Subject: Repatha (evolocumab) Original Effective Date: 09/28/2015. Policy Number: MCP-258 Revision Date(s): 5/4/16; 4/17/17

Transcription

1 Subject: Repatha (evolocumab) Original Effective Date: 09/28/2015 Policy Number: MCP-258 Revision Date(s): 5/4/16; 4/17/17 Review Date(s): 5/4/2016, 4/17/2017, 7/10/2018 DISCLAIMER This Medical Policy is intended to facilitate the Utilization Management process. It expresses Molina's determination as to whether certain services or supplies are medically necessary, experimental, investigational, or cosmetic for purposes of determining appropriateness of payment. The conclusion that a particular service or supply is medically necessary does not constitute a representation or warranty that this service or supply is covered (i.e., will be paid for by Molina) for a particular member. The member's benefit plan determines coverage. Each benefit plan defines which services are covered, which are excluded, and which are subject to dollar caps or other limits. Members and their providers will need to consult the member's benefit plan to determine if there are any exclusion(s) or other benefit limitations applicable to this service or supply. If there is a discrepancy between this policy and a member's plan of benefits, the benefits plan will govern. In addition, coverage may be mandated by applicable legal requirements of a State, the Federal government or CMS for Medicare and Medicaid members. CMS's Coverage Database can be found on the CMS website. The coverage directive(s) and criteria from an existing National Coverage Determination (NCD) or Local Coverage Determination (LCD) will supersede the contents of this Molina Clinical Policy (MCP) document and provide the directive for all Medicare members. SUMMARY OF EVIDENCE/POSITION This policy addresses the coverage of Repatha (evolocumab) for the homozygous familial hypercholesterolemia (HoFH), heterozygous familial hypercholesterolemia (HeFH) or clinical atherosclerotic cardiovascular disease (ASCVD) when appropriate criteria are met. The Proprotein Convertase Subtilisin Kexin type 9 (PCSK9) Inhibitors, alirocumab (Praluent) and evolocumab (Repatha), provide an additional adjunctive therapy for LDL- lowering in the management of hyperlipidemia, and are indicated for a specific subset of patients at high cardiovascular risk. Alirocumab (Praluent) and evolocumab (Repatha) are indicated as adjunct to diet and maximally tolerated statin therapy for the treatment of adults with heterozygous familial hypercholesterolemia or clinical atherosclerotic cardiovascular disease, who require additional lowering of 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 who require additional lowering of LDL-C. The effect of the PCSK9 inhibitors on cardiovascular outcomes is unknown and is stated in both package inserts. According to current guidelines, HMG-CoA reductase inhibitors (statins) are the mainstay of pharmacologic therapy for treating elevated LDL-C for both primary and secondary prevention of atherosclerotic cardiovascular disease. Lifestyle modifications are a critical component of treating elevated LDL-C and should be used in conjunction with pharmacologic therapy. Current guidelines suggest a limited role for PCSK9 inhibitors until outcome data become available, reserving potential use for patients with atherosclerotic cardiovascular disease and elevated LDL-C levels despite maximally tolerated statin therapy or patients with heterozygous familial hypercholesterolemia without atherosclerotic disease but who have elevated LDL-C despite maximally tolerated statin therapy ACC expert consensus decision pathway on the role of non-statin therapies for LDL-cholesterol lowering in the management of atherosclerotic cardiovascular disease risk: a report of the American College of Cardiology Task Force on Clinical Expert Consensus Documents. NLA Expert Panel. National Lipid Association recommendations for patient-centered management of dyslipidemia: Part 2 [published correction appears in J Clin Lipidol. 2016;10(1):211]. Page 1 of 35

2 IMPROVE-IT, an outcomes trial, showed marginal benefit for the non-statin ezetimibe when added to statins. In patients with high cardiovascular risk (post-acute coronary syndrome), with much of the benefit accruing from non-fatal myocardial infarctions in patients where ezetimibe was added on to a moderate intensity simvastatin dose, compared to the group receiving simvastatin alone. The study results showed that ezetimibe lowered LDL by 24% when added to simvastatin and was able to contribute to a 2% absolute risk reduction in the primary endpoint, which included CV death, nonfatal myocardial infarction/stroke, rehospitalization for unstable angina, and coronary revascularization. In comparative studies with ezetimibe, as monotherapy and as add-on therapy to maximally tolerated statin therapy, evolocumab produced greater reductions in LDL-C with comparable adverse effects. It has not been directly compared with alirocumab. Evolocumab has not been proven to reduce cardiovascular morbidity or mortality. Longterm cardiovascular trials for evolocumab are ongoing. [GAUSS trial, 2012; MENDEL trial 2012; MENDEL ; LAPLACE [PubMed ]; GAUSS ; GAUSS ] Significant long-term PCSK9 inhibitor concerns include, but are not limited to, their effect on cognition, potential negative long- term effects of very low LDL levels, ability of patients to adhere to injectable therapies for a silent disease, and significant cost and budget impact over the span of this lifelong diagnosis that may see patients using these agents for 30 to 50 years. PREFERRED PCSK9 Inhibitor: Repatha (evolocumab) While there are no head-to-head trials of the two available PCSK9 inhibitors [Repatha (evolocumab) and Praluent (alirocumab)], the results of efficacy endpoints for both drug were similar in the populations studied that led to FDA approval. In regards to safety, adverse events were similar between alirocumab and evolocumab in the clinical trials. Safety issues for both products include injection site reactions, which are expected, given their subcutaneous delivery route. There are slightly more concerns with regard to antibody development with alirocumab that is not currently found in the evolocumab data. Neutralizing antibodies can significantly impact clinical efficacy, but have not occurred to any noticeable degree in either product when examining the available safety data set. The FDA is requiring long-term monitoring for possible neurocognitive effects given the initial safety data set that was available at the time of review. The labels for both products do not differ significantly in regard to neurocognitive effects. Significant long-term PCSK9 inhibitor concerns include, but are not limited to, their effect on cognition, potential negative long- term effects of very low LDL levels, ability of patients to adhere to injectable therapies for a silent disease, and significant cost and budget impact over the span of this lifelong diagnosis that may see patients using these agents for 30 to 50 years. Therefore when there is no demonstrated difference in safety or efficacy, the most cost-effective therapy provides the best value for Molina Healthcare members and currently, Repatha (evolocumab) is the preferred PCSK9 inhibitors for the indications addressed in this policy. FOURIER Trial The FOURIER trial (N=27,654) found that evolocumab reduced major cardiovascular (CV) events significantly more than placebo. The composite of major CV events included cardiovascular death, myocardial infarction, stroke, hospitalization for unstable angina, and coronary revascularization. All patients received statin therapy throughout the trial, and rates of concurrent ezetimibe use were similar across treatment and placebo arms. This is the first trial to assess health outcomes of evolocumab as the primary efficacy endpoint. The magnitude of risk reduction with respect to major CV events increased over time, from 12% in the first year to 19% in the second year. Individual outcomes of myocardial infarction, stroke, and coronary revascularization were reduced in those treated with evolocumab. However, evolocumab had no observed effect on cardiovascular death or any other individual outcomes. There was no significant difference in the percentage of patients with serious adverse events or those withdrawing due to adverse events. Despite the intense lowering of LDL cholesterol (with average decline of 59% in LDL levels on the drug for 48 weeks), the clinical efficacy appears modest in the high-risk population [the difference in the primary endpoint Page 2 of 35

3 was achieved through the absolute reductions of 1.5% in coronary revascularization (reduced from 7% to 5.5%), 1.2% in MI (from 4.6% to 3.4%), and.4% in stroke (from 1.9% to 1.5%)]. Despite the reduction of the risk of major adverse cardiovascular events, Repatha (evolocumab) failed to show a statistically significant effect on cardiovascular mortality. There was no observed effect on cardiovascular death, and no observed effect on hospitalization for unstable angina. There was no significant difference of death rates between the treatment and placebo groups. Longer-term studies are needed to assess the long-term safety and to confirm whether evolocumab has any impact on cardiovascular mortality on patients followed over a longer time period than the two year duration of the FOURIER trial. The major limitation of the FOURIER trial is that it is relatively short duration of follow-up as compared with that in other lipid-lowering trials, in which follow-up periods have averaged approximately 5 years. The FOURIER trial results also suggests that the translation of reductions in LDL cholesterol levels into cardiovascular clinical benefit requires time; however this may translate to adverse effects as well and the possibility that side effects such as diabetes and neurocognitive dysfunction may take longer than the 2 years (as observed in FOURIER trial) to develop. Therefore, whether cognitive dysfunction may develop during long-term therapy with PCSK9 inhibitors remains to be seen and beyond the 20-month cognitive study, EBBINGHAUS (is a cognitive study of patients enrolled in the FOURIER trial). SUMMARY OF POSITION regarding FOURIER trial In consideration of the current evidence and the results of the FOURIER trial with a modest clinical efficacy in the high-risk population and the lack of impact and significant effect on cardiovascular mortality, Molina Healthcare will not approve prior authorization requests that are referring to FOURIER trial results as a demonstration of medical necessity. Molina Healthcare will continue to apply the coverage criteria (as set in the following section) as per the FDA indication for high-risk members when optimized high-intensity statin therapy is not successful in lowering (LDL) cholesterol levels to goal. FDA INDICATIONS Primary Hyperlipidemia Primary Heterozygous Familial Hypercholesterolemia: Indicated in adults as an adjunct to diet and maximally tolerated statin doses when additional lowering of LDL-C is required. Primary Hyperlipidemia Associated With Clinical Atherosclerotic Cardiovascular Disease: Indicated in adults as an adjunct to diet and maximally tolerated statin doses when additional lowering of LDL-C is required. Homozygous Familial Hypercholesterolemia For the treatment of homozygous familial hypercholesterolemia in adults and pediatric patients 13 years and older in combination with other LDL-lowering therapies when additional lowering of LDL-C is required. Limitations of Use: The effect evolocumab on cardiovascular morbidity and mortality has not been determined. Available as: Repatha 140mg/mL Prefilled Syringe Solution for Injection Repatha SureClick 140mg/mL Autoinjector Solution for Injection Repatha 420mg/3.5mL Pushtronex System (on-body infusor with prefilled cartridge) Page 3 of 35

