolemia intolerant to at least two statins.  Participants were randomized to receive evolocumab plus placebo (n=205) or ezetimibe plus placebo (n=102) either biweekly or monthly.  Mean percent reductions from baseline at a 10-12 week mean were 56.1% (95% CI, 59.7% to 52.5%) biweekly and 55.3% (95% CI, 58.3% to 52.3%) monthly as compared to ezetimibe at 36.9% (95% CI, 42.3% to 31.6%) and 38.7% (95% CI, 43.1% to 34.3%), respectively (p<0.001).  After 12 weeks, LDL-C levels in the evolocumab group were reduced by 53%-56% compared to a 37%-39% reduction in the ezetimibe group (p<0.001).  Treatment adverse events leading to study discontinuation was reported in 6 of the evolocumab group and 14 of the ezetimibe group.
In a trial assessing the effect of evolocumab on cardiovascular events, 4465 participants of earlier phase II or III trials were recruited into two open-label, randomized trials (OSLER-1 and OSLER-2).  Eligible individuals included those who had elevated LDL-C levels without history of lipid therapy, those on statin therapy with or without ezetimibe with incomplete response, statin tolerant individuals or those with HeFH with continued LDL-C elevation despite statin therapy.  Participants were randomized to receive evolocumab with standard therapy (n=2976) or standard therapy (n=1489) over a 1 year period.  Data from both trials were combined.  At 12 weeks, the LDL-C level was significantly lower in the evolocumab group versus standard therapy with the LDL-C reduced by 61% (95% CI, 59 to 63; p<0.001).  Serious adverse event occurrences were 7.5% in each group.  The authors noted that the evolocumab group reported more neurocognitive adverse events; however, the rate of these events were low (<1%).  Researchers used the Kaplan–Meier method to estimate the rate of cardiovascular events at 1 year: 0.95% in the evolocumab group verses 2.18% the standard therapy group (Hazard ratio, [HR] 0.47; 95% CI, 0.28- 0.78; p=0.003).  The authors note that while it is plausible to suggest PCSK9 inhibitors will affect cardiovascular outcomes similar to statins as they have the same mechanism of action, currently, there is no data to support this (Sabatine, 2015).
Several ongoing trials are underway to evaluate the long-term efficacy and tolerability of evolocumab.  These studies include the EBBINGHAUS (Evaluating PCSK9 Binding anti-Body Influence oN coGnitive HeAlth in High cardiovascUlar Risk Subjects) study which will assess neurocognitive changes in evolocumab therapy and is estimated to be completed in 2017.  The FOURIER study will address whether the additional evolocumab–related decrease in LDL-C levels will result in a decrease in cardiovascular events in individuals with CVD.
Published clinical trials indicate PCSK9 inhibitors reduce LDL-C by 48% to 66% in individuals at high-risk for CV events (HeFH or non-HeFH) treated with maximum tolerated doses of a statin, with or without other lipid lowering agents; such as ezetimibe (Kereiakes, 2015; Koren, 2015; McKinney, 2012; Raal, 2015; Robinson, 2015; Sabatine, 2015).  PSCK9 inhibitors reduced LDL-C by approximately 30% more than adding ezetimibe to statins (Cannon, 2015; Roth, 2014).  However, data has not been published to demonstrate that use of PSCK9 inhibitors result in greater reduction in CV events compared to statins alone or in combination with other lipid lowering agents. Trials investigating CV outcomes are ongoing with anticipated completion in 2017 and 2018.
There is no consensus on an optimal LDL-C target treatment level.  The authors of the ACC/AHA 2013 Guidelines on the Treatment of Blood Cholesterol removed specific LDL-C treatment target goals from their recommendations for either primary or secondary prevention of ASCVD.  The authors noted that while there is RCT evidence to support that the use of maximally tolerated statin intensity therapy reduced ASCVD events, there were no studies which have assessed specific LDL-C goals against improved ASCVD outcomes.  In addition, the authors noted, "As of yet, there are no data to show that adding a non-statin drug(s) to high-intensity statin therapy will provide incremental ASCVD risk reduction benefit with an acceptable margin of safety."
Alirocumab (Praluent)
The ODYSSEY program is a series of phase III trials designed to evaluate the safety and efficacy of alirocumab in multiple clinical populations.  This program includes 14 multinational trials and more than 23,500 participants (Kastelein, 2014).  The ODYSSEY Outcomes trial, with approximately 18,000 individuals with a recent history of acute myocardial infarction or unstable angina, aims to evaluate the effect of alirocumab in combination with intensive statin therapy, on future cardiovascular events.  The expected completion of ODYSSEY Outcomes trial is 2016 (Schwartz, 2014).  The primary outcome of interest will be the efficacy of alirocumab to reduce the rate cardiovascular events.
