Subject: Aimovig (erenumab) Original Effective Date: 7/10/2018. Policy Number: MCP-320. Revision Date(s):

Transcription

1 Subject: Aimovig (erenumab) Original Effective Date: 7/10/2018 Policy Number: MCP-320 Revision Date(s): Review Date(s): MCPC Approval Date: 7/10/2018 DISCLAIMER This Molina Clinical Policy (MCP) 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 MCP document and provide the directive for all Medicare members. SUMMARY OF EVIDENCE/POSITION This policy addresses the coverage of Aimovig (erenumab) for the preventive treatment of migraine in adults when appropriate criteria are met. The intent of the Aimovig (erenumab) policy is to ensure appropriate selection of patients for therapy based on product labeling, clinical guidelines, and clinical studies. Migraine Headache Disorder (MHD) A prevalent neurological disease (the 3rd most prevalent illness in the world) affecting approximately 39 million men, women and children in the U.S. and 1 billion worldwide. It has been estimated that 6% of men and 18% of women are affected (Migraine Research Foundation, 2018). A recurrent headache disorder manifesting in acute pain episodes that may last from 4 to 72 hours. Typical characteristics may include unilateral location; pulsating quality; moderate or severe intensity; aggravation by routine physical activity; and associated nausea, photophobia, phonophobia, and/or aura. Characterized by the frequency of episodes [International Headache Society s (IHS) International Classification of Headache Disorders, 3rd Edition (ICHD-III), is considered the gold standard] Episodic migraine is characterized by < 15 headache days per month, Chronic migraine is characterized by 15 headache days per month for more than 3 months Goals of long-term migraine treatment: reduce attack frequency, severity, and disability; improve quality of life; avoid acute headache medication escalation; and reduce headache-related distress and psychological symptoms. Frequent use of abortive medications may result in increased frequency of headache and medication overuse headache. Prevention is a significant component of therapy in migraine headache disorder. Current care options for migraine headache include a combination of headache trigger avoidance, preventive pharmacologic therapy, acute abortive therapy, and acute analgesic therapy. Current standard of therapy for migraine prophylaxis, include antidepressants (e.g. amitriptyline, venlafaxine), antiepileptics (divalproex sodium, topiramate), antidepressants (e.g. amitriptyline, venlafaxine, duloxetine), angiotensin-converting enzyme (ACE) inhibitor (e.g. lisinopril), angiotensin receptor blocker (ARB) (e.g. Page 1 of 20