4 FDA Approved: August 2015 Black Box Warnings: None at the time of this writing CLASSIFICATION: Antilipemic Agent, PCSK9 Inhibitor; Monoclonal Antibody RECOMMENDATIONS/COVERAGE CRITERIA Repatha (evolocumab) may be authorized for members who meet ALL of the following criteria [ALL] 1. Prescriber specialty [ONE] Prescribed by, or in consultation with, a cardiologist, endocrinologist, or physician lipidologist. Submit consultation notes. Lipidologist defined in Definitions section. 2. Diagnosis/Indication [ONE] Clinical documented diagnosis of (includes clinical notes from the member s medical records including any applicable labs and/or tests, supporting the diagnosis) ONE (1) of the following FDA approved indications: [ONE] Homozygous familial hypercholesterolemia (HoFH) as defined by meeting ONE (1) of the following: 9 [ONE: A OR B] A. Genetic confirmation of two (2) mutant alleles at the low density lipoprotein receptor (LDLR), apolipoprotein B (ApoB), protein convertase subtilisin/kexin type 9 (PCSK9) or autosomal recessive hypocholesteremia (ARH) adaptor protein gene locus B. An untreated LDL-C concentration greater than 500 mg/dl (13 mmol/l) or treated LDL-C greater than or equal to 300 mg/dl (7.76 mmol/l) AND ONE (1) of the following: [1 or 2] 1. Cutaneous or tendonous xanthoma before age of 10 years OR 2. Untreated LDL-C levels consistent with heterozygous familial hypercholesterolemia in both parents (greater than190 mg/dl) Required documentation: [ONE] Untreated LDL-C > 500 mg/l AND cutaneous or tendinous xanthoma before age 10 years Untreated LDL-C > 500 mg/l AND both parents with documented elevated LDL-C before lipid-lowering therapy consistent with heterozygous familial hypercholesterolemia (e.g., untreated LDL C > 190 mg/dl) Treated LDL-C 300 mg/dl or non-hdl-c 330 mg/dl AND cutaneous or tendinous xanthoma before age 10 years Treated LDL-C 300 mg/dl or non-hdl-c 330 mg/dl AND both parents with documented elevated LDL-C before lipid-lowering therapy consistent with heterozygous familial hypercholesterolemia (e.g., untreated LDL C > 190 mg/dl) Page 4 of 35

5 Heterozygous Familial Hypercholesterolemia (HeFH) as determined by ONE (1) of the following. a [ONE] Genotype-confirmed: HeFH confirmed by genetic testing. Documentation required a Genetic testing may provide definitive diagnosis in individuals with mutations in any of the following: low-density lipoprotein receptor gene (LDLR), apolipoprotein B gene (APOB), pro-protein convertase subtilisin/kexin 9 gene (PCSK9) Clinical criteria: HeFH confirmed as definite by a score of > 8 using the Dutch Lipid Clinic Network criteria (all points added to calculate the total score must be documented) OR confirmed as definite by the Simon-Broome 3 criteria. Clinical evidence and laboratory results must be submitted to support the diagnosis. In the trials that enrolled patients with HeFH, the diagnosis of HeFH was made either by genotyping or clinical criteria ( definite FH using either the Simon Broome or WHO/Dutch Lipid Network criteria). a Hyperlipidemia with Clinical Atherosclerotic Cardiovascular Disease (ASCVD) The 2013 ACC/AHA Guidelines define clinical ASCVD as having ONE (1) or more of the following: B [ONE] Acute coronary syndromes (ACS) History of myocardial infarction (MI) Stable or unstable angina (UA) Coronary or other arterial revascularization procedure (e.g., PTCA, CABG) Stroke or transient ischemic attack (TIA) Peripheral artery disease (PAD) 3. Age/Gender/Other restrictions [ALL] Member s age in accordance to diagnosis [ONE] Homozygous familial hypercholesterolemia (HoFH):13 years of age or older The safety and effectiveness of evolocumab have not been established in pediatric patients with HoFH who are younger than 13 years old. Heterozygous familial hypercholesterolemia (HeFH) or Primary hypercholesterolemia, Atherosclerotic cardiovascular disease: 18 years of age or older The safety and effectiveness of evolocumab have not been established in pediatric patients with primary hyperlipidemia or HeFH. Secondary causes for dyslipidemia have been excluded or, if appropriate, treated. 17 Submit clinical documentation or labs excluding secondary causes dyslipidemia (i.e., diabetes, hypothyroidism, high triglycerides, obstructive liver disease, chronic renal failure, and drugs that increase LDL-C and decrease HDL-C [progestins, anabolic steroids, and corticosteroids]) Page 5 of 35

6 4. Step/Conservative Therapy/Other condition Requirements [ALL APPLICABLE] Clinical documentation of a therapeutic failure on, intolerance to, or contraindication to high-intensity statin therapy met by ONE (1) of the following [A, B, OR C] A. Adherent* on a maximally tolerated high-intensity statin therapy B (daily dose of atorvastatin 40 to 80 mg or rosuvastatin 20 to 40mg) and Zetia (ezetimibe) 10mg/day *NOTE: Adherence is defined as at least 85% of the time as confirmed by claims history for at least 180 days OR attestation from the Prescriber. Goal levels should be achieved in approximately 6 months, therefore criterion is for 180 days (6 months) according to National Lipid Association algorithm for monitoring and progression of lipidlowering therapy. 6 Per 2016 ACC Expert Consensus on Role of Non-Statin Therapies for LDL-C Lowering for Management of ASCVD Risk: O Ezetimibe is the first non-statin medication that should be considered in most of the patient scenarios, given its safety and tolerability, as well as demonstrated, though modest, efficacy when added to moderate-dose statin in one trial of patients with acute coronary syndrome. O Alirocumab and evolocumab may be considered if the goals of therapy have not been achieved on maximally tolerated statin and ezetimibe in higher-risk patients with clinical ASCVD or familial hypercholesterolemia. Given the lack of long-term safety and efficacy data on these agents, they are not recommended for use in primary prevention patients in the absence of familial hypercholesterolemia. O AND Inability to achieve and maintain an LDL cholesterol level at or below goal (< 100 mg/dl or < 70 mg/dl based on patient risk) with a combination of medications, diet, and exercise by documentation of ONE (1) of the following: [ONE] LDL-C 100 mg/dl for HeFH (evaluated within the last 3 months) OR LDL-C 70 mg/dl for ASCVD OR ASCVD + FH (evaluated within the last 3 months) NOTE: Confirmed by claims history or an attestation from the Prescriber on behalf of the member if no claims history is available (i.e., if member is newly enrolled to Molina Healthcare) Note The 2004 update of the Adult Treatment Panel (ATP) III of the National Cholesterol Education Program (NCEP) established a target goal of < 100 mg/dl for high-risk patients and an optional target of <70 mg/dl for very high-risk patients (Grundy 2004). Refer to Appendix 3 for References/Guidelines supporting criterion goal (< 100 mg/dl or < 70 mg/dl based on patient risk) Goal of cholesterol-lowering treatment in adults with familial hypercholesterolemia: c 50% reduction in low-density lipoprotein cholesterol (LDL-C) 6,c in patients at high risk for cardiovascular disease, more aggressive goals of LDL-C < 100 mg/dl and non-hdl-c < 130 mg/dl may be needed to reduce risk of cardiovascular disease c Individuals with HeFH are typically unable to achieve an LDL-C goal of <100 mg/dl despite the use of multiple cholesterol-lowering therapies (Stone 2014). B In a study of 1249 patients with HeFH treated in lipid clinics in The Netherlands (of which 96% were on statin therapy), only 21% achieved an LDL level <100 mg/dl. An alternative >50% LDL-C reduction was achieved in 49% of patients (Pijlman 2010). 16 Page 6 of 35