In the ODYSSEY MONO trial, the first ODYSSEY study to report results, Roth and colleagues (2014) compared alirocumab to ezetimibe as a monotherapy in individuals with hypercholesterolemia at moderate cardiovascular risk.  Eligible individuals included those with a 1% to 5% - 10 year risk of fatal CD events based on the European Systematic Coronary Risk Estimation.  Participants were randomized to receive alirocumab plus ezetimibe placebo (n=52) or alirocumab placebo plus ezetimibe (n=51).  At week 12, the estimated proportions of those with ≥ 50% LDL-C reduction was 58% in alirocumab arm versus 3% in the ezetimibe arm.  At week 24, least squares mean standard error (SE) LDL-C reductions from baseline were 47% (3) alirocumab versus 16% (3) ezetimibe; with a statistically significant LS mean SE difference between groups of -32% (4) (p<0.0001). The initial dose of alirocumab was 75 mg every 2 weeks.  Per protocol, if the LDL-C level was ≥ 100 mg/dl at week 12, individuals would be up-titrated to 150 mg.  However, due to administrative error, the up-titration was performed on those with LDL-C level ≥ 70 mg/dl, a total of 13 additional individuals.  An additional analysis was performed excluding those individuals.  Results were similar to initial overall analysis.  Rates of participants with at least one treatment-emergent adverse event (TEAE) were comparable between the two groups with 69% in the alirocumab group and 78% in the ezetimibe group.  A total of 5 (10%) individuals experiencing TEAEs in the alirocumab group and 4 (8%) individuals in the ezetimibe group discontinued study treatment.
Robinson and colleagues (2015) assessed 2341 high-risk cardiovascular participants receiving maximal statin therapy with or without other lipid lowering drugs in the ODYSSEY LONG TERM trial.  Eligible individuals included those with HeFH (established by genotyping or clinical criteria), those with a diagnosis of coronary heart disease (CHD) or those CHD risk equivalent individuals with an LDL-C level ≥ 70 mg per deciliter.  Participants were randomized to receive alirocumab or placebo in addition to high-dose or maximally tolerated statin therapy.  The study reported a significant reduction in LDL-C levels from baseline (-61.0% alirocumab versus 0.8% placebo; difference -61.9%; p<0.001).  Rates remained constant over the 78 week study period.  In a post hoc analysis, the alirocumab group rate of major adverse cardiovascular events was lower than the placebo group (1.7% versus 3.3% respectively; p=0.02).  However, the number of cardiovascular events was relatively small and confidence in the robustness of this data is limited.
In the 2015 ODYSSEY COMBO II trial, Cannon and colleagues compared the safety and efficacy of alirocumab to ezetimibe as add-on therapy to maximally tolerated statin therapy in high-risk cardiovascular individuals with inadequately controlled hypercholesterolemia.  Eligible individuals included those with documented cardiovascular disease (CVD) and LDL-C ≥ 70 mg/dL or no documented history of CVD but who were at high cardiovascular risk and had LDL-C ≥ 100 mg/dL.  Participants were randomized to receive subcutaneous (SQ) alirocumab plus oral placebo (n=479) or SQ placebo plus oral ezetimibe (n=241).  At week 24, the differences were significant.  The mean ± standard error (SE) reductions in LDL-C from baseline were -50.6 ± 1.4% in the alirocumab arm and -20.7 ± 1.9% in the ezetimibe arm with a mean SE difference of -29.8 (95% Confidence Interval (CI), -34.4 to -25.3;  p<0.0001).  Mean LDL-C concentrations dropped rapidly in both groups in the first 4 weeks, the alirocumab arm to a greater extent, and remained constant through week 52.  Overall, 71.2% of the alirocumab arm and 67.2% of the ezetimibe arm reported treatment-emergent adverse events (TEAEs) over a mean of 58 ± 19 weeks.  These TEAEs resulted treatment discontinuation in 7.5% of the alirocumab group and 5.4% of the ezetimibe group.  Result will continue to be reported through 104 weeks.  The study did report slightly higher cardiovascular events in the alirocumab group (4.8%) vs. ezetimibe group (3.7%).
In the ODYSSEY COMBO I study, Kereiakes and colleagues (2015) evaluated the efficacy and safety of alirocumab as an add-on therapy in high-risk individuals with inadequately controlled hypercholesterolemia despite maximally tolerated daily statin, with or without other lipid-lowering therapy.  The trial included 316 individuals randomized to receive either alirocumab or a matching placebo in addition to their current therapy.  At week 24, the intention to treat (ITT) analysis results showed an LDL change in the alirocumab group of -48.2% (-52.0% to -44.4%) compared to -2.3% (-7.6% to 3.1%) for the placebo group (p<0.0001).  These results were sustained throughout the 52 week study period.  Reported treatment adverse event rates were similar across both groups.  A total of 6.6% (13/197) of the alirocumab group developed anti-alirocumab antibodies, the presence of these antibodies was transient in 7 of the individuals despite continued treatment.  The presence of these antibodies were not associated with any specific clinical events.