2 candesartan), beta-blockers (e.g. metoprolol, propranolol), calcium channel blocker (e.g. verapamil), NSAIDs (e.g. naproxen, ibuprofen), and triptans (e.g. sumatriptan) Aimovig (erenumab) The first biologic product specifically for migraine prevention: Erenumab is a monoclonal antibody and the first-in-class of calcitonin-gene-related peptide (CGRP) antagonist to receive FDA-approval for preventive migraine treatment. By targeting and blocking the CGRP receptor, thereby disrupting a key pathway in the pathophysiology of migraine headaches. This is achieved by inducing a CGRP receptor complex with a CGRP protein to emit migraine-associated pain signals. CGRP levels rise during migraine pain and subside to normal when pain reduces. Effectiveness for the preventive treatment of migraine was evaluated in three clinical trials, comparing erenumab to placebo in 3 major clinical trials Episodic Migraine Enrolled adults (18 to 65 years of age) with at least 12 months history of *episodic migraine with or without aura) of 4 and < 15 migraine days per month and < 15 headache days per month on average during the 3-month period before screening [*Episodic migraine is defined as fewer than 15 headache days per month, with at least 4 migraine days] STRIVE (955 patients) Participants had an average of 8.3 ± 2.5 migraine days per month at baseline The primary endpoint was the change in mean number of migraine days* per month from baseline to the final 3 months of the double-blind treatment phase *A migraine day was defined as any calendar day on which the patient had onset, continuation, or recurrence of a qualified migraine. By months 4 through 6, mean reduction in MMD from baseline was 3.2 days with erenumab 70 mg (P<0.001 vs placebo), 3.7 days with erenumab 140 mg (P<0.001 vs placebo), and 1.8 days with placebo during weeks 13 to 24 Monthly acute migraine-specific medication days were reduced by 1.1, 1.6, and 0.2 days per month in the erenumab 70 mg, erenumab 140 mg, and placebo groups, respectively (P<0.001 for both erenumab groups vs placebo). A 50% or greater reduction in the mean number of migraine days per month was achieved for 43.3% of patients in the 70 mg Aimovig group and 50.0% of patients in the 140 mg Aimovig group, compared with 26.6% in the placebo group (P<0.001 for each dose vs. placebo), and the number of days of use of acute migraine-specific medication was reduced by 1.1 days in the 70 mg Aimovig group and by 1.6 days in the 140 mg Aimovig group, as compared with 0.2 days in the placebo group (P<0.001 for each dose vs. placebo). ARISE (577 patients) Participants randomized to receive Aimovig 70 mg via subcutaneous injection (n=286) or placebo (n=291) once monthly. The mean age of participants was 42 years, and 85.3% were female; mean migraine days per month at baseline was 8.3 days. The primary endpoint was change from baseline in monthly migraine days. At week 12, mean reduction in MMD from baseline was 2.9 days with erenumab compared to 1.8 days in the placebo arm (P<0.001) during weeks 9 to 12 Aimovig was statistically superior to placebo for the key week 12 secondary outcomes of at least a 50% reduction in monthly migraine days and change in monthly acute migraine-specific medication treatment days (P 0.01 for both). A 50% reduction in monthly migraine days was achieved by 39.7% and 29.5% in the Aimovig and placebo groups respectively (P=0.010). Both published phase III trials (ARISE and STRIVE) demonstrated a significant reduction in MMDs in episodic migraine patients treated with Aimovig compared with placebo. Page 2 of 20

3 Chronic Migraine Study (Tepper et al., 2017) (667 patients) randomized, double blind, placebo-controlled phase II trial evaluating adults (18 to 65 years of age) with chronic migraine ( 15 headache days per month with 8 migraine days per month) Average age of participants was 42 years, and 83% were women; the mean number of migraine days at baseline was 18 days Baseline characteristics were similar among treatment groups. Patients who failed > 3 medication categories due to lack of efficacy for prophylactic treatment of migraine were excluded. Participants were randomized to receive Aimovig 70 mg (n=191), Aimovig 140 mg (n=190), or placebo (n=286) via subcutaneous injection once monthly for the duration of the 12-week treatment phase. The primary outcome measure was change in monthly migraine days from baseline in the last 4 weeks of the 12-week double-blind treatment phase. Aimovig 70 mg and 140 mg reduced monthly migraine days versus placebo (both doses -6.6 days versus placebo -4.2 days; difference -2.5, 95% CI -3.5 to -1.4, P<0.0001). For the secondary endpoint of cumulative monthly headache hours, changes from baseline during the last 4 weeks of the 12-week double-blind treatment phase were not significant for either of the Aimovig groups compared with placebo. Summary: Erenumab was evaluated in studies for both episodic migraines and chronic migraines. In the episodic migraine trials, greater reductions in mean monthly migraine days were achieved with erenumab vs. placebo (-2.9 to -3.7 days vs days, p < 0.001). Comparable results were achieved with erenumab in its chronic migraine trial (-6.63 days vs days, p < 0.001). Supplied as an injection for subcutaneous use once monthly Common adverse events reported included infections, injection site pain, and nasopharyngitis. No apparent evidence of increased risk of cardiovascular outcomes or changes in blood pressure associated with erenumab. Anti-erenumab-binding antibodies have been detected; however, the clinical importance of this has not been determined. No correlation was found between the development of neutralizing antibodies and the development of adverse effects. Erenumab consistently demonstrated an ability to reduce monthly migraine days in patients with episodic and chronic migraine in the major clinical trials. Overall, data from clinical trials indicate that erenumab is well-tolerated. However, long-term safety data remain unknown. Comparative Efficacy No head-to-head trials comparing erenumab with other CGRP antagonist treatments are available at this time. Head-to-head trials comparing CGRP antagonists to conventional drug therapies for migraine prophylaxis (including beta-blockers, antidepressants, anticonvulsants, nonsteroidal anti-inflammatory drugs, angiotensin blockade agents, and calcium channel blockers) are unavailable or clinical studies have not been conducted. In addition to erenumab, three other anti-cgrp antibody treatments are in development at the time, including fremanezumab (Teva Pharmaceuticals) and galcanezumab (Eli Lilly and Co), which are currently under review. The manufacturer of eptinezumab (Alder BioPharmaceuticals) is expecting to file for FDA approval as well. Concurrent use of Aimovig (erenumab) with other CGRP antagonist treatments: The efficacy and safety of this combination therapy has not been established. There are no comparative trials among the agents in this class to suggest preference of one agent over another for the preventive treatment of migraine in adults. Page 3 of 20