7 Has not achieved a 50% reduction in LDL-C from baseline without meeting treatment goal while on maximally tolerated statin therapy B,3,6 Goal of cholesterol-lowering treatment in adults with familial hypercholesterolemia:c 50% reduction in low-density lipoprotein cholesterol (LDL-C) 6,c in patients at high risk for cardiovascular disease, more aggressive goals of LDL-C < 100 mg/dl and non-hdl-c < 130 mg/dl may be needed to reduce risk of cardiovascular disease c High intensity statin therapy is anticipated to lower LDL-C levels by approximately 50% and moderate intensity statin therapy is anticipated to lower LDL-C levels by approximately 30% to < 50% (2013 ACC/AHA). B Refer to Appendix 1 for Statin Intensity Chart The ACC/AHA guidelines define high-intensity statin therapy as a daily dosage that lowers LDL cholesterol approximately 50% and can be achieved with atorvastatin 40 mg to 80 mg per day or rosuvastatin 20 mg to 40 mg per day. B Goal levels should be achieved in approximately 6 months, therefore criterion is for 180 days (6 months) according to National Lipid Association algorithm for monitoring and progression of lipid-lowering therapy. 6 Individuals with HeFH are typically unable to achieve an LDL-C goal of <100 mg/dl despite the use of multiple cholesterol-lowering therapies (Stone 2014). B In a study of 1249 patients with HeFH treated in lipid clinics in The Netherlands (of which 96% were on statin therapy), only 21% achieved an LDL level <100 mg/dl. An alternative >50% LDL-C reduction was achieved in 49% of patients (Pijlman 2010). 16 B. Member has ANY of the following contraindication(s) to statin therapy [ONE] NOTE: Laboratory tests showing evidence of muscle inflammation, alterations of liver function tests from baseline and/or liver damage required. Hypersensitivity to statins or any component of the product Active liver disease CK levels (defined as >10 times the Upper Limit of Normal [ULN]) Myositis or myopathy (elevated CK >10 times ULN) G Rhabdomyolysis is defined as muscle symptoms, very high creatine kinase (10 times ULN), and increased serum creatinine, often with dark urine and myoglobinuria: G CK level >10 ULN or >10,000 IU/L accompanied by significant an elevation in serum creatinine or a requirement for IV hydration therapy (National Lipid Association Statin Safety Assessment Task Force, Am J Cardiology 2006) Unexplained persistent elevation of hepatic transaminases [greater than 3 times the upper limit of normal (ULN) occurring on 2 or more occasions] Women who are pregnant or may become pregnant Breastfeeding C. If a re-trial of statins is not contraindicated (refer to Contraindication criterion below) medical record documentation of TWO (2) statin re-trials with switching to an alternate statin [low- or moderate-intensity statin (e.g., simvastatin, pravastatin)], reducing statin dose, every other day statins required. *EXCEPTIONS to re-trials may be considered by a Molina Medical Director and may require additional supporting documentation, discussion with the prescribing physician, or consultation with a physician affiliated with a transplant center, as deemed necessary by Molina Medical Director. Refer to Appendix 2: Proposed Definitions for Statin-Related Muscle Disease Pravastatin and fluvastatin appear to have much less intrinsic muscle toxicity than other statins (see 'Statin characteristics' above). In patients who have developed statin myopathy (other than Page 7 of 35

8 rhabdomyolysis) on a statin other than pravastatin or fluvastatin, an option is to switch to one of those two medications once symptoms have resolved off statin therapy. H In patients who develop evidence of muscle toxicity while on statin therapy, recommendation is to assess for drug interactions, and if none are noted, we check vitamin D and thyroid function status. H Daily dosing of statins is preferred whenever possible, since daily regimens are the ones that have been studied and proven to reduce clinical events. Clinical experience suggests that alternate-day dosing may improve the tolerability of statins in patients experiencing myalgias, and this strategy can reasonably be tried in patients unable to tolerate daily statin therapy. H Per 2016 ACC Expert Consensus on Role of Non-Statin Therapies for LDL-C Lowering for Management of ASCVD Risk: O The approach to suspected statin intolerance should include temporary discontinuation of statin therapy, lower dosing, re-challenge preferably with 2-3 statins of differing metabolic pathways, and intermittent (1-3x weekly) dosing of long half-life statins. For members not on ezetimibe (Zetia) therapy: [BOTH] Medical record documentation of a therapeutic failure on, intolerance to, or contraindication to ezetimibe (Zetia) ACC/AHA guidelines recognize that maximal statin therapy may be inadequate to provide LDL-C reductions sufficient to reduce ASCVD risk in patients with primary severe elevations of LDL-C. In addition to a maximally tolerated dose of statin, non-statin cholesterol-lowering medications are recommended to lower LDL-C to acceptable levels in such cases (Stone 2014). Ezetimibe (Zetia) is a non-statin included in a number of pivotal trials as a monotherapy comparator, add-on therapy to atorvastatin, and as a non-statin lipid modifying background therapy. If therapeutic failure on, intolerance to, or contraindication to ezetimibe (Zetia): Submit non-statin cholesterol-lowering medications regimen Member will be adherent to Repatha (evolocumab) AND continue adherence to maximally tolerated highintensity statin therapy B AND Zetia (ezetimibe) 10mg/day [as applicable to member therapy] Molina Reviewer: Verify member s medication fill history for compliance on maximally tolerated highintensity statin therapy AND Zetia (ezetimibe) 10mg/day Not prescribed for, or intended for, concurrent therapy with other PCSK9 Inhibitors [e.g. Praluent (alirocumab)] 5. Contraindications/Exclusions/Discontinuations to Repatha (evolocumab) Authorization will not be granted if ANY of the following conditions apply [ANY] Non-FDA approved indications Hypersensitivity reactions, including rash or urticaria, have been reported; discontinue use if serious allergic reactions occur NOTE: For members with a documented latex allergy, Repatha Pushtronex once monthly may be utilized instead of Repatha (evolocumab) syringe or autoinjector Concurrent use of other PCSK9 inhibitors (e.g. evolocumab) Concurrent therapy with of other PCSK9 inhibitors (e.g. evolocumab) has not been studied. Concurrent use with Juxtapid (lomitapide), Kynamro (mipomersen) Concurrent therapy with Juxtapid (lomitapide) or Kynamro (mipomersen) has not been studied. Page 8 of 35

9 6. Labs/Reports/Documentation required [ALL] All documentation for determination of medical necessity must be submitted for review. Prescriber to submit medical records and specific labs, chart notes, and documentation as indicated in the criteria above. Letters of support and/or explanation are often useful, but are not sufficient documentation unless ALL specific information required by this MCP is included. Baseline LDL at the start of Repatha (evolocumab) therapy. Laboratory documentation required. Page 9 of 35

10 CONTINUATION OF THERAPY Repatha (evolocumab) may be authorized for continuation of therapy if meet ALL of the following criteria are met: [ALL] 1. Initial Coverage Criteria Currently meets ALL initial coverage criteria Documented contraindication(s) to statin therapy [as documented in #5 in the Initial Coverage Criteria ] OR continues to receive ONE (1) of the following: [ONE] 2. Compliance [ALL] High-intensity statin [i.e. atorvastatin, Crestor (rosuvastatin)] at maximally tolerated dose For members with documented intolerance to high-intensity statin: Low- or moderate-intensity statin (e.g. simvastatin, pravastatin) at maximally tolerated dose or alternative lower dose therapy of statins (i.e. reduction in dose, every other day dosing) Continued adherence to maximally tolerated statin dose established prior to Repatha (evolocumab) AND Maximally tolerated high-intensity statin therapy B NOTE: Statin adherence is required to avoid PCSK9 use as an alternative to statin non-adherence. Adherence to standard therapy is defined as filling 85% of therapy as prescribed in the recent authorization period. MOLINA REVIEWER: Verify member s medication fill history for compliance and adherence (defined as filling 85% of the therapy at an FDA-approved dose in the recent authorization period). Therapy may be discontinued due to poor adherence upon discussion of the Molina Medical Director and Prescriber. Tolerance to therapy [Member should not experience intolerable adverse effect(s) while on prescribed regimen] 3. Labs/Reports/Documentation required [ALL APPLICABLE] Documentation of a recent LDL level (since the previous authorization and within the recent 3 months) demonstrating a clinically significant response to treatment [demonstrated a percent change of 45% in LDL- C from baseline (LDL-C before PCSK9 therapy)] RATIONALE of criterion: The following is an extrapolation from the Praluent trial for the rationale of this criterion Measure LDL-C levels within 4 to 8 weeks of initiating or titrating Praluent to assess response and adjust the dose, if needed. a In Study 2 of pivotal trial, at week 12, the mean percent change from baseline in LDL-C was -45% with Praluent compared to 1% with placebo, and the treatment difference between Praluent (alirocumab) 75mg Q2W and placebo in mean LDL-C percent change was -46% (95% CI: -53%, -39%). Page 10 of 35