J3490Unclassified drugs
J3590Unclassified biologics

References: Cannon CP, Cariou B, Blom D, et al.(2015) Efficacy and safety of alirocumab in high cardiovascular risk patients with inadequately controlled hypercholesterolaemia on maximally tolerated doses of statins: the ODYSSEY COMBO II randomized controlled trial. Eur Heart J. 2015; 36(19):1186-1194.

Kereiakes DJ, Robinson JG, Cannon CP, et al.(2015) 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.

Koren MJ, Roth EM, McKenney JM, et al.(2015) Safety and efficacy of alirocumab 150 mg every 2 weeks, a fully human proprotein convertase subtilisin/kexin type 9 monoclonal antibody: a Phase II pooled analysis. Postgrad Med. 2015; 127(2):125-132.

Koren MJ., Lundqvist P., Bolognese M., et al.(2014) Anti-PCSK9 monotherapy for hypercholesterolemia: the MENDEL-2 randomized, controlled phase III clinical trial of evolocumab. J Am Coll Cardiol. 2014 Jun 17;63(23):2531-40.

McKenney JM, Koren MJ, Kereiakes DJ, et al.(2012) Safety and efficacy of a monoclonal antibody to proprotein convertase subtilisin/kexin type 9 serine protease, SAR236553/REGN727, in patients with primary hypercholesterolemia receiving ongoing stable atorvastatin therapy. J Am Coll Cardiol. 2012; 59(25):2344-2253.

Raal FJ, Honarpour N, Blom DJ, et al.; TESLA Investigators.(2015) Inhibition of PCSK9 with evolocumab in homozygous familial hypercholesterolaemia (TESLA Part B): a randomised, double-blind, placebo-controlled trial. Lancet. 2015a; 385(9965):341-350.

Robinson JG, Farnier M, Krempf M, et al.(2015) ODYSSEY LONG TERM Investigators. Efficacy and safety of alirocumab in reducing lipids and cardiovascular events. N Engl J Med. 2015; 372(16):1489-1499.

Roth EM, Taskinen MR, Ginsberg HN, et al.(2014) Monotherapy with the PCSK9 inhibitor alirocumab versus ezetimibe in patients with hypercholesterolemia: results of a 24 week, double-blind, randomized Phase 3 trial. Int J Cardiol. 2014; 176(1):55-61.

Sabatine MS., Giugliano RP., Wiviott SD., et al.(2015) Efficacy and Safety of Evolocumab in Reducing Lipids and Cardiovascular Events. N Engl J Med 2015; 372:1500-1509.

Stone NJ., Robinson J., Lichtenstein AH., et al.(2013) ACC/AHA Guideline on the Treatment of Blood Cholesterol to Reduce Atherosclerotic Cardiovascular Risk in Adults. Circulation. 2014;129:S1-S45.

Stroes E., Colquhoun D., Sullivan D., et al.(2014) Anti-PCSK9 antibody effectively lowers cholesterol in patients with statin intolerance: the GAUSS-2 randomized, placebo-controlled phase 3 clinical trial of evolocumab. J Am Coll Cardiol. 2014 Jun 17;63(23):2541-8.

Group specific policy will supersede this policy when applicable. This policy does not apply to the Wal-Mart Associates Group Health Plan participants or to the Tyson Group Health Plan participants.
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