4 FDA INDICATIONS MIGRAINE PROPHYLAXIS Preventive treatment of migraine in adults Available as: Packs, containing one or two Aimovig SureClick 70mg/mL Autoinjector Solution for Injection 1 pre-filled syringe autoinjector, 1 ml Erenumab 70mg/1mL, Solution for injection (box) 2 pre-filled syringe autoinjector, 1 ml Erenumab 70mg/1mL, Solution for injection (box) FDA Approved: May 17, 2018 Black Box Warning: None at the time of this writing REMS: None at the time of this writing CLASSIFICATION: Calcitonin Gene-Related Peptide Receptor (CGRP) Antagonist; Calcitonin Gene-Related Peptide Receptor Monoclonal Antibodies Page 4 of 20

5 RECOMMENDATIONS/COVERAGE CRITERIA Aimovig (erenumab) may be authorized for members who meet ALL of the following criteria [ALL] 1. Prescriber specialty [ONE] Prescribed by, or in consultation with, a board-certified neurologist, headache specialist, UCNS certified specialists,* or pain specialist. Submit consultation notes if applicable. *The United Council for Neurologic Subspecialties (UCNS) is an organization that provides accreditation to fellowship programs and certification to individual practitioners in neurologic subspecialties, including headache medicine. UCNS certified headache specialists may be neurologists or other type of physicians with expertise in the treatment of headache disorders. NOTE: Consultation notes must be submitted for initial request and for continuation of treatment requests at least ONCE annually. 2. Diagnosis/Indication [ALL] Clinical documentation of ALL of the following (includes clinical notes from the member s medical records, applicable labs and/or relevant tests supporting the diagnosis): [ALL] Diagnosis of Episodic Migraine or Chronic Migraine as defined the International Classification of Headache Disorders (ICHD), 3rd edition [ONE: A OR B] A. Episodic migraines confirmed by the following: [ALL] Less than 15 headache days per month on average across the 3 months 4 and < 15 migraine days per month on average across the 3 months Headaches are not attributable to another causative disorder and not better accounted for by another ICHD-3 diagnosis B. Chronic migraines confirmed by the following: [ALL] Headache (tension-type and/or migraine) on 15 or more days per month for at least 3 months Member has had at least 5 attacks fulfilling criteria for a migraine without an aura On 8 or more days per month for at least 3 months headache has fulfilled criteria for pain and associated symptoms of migraine without aura in EITHER or BOTH criteria 1 or 2 below: [ONE: 1 or 2] 1) At least TWO (2) of the following criteria are met: [TWO: a, b, c, or d] a) Unilateral location b) Pulsating quality c) Moderate or severe pain intensity d) Aggravation by or causing avoidance of routine physical activity (e.g. walking or climbing stairs) and at least ONE (1) of the following criteria below are met: o Nausea and/or vomiting o Photophobia and phonophobia 2) Treated and relieved by triptan(s) or ergot before the expected development of the above symptoms No medication overuse and not attributed to another causative disorder Page 5 of 20