11 AHA/ACC guidelines note that with high-intensity statin therapy, LDL-C reductions 50% can be anticipated and used as an indicator of therapeutic response. B While clinical trials of alirocumab have shown decreases of LDL-C of 36-61% from baseline, it is difficult to assign a threshold value for the clinical significance of treatment specific to this drug. Indeed, recent guidelines for the treatment of blood lipids have moved away from the use of targeted levels of cholesterol reduction. Published literature describing non-responders to alirocumab was not found. [AMR Review 2015] 4. Discontinuation of Treatment [ANY] Discontinue treatment if ANY of the following conditions applies: [ANY] Intolerable adverse effects or drug toxicity Persistent and uncorrectable problems with adherence to treatment Poor response to treatment as evidenced by physical findings and/or clinical symptoms Contraindications/Exclusions to therapy [ANY] Non-FDA approved indications Serious hypersensitivity to evolocumab or any component of the formulation NOTE: For members with a documented latex allergy, Repatha Pushtronex once monthly may be utilized instead of Repatha (evolocumab) syringe or autoinjector Concurrent use of other PCSK9 inhibitors [e.g. Praluent (alirocumab)] Concurrent therapy with of other PCSK9 inhibitors has not been studied. Concurrent use with Juxtapid (lomitapide), Kynamro (mipomersen) Concurrent therapy with Juxtapid (lomitapide) or Kynamro (mipomersen) has not been studied. Page 11 of 35

12 ADMINISTRATION, QUANTITY LIMITATIONS, AND AUTHORIZATION PERIOD 1. Recommended Dosage [ALL] The recommended subcutaneous (SQ) dosage of Repatha (evolocumab) in patients with: [ONE] Familial hypercholesterolemia - homozygous, In combination with other lipid-lowering therapies: 420mg SQ once monthly Primary heterozygous familial hypercholesterolemia, In combination with a statin: 140mg SQ every 2 weeks OR 420mg SQ once monthly Primary hypercholesterolemia, Atherosclerotic cardiovascular disease; in combination with a statin: 140mg SQ every 2 weeks OR 420mg SQ once monthly 2. Authorization Limit [ALL] Maximum Dosage Limits: 420 mg/month subcutaneously Repatha 140mg/mL Prefilled Syringe: 3mL per month (3 syringes per 30 days) Repatha SureClick 140mg/mL Autoinjector: 3mL per month (3 syringes per 30 days) Repatha 420mg/3.5mL Pushtronex System: 3.5mL per month (1 syringes per 30 days) Dispensing limit: Only a 1-month supply may be dispensed at a time a-e Duration of initial authorization: 3 months Continuation of treatment: Re-authorization for continuation of treatment is required every 6 months to determine continued need based on documented positive clinical response In patients with HoFH, measure LDL-C levels 4 to 8 weeks after starting evolocumab, since response to therapy will depend on the degree of LDL-receptor function. Duration of continuation of treatment: May be authorized up to 6 months at a time. 3. Route of Administration [ALL] Repatha (evolocumab) is considered a self-administered medication a If member meets all criteria and approval for therapy is granted, medication will be dispensed by a specialty pharmacy vendor at the discretion of Molina Healthcare. Self-administered medications may not be dispensed for self-administration and billed through the medical benefit by a provider; they must be dispensed through a participating pharmacy. Page 12 of 35

13 COVERAGE EXCLUSIONS Repatha (evolocumab) is considered experimental and investigational for indications that are not FDA-approved or included in Coverage Criteria and is not a covered benefit addressed in this particular policy. This subject to change based on research and medical literature, or at the discretion of Molina Healthcare. Pharmaceutical samples: The use of pharmaceutical samples (from the prescriber or manufacturer assistance program) will not be considered when evaluating the medical condition, prior prescription history, or as continuation of therapy. SUMMARY OF EVIDENCE Coronary heart disease (CHD) is a major cause of death in the United States. A Elevated LDL-C is recognized as a major risk factor for cardiovascular disease (CVD). A Approximately one-third of American adults have cardiovascular disease (CVD), making it the most common cause of death in the United States. 20 Reduction of LDL-C has been shown to reduce cardiovascular morbidity and mortality. A According to the Centers for Disease Control and Prevention, more than 71 million American adults (33.5%) have high LDL-C. A Familial hypercholesterolemia (FH) is an inherited condition that causes severe increases in total cholesterol and LDL-C. Individuals with FH are at a high risk for premature coronary artery disease. Homozygous FH is the more severe form of the disease affecting approximately 1 in 1,000,000 people while heterozygous FH affects approximately 1 in 500 people. Homozygous familial hypercholesterolemia (HoFH) HoFH is rare, genetic disease caused primarily by homozygous mutations in the low-density lipoprotein receptor (LDLR) gene, but also by mutations in apolipoprotein B (Apo-B), proprotein convertase subtilisin/kexin 9 (PCSK9), and (more rarely) autosomal recessive hypercholesterolemia (ARH) adaptor protein.1 Individuals with HoFH present with severe hypercholesterolemia associated with accumulation of low-density lipoprotein cholesterol (LDL-C) in plasma, tendons, and skin, and exhibit accelerated atherosclerosis, particularly coronary heart disease within the first two decades of life. 9,18,19 HoFH is characterized by severely elevated cholesterol levels and an increased risk for early onset coronary heart disease. LDL levels can range from 300 to over 1000 mg/dl. If not treated, affected patients often die in early adulthood. Current treatment options for HoFH include evolocumab, ezetimibe (Zetia), lomitapide (Juxtapid), mipomersen (Kynamro), traditional lipid-lowering medications (such as niacin, bile acid sequestrants, fibrates, and omega-3 fatty L, M, acids) and LDL-apheresis. These guidelines have not been updated since the approval of lomitapide and mipomersen. N Heterozygous familial hypercholesterolemia (HeFH) HeFH is an inherited genetic disorder of lipid metabolism that affects about 1 in every 300 to 500 people. Based on that estimate there may be over 600,000 people with HeFH in the US. HeFH is characterized by lifelong elevated LDL-C levels due to defective LDL receptors that have reduced capacity for LDL-C uptake (Hopkins 2011). Compared with unaffected siblings, people with HeFH have approximately 2-fold higher LDL-C levels. Adult LDL-C levels are approximately 200 to 400 mg/dl (Reiner 2011). The goal of treatment for FH is to reduce the risk of coronary heart disease (CHD) or risk of a CHD equivalent condition (e.g. carotid artery disease, diabetes, peripheral arterial disease, or abdominal aortic aneurysm). 11 Hypercholesterolemia is a major public health issue in most countries as it contributes to the risk of developing cardiovascular disease and is the leading cause of death among men and women. C,D Treatment of high cholesterol is aimed at lowering a patient s LDL-C to reduce their risk of cardiovascular events, such as heart attacks and strokes. C,B Page 13 of 35

14 HMG-CoA reductase inhibitors (statins) Statins are a class of drugs that lower LDL through inhibition of HMG-CoA, an enzyme regulating the early and ratelimiting step in cholesterol biosynthesis that ultimately results in an increase in LDL receptors to increase the uptake of plasma LDL lipoproteins. Statins are a cornerstone of therapy for hyperlipidemia F and have demonstrated effectiveness in considerable reduction of LDL-C levels. However, some patients do not respond adequately to statins, and others are unable to tolerate statin therapy due to side effects. Many patients continue to have cardiovascular events. 1 Additionally, it is estimated that five to 15 percent of patients are statin intolerant, primarily due to muscle-related side effects. 2 Statins include atorvastatin, pravastatin, simvastatin, fluvastatin, lovastatin, rosuvastatin, and pitavastatin. Existing nonstatin therapies, as compared with statin therapy, do not provide acceptable ASCVD risk-reduction benefits relative to their potential for adverse effects in the routine prevention of ASCVD (2013 ACC/AHA). B Existing non-statin therapies include niacin, bile acid sequestrants, fibrates, omega-3 fatty acids, and cholesterol absorption inhibitors. Therefore, novel non-statin, LDL-C-lowering therapies such as PCSK9 inhibitors are expected to meet this need. PREFERRED: STATINS have been proven to reduce cardiovascular events and mortality, therefore statins are the preferred treatment to reduce the risk ASCVD and recommended as the first-line treatment by multiple guidelines. Based on guidelines from the American College of Cardiology and American Heart Association (ACC/AHA), statins are the standard of care for most patients due to extensive evidence that statins significantly reduce the risk of major coronary heart disease, strokes, revascularizations, and death. The ACC/AHA guidelines emphasize the appropriate intensity of statin therapy to reduce CV risk in patients who will benefit. No statin was specified as the preferred, but instead, statins with related doses are categorized as highintensity (lowers LDL-C by approximately 50%), moderate-intensity (lowers LDL-C by approximately 30% to < 50%), and low-intensity (lowers LDL-C by < 30%). Only atorvastatin and Crestor (rosuvastatin tablets) are categorized as high-intensity statin therapy, which is recommended for many patient populations at high CV risk. ACA/AHA guidelines provide treatment recommendations for patients with HeFH; however guidelines specifically for HeFH have been produced by the National Lipid Association (NLA) and European Atherosclerosis Society (EAS). National Lipid Association (NLA) treatment guidelines for HeFH recommend targeting a 50% reduction in LDL-C from baseline; however higher risk patients may require a more aggressive treatment goal of less than 100 mg/dl. Patients will generally require treatment with multiple agents to achieve LDL-C goals. PROPROTEIN CONVERTASE SUBTILISIN/KEXIN TYPE 9 (PCSK9) INHIBITOR PCSK9 is a circulating protein that binds to the LDL receptor and targets it for degradation. PCSK9 binds to the lowdensity lipoprotein receptors (LDLR) on the surface of hepatocytes to promote LDLR degradation within the liver. LDLR is the primary receptor that clears circulating LDL, therefore the decrease in LDLR levels by PCSK9 results in higher blood levels of LDL-C. By inhibiting the binding of PCSK9 to LDLR, alirocumab increases the number of LDLRs available to clear LDL, thereby lowering LDL-C levels. Repatha (evolocumab) Repatha (evolocumab) is a human monoclonal IgG2 directed against human proprotein convertase subtilisin kexin 9 (PCSK9). Evolocumab binds to PCSK9 and inhibits circulating PCSK9 from binding to the low density lipoprotein (LDL) receptor (LDLR), preventing PCSK9-mediated LDLR degradation and permitting LDLR to recycle back to the liver cell surface. By inhibiting the binding of PCSK9 to LDLR, Evolocumab increases the number of LDLRs available to clear LDL from the blood, thereby lowering LDL-C levels. Repatha (evolocumab) was approved by the U.S. Food and Drug Administration on August 2015 August 31, 2015 for the treatment of patients who require additional lowering of low-density lipoprotein cholesterol level (LDL-C), specifically: adults with heterozygous familial hypercholesterolemia (HeFH) or clinical atherosclerotic cardiovascular disease (ASCVD), as an adjunct to diet and maximally tolerated statin therapy patients with homozygous familial hypercholesterolemia (HoFH), as an adjunct to diet and other LDL-lowering therapies (e.g., statins, ezetimibe, LDL apheresis) Page 14 of 35

15 Efficacy a In Phase 3 trials, adding Repatha to background lipid-lowering therapy that included statins resulted in intensive reductions in LDL-C levels with favorable effects on other lipid parameters. In patients with clinical ASCVD or HeFH, Repatha reduced LDL-C by approximately 54 to 77 percent compared with placebo. In a pivotal Phase 3 trial, 90 percent of clinical ASCVD patients who received Repatha in addition to maximum doses of statins achieved a LDL-C level less than 70 mg/dl. In patients with HoFH, Repatha reduced LDL-C by approximately 30 percent compared with placebo. Safety a Repatha is generally well-tolerated with an established safety profile. The most common adverse reactions that occurred in greater than 5 percent of the Repatha group, and more frequently than in the placebo group, were nasopharyngitis, upper respiratory tract infection, influenza, back pain and injection site reactions. Although, evolocumab appears to be well tolerated with minimal serious adverse events, there is limited long-terms safety experience. Adverse events of special interest include: the long-term safety of prolonged periods of very low LDL-C reductions are unknown, the effect of PCSK9 inhibitors on neurocognitive events and new-onset diabetes. Pivotal Trials Evolocumab is in phase 3 studies evaluating evolocumab in multiple patient populations, including in combination with statins in patients with hyperlipidemia (LAPLACE-2), in patients with hyperlipidemia who cannot tolerate statins (GAUSS-2), in patients with hyperlipidemia at risk for cardiovascular disease (DESCARTES), as monotherapy in patients with hyperlipidemia (MENDEL-2), and in patients with heterozygous (RUTHERFORD-2) and homozygous (TESLA and TAUSSIG) familial hypercholesterolemia. The evidence supporting evolocumab demonstrates substantial reductions in LDL-C; however, its effect on clinical outcomes such as reductions in mortality, heart attacks, and stroke is uncertain. The primary endpoint in the majority of evolocumab phase 3 studies was percent change in LDL-C. FDA approval of Repatha was based on the following trials: a-e Primary Hyperlipidemia in Patients with Clinical Atherosclerotic Cardiovascular Disease: Study 1 was a multicenter, double-blind, randomized controlled trial in which patients were initially randomized to an open-label specific statin regimen for a 4-week lipid stabilization period followed by random assignment to subcutaneous injections of Repatha 140 mg every 2 weeks, Repatha 420 mg once monthly, or placebo for 12 weeks. The trial included 296 patients with atherosclerotic CVD who received Repatha or placebo as add-on therapy to daily doses of atorvastatin 80 mg, rosuvastatin 40 mg, or simvastatin 40 mg. After 4 weeks of statin therapy, the mean baseline LDL-C was 108 mg/dl. In these patients with atherosclerotic CVD who were on maximum-dose statin therapy, the difference between Repatha and placebo in mean percent change in LDL-C from baseline to Week 12 was -71% (p < ) and -63% (p ) for the 140 mg every 2 weeks and 420 mg once monthly dosages, respectively. Study 2 was a multicenter, double-blind, randomized, placebo-controlled, 52-week trial that included 139 patients with atherosclerotic CVD who received protocol-determined background lipid-lowering therapy of atorvastatin 80 mg daily with or without ezetimibe 10 mg daily. After stabilization on background therapy, patients were randomly assigned to the addition of placebo or Repatha 420 mg administered subcutaneously once monthly. After stabilization on the assigned background therapy, the mean baseline LDL-C was 105 mg/dl. In these patients with atherosclerotic CVD on maximumdose atorvastatin therapy with or without ezetimibe, the difference between Repatha 420 mg once monthly and placebo in mean percent change in LDL-C from baseline to Week 52 was -54 % (p ). Heterozygous Familial Hypercholesterolemia (HeFH): Study 3 was a multicenter, double-blind, randomized, placebo-controlled, 12-week trial in 329 patients with heterozygous familial hypercholesterolemia (HeFH) on statins with or without other lipid-lowering therapies. Patients were randomized Page 15 of 35

16 to receive subcutaneous injections of Repatha 140 mg every two weeks, 420 mg once monthly, or placebo. HeFH was diagnosed by the Simon Broome criteria (1991). In Study 3, 38% of patients had clinical atherosclerotic cardiovascular disease. The average LDL-C at baseline was 156 mg/dl with 76% of the patients on high- intensity statin therapy. In these patients with HeFH on statins with or without other lipid lowering therapies, the differences between Repatha and placebo in mean percent change in LDL-C from baseline to Week 12 was -61% (p < ) and -60% (p < ) for the 140 mg every 2 weeks and 420 mg once monthly dosages, respectively. Homozygous Familial Hypercholesterolemia: Study 4 was a multicenter, double-blind, randomized, placebo-controlled, 12-week trial in 49 patients (not on lipidapheresis therapy) with homozygous familial hypercholesterolemia (HoFH). In this trial, 33 patients received subcutaneous injections of 420 mg of Repatha once monthly and 16 patients received placebo as an adjunct to other lipidlowering therapies (e.g., statins, ezetimibe). The trial included 10 adolescents (ages 13 to 17 years), 7 of whom received Repatha. The mean LDL-C at baseline was 349 mg/dl with all patients on statins (atorvastatin or rosuvastatin) and 92% on ezetimibe. The diagnosis of HoFH was made by genetic confirmation or a clinical diagnosis based on a history of an untreated LDL-C concentration > 500 mg/dl together with either xanthoma before 10 years of age or evidence of HeFH in both parents. In these patients with HoFH, the difference between Repatha and placebo in mean percent change in LDL-C from baseline to Week 12 was -31% (p < ). TESLA (Trial Evaluating PCSK9 Antibody in Subjects with LDL Receptor Abnormalities) is a two-part Phase 2/3 trial designed to evaluate the safety, tolerability and efficacy of evolocumab. TESLA Part B Homozygous familial hypercholesterolemia (HoFH) Primary Endpoint: Percent change from baseline in LDL-C after 12 weeks of treatment Patient Population: Subjects at least 12 years of age with homozygous familial hypercholesterolemia diagnosed by genetic analysis or clinical criteria and on baseline lipid-lowering therapy Number of enrollees: 50 Duration of follow-up: 12 weeks Mean patient age: 31 years Percentage female: 49% Exclusions: Lipoprotein apheresis within the previous 8 weeks Use of mipomersen or lomitapide within the last 5 months Primary Endpoints: Percent change in LDL from baseline at 12 weeks Secondary Endpoints: Absolute change in LDL from baseline at 12 weeks Proportion of patients with LDL <70 mg/dl Change in other lipoproteins from baseline The Phase 3 12-week, double-blind, randomized, placebo-controlled, multicenter part of the TESLA trial (TESLA Part B) evaluated evolocumab compared to placebo in 49 adults and adolescents aged 12 years and over with HoFH (LDL-C >130 mg/dl) who were on a stable dose of statin therapy and other lipid-lowering medications and were not receiving apheresis. Patients were randomized to evolocumab 420 mg subcutaneous monthly or placebo subcutaneous monthly. Conclusion: The TESLA study evaluating 49 patients with homozygous FH (HoFH), not on apheresis, showed that adding evolocumab 420 mg subcutaneous monthly to a stable dose of statin therapy and other lipid-lowering medications significantly reduced LDL-C by 31 percent (95 percent CI, -44, -18, p<0.001) from baseline at week 12 compared to placebo. Page 16 of 35