6 Baseline (prior to start of requested therapy) migraine/headache days per month NOTE: Treatment goal is at least 50% reduction in migraine days for continuation of therapy Medication Overuse Headache (MOH) has been ruled out. International Classification of Headache Disorders, 3rd beta edition defines Medication Overuse Headache as: [ALL] MOH is defined as an existing headache disorder who experience headaches on at least 15 days per month and have regularly overused drugs taken for acute or symptomatic treatment of headaches for more than three months Headache present on > 15 days/month Regular overuse for > 3 months of one or more drugs that can be taken for acute and/or symptomatic treatment of headache Headache has developed or markedly worsened during medication overuse NOTE: For simple analgesics and for combination of acute medications, the intake must be 15 days or more per month for triptans, ergotamins, opioids and combination analgesics; 10 days per month is enough to get the diagnosis of MOH. NOTE: If headaches are attributable to MOH or another causative disorder or better accounted for by the ICHD-3 diagnosis, Aimovig (erenumab) will not be authorized as this is not an FDA approved indication. Consider treatment according to the standard of care for a diagnosis of MOH (such as withdrawal of the overused drug(s), providing pharmacological and nonpharmacological support, and prevention of relapse). 3. Age/Gender/Other restrictions [ALL] 18 years of age or older Safety and efficacy of erenumab have not been established in pediatric patients 4. Step/Conservative Therapy/Other condition Requirements [ALL] Ineffectiveness/failure [No reduction in headache frequency, duration, or severity after administration of the medication for at least 12 weeks at the generally accepted therapeutic dose(s) based on the Prescriber s assessment]; clinical intolerance (defined as an intolerance to the drug or its excipients, not to the route of administration); FDA-labeled contraindication or hypersensitivity [A OR B] A. Symptoms inadequately controlled after an adherent* 2 month trial of the following migraine prophylactic classes of at least TWO (2) of the following prophylactic classes:[two] *Adherence to therapy is defined at least 80% of the time as verified by Prescriber and member s Clinical trials: STRIVE; ARISE, CHRONIC MIGRAINE: Phase II Study medication fill history (review Rx history for compliance) FDA-approved for the indication of migraine prophylaxis Beta Blockers **First-line option** o propranolol o timolol o atenolol o metoprolol o nadolol Page 6 of 20

7 Antiepileptics **First-line option** o divalproex sodium o topiramate Antidepressants **First-line option** Tricyclic Antidepressants (TCAs) o amitriptyline o nortriptyline Serotonin-Norepinephrine Reuptake Inhibitors (SNRIs) o venlafaxine o duloxetine Calcium Channel Blocker o verapamil Angiotensin-Converting Enzyme (ACE) Inhibitor and Angiotensin Receptor Blocker (ARB) o Lisinopril o candesartan Botulinum Toxin Type A (Onabotulinumtoxin A) [For diagnosis of Chronic Migraine only] Botox (not Botox Cosmetic) is FDA approved for the prevention of chronic migraine, defined as 15 or more headache days per month lasting at least four hours per headache day. Botulinum toxin is not recommended for prevention of episodic migraine. The AAN considers onabotulinum toxin A ineffective as a treatment for episodic migraine and recommends that it not be offered to such patients. (AAN 2016) MOLINA STAFF: Verify pharmacy claims data for fill and adherence above 80% within the last 90 days. For new members to Molina Healthcare, confirm medications use in medical or chart notes. Noncompliance or non-adherence does not constitute therapeutic failure. B. Documented intolerance, labeled contraindication, or hypersensitivity to ALL of the first-line classes for migraine prevention listed above: Antiepileptics, Beta blockers AND Antidepressants NOTE: Refer to labeling of each drug for information on clinical intolerance, labeled contraindication, or hypersensitivity Concurrent Therapy Aimovig (erenumab) is NOT prescribed for, or intended for, concurrent or combination therapy with the following agents: [ANY] Other CGRP agents (i.e. obtained through enrollment in clinical trials) Botulinum toxin as headache prophylaxis Member has not received botulinum toxin injection for headache prophylaxis in the past 4 months STRIVE, Chronic Migraine Phase II Study Page 7 of 20