17 Patients with defective receptor mutation had the best response to treatment, and had significantly higher reduction in LDL-cholesterol compared to those with single LDL receptor negative mutation. Evolocumab had no effect in patients with negative/negative mutation and LDL-C increased 10% from baseline. No serious clinical or laboratory adverse events occurred, and no anti-evolocumab antibody development.the most common AEs (more than one subject) in evolocumab-treated patients were upper respiratory tract infection, influenza, gastroenteritis and nasopharyngitis. Reference: Raal FJ, et al; TESLA Investigators. Inhibition of PCSK9 with evolocumab in homozygous familial hypercholesterolaemia (TESLA Part B): a randomized, double-blind, placebo-controlled trial. Lancet. 2015;385: DESCARTES (Durable Effect of PCSK9 Antibody CompARed with PlacEbo Study) Drug: Evolocumab vs Placebo A Phase 3, randomized, double-blind, placebo-controlled, multicenter, 52-week global study to provide longer term data on the efficacy and safety of evolocumab in 901 patients with hyperlipidemia and a range of cardiovascular risk inadequately controlled with lifestyle modifications and/or lipid-lowering therapies. The eligible population included adults with an LDL-C level 75 mg/dl. Approximately 15% of the participants had prior CVD and 12% had diabetes. 901 participants were randomized in a 2:1 ratio to evolocumab 420 mg every two weeks (n=599) or to identical placebo (n=302) and followed for 52 weeks. At 52 weeks LDL-C levels declined 50.6% from a baseline of mg/dl in the evolocumab group and increased 8.7% from mg/dl in the placebo group (between group difference: 57.0%, p<0.001). The DESCARTES study showed that in 901 patients with high LDL-C and a range of cardiovascular risk, evolocumab 420 mg subcutaneous monthly reduced mean LDL-C by 57 percent from baseline at week 52 compared to placebo (p<0.001). The primary efficacy end-point was the percent change from baseline in the LDL cholesterol level at week 52. Secondary end-points included the absolute change in LDL-C from baseline at week 52, the percent change from baseline in the LDL-C at week 12, and the percentage of patients achieved LDL-C level of < 70 mg/dl at week 52, the percent change from baseline at week 52 in other lipids and lipoproteins. The long-term consistency of evolocumab effect was tested by comparing the percent change in the LDL-C level at week 12 with that at week 52. Among 901patients were included in the study, 800 (88.4%) completed 52 weeks of treatment. LDL-C reduction for evolocumab at week 12 was consistent with the long-term efficacy at week 52. Compared to placebo, the mean percent LDL-C reductions from baseline with evolocumab at week 52 are 56 percent, 62 percent, 57 percent and 49 percent in diet alone, atorvastatin 10 mg, atorvastatin 80 mg, and atorvastatin 80 mg plus ezetimibe 10 mg groups, respectively. At 52 weeks, evolocumab treatment resulted in 57% mean reduction in LDL-C versus placebo. LDL-C reduction was 55.7 ± 4.2% in the diet-alone group, 61.6 ± 2.6% in the atorvastatin 10 mg group, 56.8 ± 5.3% in the atorvastatin 80 mg group, and 48.5 ± 5.2% in the atorvastatin 80 mg plus ezetimibe 10 mg group. Adverse events occurred in 74.8% patients treated with evolocumab and in 74.2% treated with placebo. The most common adverse events on evolocumab were nasopharyngitis, upper respiratory tract infection, influenza, and back pain. Serious adverse events were slightly higher with evolocumab than placebo (5.5% versus 4.3%). Myalgia was reported by 4% of patients on evolocumab vs. 3% on placebo. No anti-evolocumab neutralizing antibodies were detected in any patient. Reference: Blom DJ, Hala T, et al. A 52-Week Placebo-Controlled Trial of Evolocumab in Hyperlipidemia. NEJM. 2014;370(19): Page 17 of 35

18 SYSTEMATIC REVIEWS AND META-ANALYSES One meta-analysis assessing the use of evolocumab for lowering cholesterol levels was identified in the literature search (Zhang et al., 2015). The analysis showed that evolocumab decreased LDL-C and increased HDL-C levels versus placebo and ezetimibe. Relative to placebo, the monthly dose of 420 mg evolocumab treatment significantly reduced LDL-C by 54.6% (95% CI, 58.7% to 50.5%) and by 78.9 mg/dl (95% CI, 88.9 to 68.9 mg/dl) and significantly increased HDL-C by 7.6% (95% CI, 5.7% to 9.5%). Compared with ezetimibe, monthly 420 mg evolocumab significantly lowered LDL-C by 36.3 % (95% CI, 38.8% to 33.9%) and significantly increased HDL-C by 6.4% (95% CI, 4.3% to 8.4%). An equivalent or even greater change was observed following biweekly140 mg administration, and all 6 doses of evolocumab significantly reduced LDL-C levels. Significant and favorable changes were also seen in other lipids following treatment with evolocumab. HAYES Annual Review: September 8, 2016 (Publication Date: September 3, 2015) Medical Technology Directory report on PCSK9 Inhibitors for Cholesterol Reduction: Evolocumab Hayes noted the following insights: Evolocumab consistently lowers LDL-C and Lp(a), and increases HDL-C in short-term clinical trials. However, the long-term clinical benefits on cardiovascular health and mortality, as well as the long-term safety, remain to be seen. Evolocumab is self-administered by subcutaneous injection. Patients, especially those with needle phobias, may prefer other noninvasive lipid-lowering therapies. Evolocumab was assigned the following ratings: C: For administration of evolocumab in adult patients with hypercholesterolemia or hyperlipidemia. This Rating reflects moderate-quality evidence suggesting consistent improvements in surrogate endpoints of cardiovascular health following treatment of relatively short duration (3 months for all but 1 study). The Rating also reflects the lack of evidence with respect to long-term clinical benefit of evolocumab, especially on cardiovascular health and mortality. D2: For administration of evolocumab in children and adolescents with hypercholesterolemia or hyperlipidemia. This Rating reflects the paucity of evidence pertaining to efficacy and safety in this patient population. Page 18 of 35

19 FOURIER Further Cardiovascular OUtcomes Research with PCSK9 Inhibition in Subjects with Elevated Risk Multinational, Phase 3, randomized, double-blind, placebo-controlled study The first cardiovascular outcomes trial with the PCSK9 inhibitors and one of the largest randomized placebocontrolled trials on drug therapy so far performed. *A second trial, Odyssey Outcomes, is about a year behind FOURIER and is testing alirocumab (Praluent), the PCSK9 inhibitor from Sanofi and Regeneron, in 18,600 patients. Objective: To evaluate whether treatment with evolocumab (Repatha) in combination with statin therapy compared with placebo plus statin therapy reduces cardiovascular events Randomized, double blind, placebo controlled Phase III trial with Repatha in combination with statin therapy for the treatment of patients with high cholesterol and clinical ASCVD. Patients with established cardiovascular disease on statin therapy were randomized to evolocumab 140 mg subcutaneous every 2 weeks or 420 mg monthly (n=13,784) versus placebo every 2 weeks (n =13,780) patients were enrolled into the following treatment arms with concurrent statin therapy: 140 mg subcutaneous evolocumab (Repatha) every two weeks [plus an effective statin dose] 420 mg subcutaneous Repatha once monthly [plus an effective statin dose] Subcutaneous placebo every two weeks [plus an effective statin dose] Subcutaneous placebo once monthly [plus an effective statin dose] *Effective statin therapy was defined as at least atorvastatin 20 mg or its equivalent daily, with a recommendation for at least atorvastatin 40 mg or its equivalent daily where approved. Inclusion criteria (n= 27,564) Established cardiovascular disease defined as prior heart attack (MI), ischemic stroke or symptomatic peripheral artery disease On statin therapy with (LDL-C 70 mg/dl or non-high-density lipoprotein cholesterol [non-hdl-c] 100mg/dL) Exclusion criteria Myocardial infarction or stroke within 4 weeks New York Heart Association class III or IV heart failure symptoms or left ventricular ejection fraction <30% Hemorrhagic stroke Uncontrolled ventricular tachycardia Planned revascularization within the next 3 months Uncontrolled hypertension Chronic kidney disease Organ transplant Major active infection Other significant features/characteristics Mean patient age: 63 years Percentage female: 25% Percentage with diabetes: 37% 69% were on a high-intensity statin, while 30% were on a moderate-intensity statin Median LDL-C = 92 mg/dl Page 19 of 35

20 Primary endpoint: Time to cardiovascular death, heart attack, stroke, hospitalization for unstable angina, or coronary revascularization Secondary endpoint: Major adverse cardiovascular events (MACE), as defined by first heart attack, stroke, or cardiovascular death. The secondary endpoint removed hospitalization for unstable angina, or coronary revascularization. Duration of follow-up: median 26 months Trial conducted between February 2013 and June 2015, the FOURIER trial Trial concluded when at least 1630 patients experienced a key secondary major adverse cardiac event. OUTCOMES 12.5% discontinued treatment and 0.8% withdrew consent or were lost to follow-up, but all patients were included in analysis Major cardiovascular events was composite of cardiovascular death, myocardial infarction, stroke, hospitalization for unstable angina, or coronary revascularization Comparing evolocumab vs. placebo Major cardiovascular events in 9.8% vs. 11.3% (p < 0.001, NNT 67) Cardiovascular death in 1.8% vs. 1.7% (not significant) Myocardial infarction in 3.4% vs. 4.6% (p < 0.001, NNT 84) Stroke in 1.5% vs. 1.9% (p = 0.01, NNT 250) Coronary revascularization in 5.5% vs. 7% (p < 0.001, NNT 67) LDL cholesterol 70 mg/dl (1.8 mmol/l) at 48 weeks in 87% vs. 18% (p < 0.001, NNT 2) Injection site reaction in 2.1% vs. 1.6% (p < 0.001, NNH 200) Principal Findings The primary outcome, incidence of cardiovascular death, MI, stroke, hospitalization for unstable angina, or coronary revascularization, occurred in 12.6% of the evolocumab group versus 14.6% of the placebo group (p < ). This finding was consistent among all tested subgroups. No significant differences in hospitalization for unstable angina, serious adverse events, muscle-related events, cataract, neurocognitive adverse events, allergic reaction, and hemorrhagic stroke Secondary outcomes Absolute reduction in LDL-C was 56 mg/dl with evolocumab versus placebo (median LDL-C = 30 mg/dl) Any serious adverse event: 24.8% with evolocumab versus 24.7% with placebo A proportion of patients underwent cognitive testing (n = 1,204). Among this cohort, there was no difference between evolocumab versus placebo for a battery of cognitive tests, patient-reported everyday cognition, and physician-reported adverse cognitive events. Page 20 of 35

21 SUMMARY OF EVIDENCE/POINTS OF CONSIDERATION FOURIER was a two-year trial following 27,564 patients with heart disease who were already taking a maximum dose of statins and still had high cholesterol. 69.3% were taking high-intensity statin therapy 30.4% moderate-intensity statin therap 5.2% were also taking ezetimibe However, the benefit of evolocumab was consistent regardless of the intensity of statin therapy or ezetimibe use. Secondary preventative therapies included antiplatelet therapy in 92.3%; beta-blockers in 75.6%; and angiotensinconverting-enzyme (ACE) inhibitor or angiotensin-receptor blocker (ARB), aldosterone antagonist, or both in 78.2% 2-year study endpoints: Evolocumab reduced the primary and secondary composite endpoints by 15% and 20% respectively. However, the absolute risk reduction was modest, at 1.5% for both. Primary endpoint met with a 15% reduction: those who received Repatha were 15% less likely to suffer a negative outcome, defined as heart attack, stroke, hospitalization for chest pain, placement of a stent, or cardiovascular death. Primary endpoint risk reduction rose from 12% in the first year to 19% beyond that time period. Secondary endpoint met with a 20% reduction in the major adverse cardiovascular event (MACE) composite endpoints of first heart attack, stroke, or cardiovascular death. For this measurement, the patients who combined Repatha with a statin 5.9% suffered a heart attack, stroke or died, compared with 7.4% of patients who took a statin plus a placebo. LDL-C lowering An average decline of 59% in LDL levels among the 14,000 people in 49 countries who were put on the drug for 48 weeks. Additionally 87% of the treatment group had a reduction to <70 mg/dl, 42% had a reduced level of <25 mg/dl, from a baseline of 92 mg/dl. For the 42% of patients who obtained LDLs of under 25 mg/dl Repatha comes near taking LDL off the table as a risk factor. GUIDELINES The current guidelines from the American College of Cardiology (ACC) and American Heart Association (AHA), developed in conjunction with the National Heart, Lung, and Blood Institute (NHLBI) in 2013, made no recommendations for specific LDL-cholesterol for the primary and secondary prevention of cardiovascular disease. The guidelines identified four groups of primary- and secondary-prevention patients in whom physicians should focus their efforts to reduce cardiovascular disease events. Additionally, recommendations were also made based on intensity of statin choice, and not LDL goals. However, the new data in the FOURIER Study returns to the strategy of lower is better with the data showed that the lower LDL goes, the lower CV risks go, and extremely low LDL levels aren t unsafe. Some cardiologists and researchers are concerned that very low LDL might have negative effects. Repatha cut heart attack risks by 27% over the course of the study and cut the risk of stroke by 21% compared to placebo group. When you combine these numbers, Repatha patients saw a 19% reduction in risk for the first year and 33% starting in year two. Page 21 of 35

22 Evolocumab had no observed effect on cardiovascular mortality. There was no observed effect on cardiovascular death, and no observed effect on hospitalization for unstable angina. There was no significant difference of death rates between the treatment and placebo groups. There was no increased risk of side effects, including the development of diabetes or cognitive complications. Some of the side effects that statins produce such as muscular issues and liver safety concerns also did not occur. Injection site reactions were small in both arms of the study, and only slightly higher with Repatha patients. Major limitation of this trial: A relatively short duration of follow-up as compared with that in other lipidlowering trials, in which follow-up periods have averaged approximately 5 years (Silverman et al. 2016). Although the median follow-up period in FOURIER was originally planned to be approximately 4 years, an event rate that was approximately 50% higher than had been postulated led to a shorter required duration of follow-up to accrue the pre-specified number of events. Since the FOURIER trial only lasted two years, longer-term studies are needed to assess the longterm safety and to confirm whether evolocumab has any impact on cardiovascular mortality when patients are followed up over a longer time period. FOURIER study investigators noted that the magnitude of the risk reduction with regard to the key secondary end point appeared to grow over time. At one year, there was a 16% relative risk reduction for the combination of cardiovascular death, heart attack and stroke. After one year, that risk reduction rose to 25%. While FOURIER trial investigators suggest that the translation of reductions in LDL cholesterol levels into cardiovascular clinical benefit requires time, there was not mention that this may be true for adverse effects as well and it is possible that side effects such as diabetes and neurocognitive dysfunction may take longer than 2 years to develop. EBBINGHAUS (Evaluating PCSK9 Binding antibody Influence on cognitive HeAlth in high cardiovascular risk Subjects) Study EBBINGHAUS is a cognitive study of patients enrolled in the FOURIER trial. Double-blind, placebo-controlled randomized non-inferiority trial involving of 1,974 patients with clinically evident atherosclerotic cardiovascular disease enrolled in the Repatha cardiovascular outcomes trial (FOURIER). There are concerns that vigorous lowering of LDL cholesterol to very low levels may harm to the brain and cause neurocognitive dysfunction. The EBBINGHAUS study addressed neurocognitive function in almost 1974 patients participating in FOURIER. This analysis included 1974 patients (72% men; mean age 63 years) who were on moderate or highintensity statins. In addition, 75% had had an MI prior to the study's start and 20% had had an ischemic stroke. Mean follow-up was about 19 months. The subjects underwent a battery of neurocognitive tests, and neurocognitive adverse events were tracked. No differences were found between evolocumab and placebo. It has been noted that most PCSK9 inhibitors are large molecules that do not cross the intact blood brain barrier and therefore should not affect cholesterol metabolism within the brain. Key clinical point: Results from a large randomized trial showed absolutely no signal of impaired cognition or memory after patients received nearly 2 years of treatment with the PCSK9 inhibitor evolocumab. The limitation of the study was that the participants were followed for only about 20 months and patients with hyperlipidemia are treated for decades. Page 22 of 35

23 However, patients were only followed for 20 months in EBBINGHAUS; therefore the outcome beyond this time is unknown and whether cognitive dysfunction may develop during long-term therapy with PCSK9 inhibitors remains to be seen. A recent Biopharm Insight Report suggested that anything lower than 35 percent risk reduction in FOURIER may mean that the cost outweighs the treatment benefit. As previously mentioned, FOURIER was powered to detect a 15% risk reduction, which in this case may be far from cost-effective. Reference: While Repatha reduced the risk of major adverse cardiovascular events, the drug failed to show a statistically significant effect on cardiovascular death. It is estimated that 74 patients would need to be treated for 2 years to prevent one event (cardiovascular death, myocardial infarction or stroke). HYPERLIPIDEMIA TREATMENT GUIDELINES (Reference Appendix for Additional Guidelines) American College of Cardiology (ACC) and the American Heart Association (AHA): In 2013, the ACC/AHA Task Force on Practice Guidelines released a practice guideline for the treatment of blood cholesterol to reduce cardiovascular risk in adults. This guideline was created in collaboration with the National Heart, Lung, and Blood Institute (NHLBI). A systematic review of the literature was conducted, and recommendations were based on the highest-quality evidence available. In addition to recommending education and reinforcement of heart-healthy lifestyle habits, recommendations for appropriate intensities of statin therapy were made. The use of PCKS9 inhibitors was not mentioned in this guideline (Stone et al., 2014).Reference: ACC/AHA Guidelines B The 2013 ACC/AHA cholesterol guidelines no longer recommend specific LDL-C goals for treatment. Instead, the guidelines emphasize lifestyle modifications and treatment with moderate or high intensity statins depending upon a patient s risk. The 4 risk groups include those with ASCVD, patients with DM, patients with 10 year risk of ASCVD >7.5%, and those with LDL-C > 190mg/dL. The stated rationale for removing LDL-C treatment targets is that no studies have focused on treatment or titration to a specific LDL-C goal in adults with clinical ASCVD. The majority of randomized controlled studies confirming the efficacy of cholesterol reduction in improving clinical outcomes in patients with clinical ASCVD used a single fixed-dose statin therapy to lower LDL-C levels. Highlights include: Statin therapy is recommended for individuals at increased risk of atherosclerotic cardiovascular disease (ASCVD) in whom the potential for ASCVD risk reduction outweighs the potential for adverse effects from statins. Lifestyle modification (i.e., adhering to a heart-healthy diet, exercising regularly, avoiding tobacco products, and maintaining a healthy weight) remains a crucial component of health promotion and ASCVD risk reduction, both before and while using cholesterol-lowering drug therapies. The current gold standard of pharmacologic treatment of hypercholesterolemia is the use of 3-hydroxy-3- methylglutaryl-coenzyme A (HMG-CoA) reductase inhibitors, also known as statins. B Use of statins reduces mortality and myocardial infarction in adults with coronary heart disease and reduces cardiovascular disease and stroke in patients with diabetes or elevated cardiovascular disease risk. Page 23 of 35

24 In 2013, ACC/AHA updated their guidelines on treatment of blood cholesterol to emphasize cardiovascular risk rather than LDL cholesterol goals. These guidelines identified 4 major patient groups that benefit from statin therapy: Patients with clinical atherosclerotic cardiovascular disease Patients with LDL 190 mg/dl Patients ages 40 to 75 years with diabetes and LDL 70 to 189 mg/dl Patients ages 40 to 75 years without diabetes and LDL 70 to 189 mg/dl with an estimated 10-year risk of atherosclerotic cardiovascular disease of 7.5% It is recommended that patients who fit into these categories receive moderate- to high-dose statin therapy ACC Expert Consensus Decision Pathway on the Role of Non-Statin Therapies for LDL-Cholesterol Lowering in the Management of Atherosclerotic Cardiovascular Disease Risk: A Report of the American College of Cardiology Task Force on Clinical Expert Consensus Documents. The 2013 ACC/AHA cholesterol guidelines de-emphasized LDL-C targets, recommended statins as the primary evidence-based agent to reduce cardiovascular events, and thereby the use of non-statin lipid lowering agents were discouraged. Following the publication of the positive results of the IMPROVE-IT trial, as well as encouraging data with PCSK9 inhibitors in the phase III lipid-lowering trials, the 2016 ACC expert consensus document expanded the role of non-statin therapies for LDL-C lowering in the management of ASCVD. O In this expert consensus document, addition of non-statin therapies, namely ezetimibe as the first-line and PCSK9 inhibitors as the second line of choice, is encouraged for patients at high ASCVD risk who continue to have high LDL-C despite maximally tolerated statin therapy. Page 24 of 35

25 DEFINITIONS Abbreviations Low-density lipoprotein cholesterol (LDL-C) Non-high-density lipoprotein cholesterol (non HDL-C) ASCVD, or atherosclerotic cardiovascular disease, is caused by plaque buildup in arterial walls and refers to the following conditions: Coronary heart disease (CHD), such as myocardial infarction (MI), angina, and coronary artery stenosis greater than 50%. Cerebrovascular disease, such as transient ischemic attack (TIA), ischemic stroke, and carotid artery stenosis greater than 50%. Peripheral artery disease, such as claudication. Aortic atherosclerotic disease, such as abdominal aortic aneurysm (AAA) and descending thoracic aneurysm. Primary prevention refers to the effort to prevent or delay the onset of ASCVD disease. Secondary prevention refers to the effort to treat known, clinically significant ASCVD disease, and to prevent or delay the onset of disease manifestations. Dyslipidemia is a broad term describing a number of conditions, including hypercholesterolemia, hyperlipidemia and mixed dyslipidemia, in which disturbances in fat metabolism lead to changes in the concentrations of lipids in the blood. Along with other risk factors, dyslipidemia may lead to the development of atherosclerosis and cardiovascular disease. Familial hypercholesterolemia (FH) is an inherited condition caused by genetic mutations which lead to high levels of LDL-C at an early age. 5 Patients can have either one of two types of FH. 5 Heterozygous FH is the more common type of FH and can cause LDL-C levels twice as high as normal (e.g., >190 mg/dl). 6 Individuals with HeFH have one altered copy of a cholesterol-regulating gene. 6 Homozygous FH is the rare, more severe form, occurring in approximately one in a million individuals. 7 It has been reported that HoFH can cause LDL-C levels more than six times as high as normal (e.g., 500-1,000 mg/dl). 8,9 An individual with HoFH has two altered copies of cholesterolregulating genes (one from each parent). 5 Hypercholesterolemia is defined as a raised level of cholesterol in the blood, typically including elevated lowdensity lipoprotein cholesterol (LDL-C). Hyperlipidemia refers to raised cholesterol and/or raised triglycerides, and mixed dyslipidemia is a wider term that encompasses hyperlipidemia as well as decreased levels of high-density lipoprotein cholesterol (HDL-C). Lipidologist is a certified physician specializing in the prevention of dyslipidemia (cholesterol and other lipid disorders disorders) or related metabolic diseases (such as diabetes) which often lead to heart disease, stroke or atherosclerosis (vascular disease). Physicians who have passed a rigorous credentialing and examination process can be certified in clinical lipidology. Such members carry the designation Diplomate, American Board of Clinical Lipidology and are considered by the NLA to be lipidologists. (Please visit for more information.) Simon Broome Register criteria: A list of criteria used to diagnose familial hypercholesterolemia. Definitive diagnosis according to Simon Broome diagnostic criteria include total cholesterol concentrations >6.7 mmol/l or LDLc > 4.0 mmol/l in children or total cholesterol > 7.5 mmol/l or LDLc > 4.9 mmol/l in adults and tendon xanthoma; evidence of these signs in first or second degree relative; or DNA evidence of an LDL-receptor mutation, familial defective apo B-100, or a PCSK9 mutation. Reference: Identification and Management of Familial Hypercholesterolemia. Simon Broome Diagnostic criteria for index individuals and relatives. Available at: Accessed July 15 Page 25 of 35

26 APPENDIX Appendix 1: STATIN INTENSITY CHART Recommendations are from the American Heart Association (AHA) 2013 guidelines on the treatment of blood cholesterol. All guidelines pertain to adult patients only. B High-intensity statin therapy lowers cholesterol by 50% Moderate-intensity statin therapy lowers cholesterol by 30-50% Low-intensity statin therapy lowers cholesterol by < 30% Atorvastatin (Lipitor ): 40-80mg per day Rosuvastatin (Crestor ) 20-40mg per day Atorvastatin (Lipitor ) 10-20mg per day Rosuvastatin (Crestor ) 5-10mg per day Simvastatin (Zocor ) 20-40mg per day Pravastatin (Pravachol ) 40-80mg per day Lovastatin (Mevacor ) 40mg per day Fluvastatin XL (Lescol XL ) 80mg per day Fluvastatin (Lescol ) 40mg twice per day Pitavastatin (Livalo ) 2-4mg per day Simvastatin (Zocor ) 10mg per day Pravastatin (Pravachol ) 10-20mg per day Lovastatin (Mevacor ) 20mg per day Fluvastatin (Lescol ) 20-40mg per day Pitavastatin (Livalo ) 1mg per day *Simvastatin 80 mg dose is available, but is associated with increased risk of muscle injury and should not be started in new patients. Only patients taking simvastatin 80 mg for 12 months without evidence of muscle injury should continue this dose Reference: For the full ACC/AHA guideline for the treatment of blood cholesterol to reduce ASCVD risk in adults, refer to: Appendix 2: Proposed Definitions for Statin-Related Muscle Disease Page 26 of 35