8 5. Contraindications*/Exclusions/Discontinuations *There are no contraindications listed in the manufacturer's labeling Authorization will not be granted if ANY of the following conditions apply [ANY] Non-FDA approved indications Non-FDA approved dosing regimen or route of administration (for subcutaneous use only; intended for selfadministration) Severe hypersensitivity reaction to Aimovig (erenumab) or any of its excipients Hypersensitivity reactions may occur with latex since the packaging (needle shield of auto-injector and needle cap of prefilled syringe) may contain latex Exclusion Concurrent Therapy Other CGRP agents (i.e. obtained through enrollment in clinical trials) Botulinum toxin as headache prophylaxis Received botulinum toxin injection for headache prophylaxis in the past 4 months STRIVE, Chronic Migraine Phase II Study (3 months) Medication Overuse Headache has not been ruled out 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. NOTE: Additional documentation, rationale, and/or supporting evidence may be requested for review as deemed necessary or appropriate by Molina Medical/Pharmacy staff. Page 8 of 20

9 CONTINUATION OF THERAPY Aimovig (erenumab) may be authorized for continuation of therapy if meet ALL of the following criteria are met: [ALL] 1. Initial Coverage Criteria Member currently meets ALL initial coverage criteria Consultation notes must be submitted for initial request and for continuation of treatment requests at least ONCE annually. The prescribing physician should periodically reassess the need for continuation of therapy based on the member s disease severity and level of asthma control. Continuation of therapy requires submission of relevant medical records or chart notes documenting continued efficacy. 2. Compliance Adherence to therapy at least 80% of the time as verified by Prescriber and member s medication fill history (review Rx history for compliance), including: Adherent to the prescribed medication regimen Tolerance to therapy No severe adverse reactions or drug toxicity NOTE: Therapy may be discontinued due to poor adherence upon recommendation of the Molina Medical Director when adherence < 80% has been demonstrated in at least two months during the course of therapy NOTE: History of non-compliance or non-adherence as verified by member s medication fill history or prescription drug profile may result in continuation of therapy request not being authorized. [MOLINA MEDICAL/PHARMACY REVIEWER TO VERIFY 3. Labs/Reports/Documentation required [ALL] Aimovig (erenumab) therapy has resulted in clinical improvement from baseline as documented by the following. Documentation required. [ONE] Response to therapy as defined by 50% reduction in monthly migraine days (MMD) [Molina Reviewer: Compare baseline to follow-up MMD to determine if at least a 50% reduction attained] 4. Discontinuation of Treatment [ANY] Discontinue treatment if ANY of the following conditions applies: [ANY] Intolerable adverse effects or absence of unacceptable toxicity from the drug 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 Authorization will not be granted if ANY of the following conditions apply [ANY] Non-FDA approved indication Non-FDA approved dosing regimen or route of administration (for subcutaneous use only; intended for selfadministration) Severe hypersensitivity reaction to erenumab or any of its excipients Page 9 of 20

10 Exclusions Authorization will not be granted if ANY of the following conditions apply [ANY] Younger than 18 years of age Concurrent Therapy Other CGRP agents (i.e. obtained through enrollment in clinical trials) Botulinum toxin as headache prophylaxis Received botulinum toxin injection for headache prophylaxis within the past 4 months Medication Overuse Headache has not been ruled out Page 10 of 20

11 ADMINISTRATION, QUANTITY LIMITATIONS, AND AUTHORIZATION PERIOD 1. Recommended Dosage Migraine Prophylaxis: 70 mg subcutaneously (SC) once monthly. Some patients may benefit from a dosage of 140 mg injected SC once monthly, which is administered as two consecutive SC injections of 70 mg each. Administer in the abdomen, thigh, or upper arm subcutaneously. For requests of 140 mg once monthly [ALL] 1) 70 mg SC once monthly has been tried for at least one treatment (30 days) and clinical response has not been optimal as defined by 50% reduction in monthly migraine days (MMD). Documentation of follow-up MMD required. [Molina Reviewer: Compare baseline MMD versus follow-up MMD) As a preventive treatment of episodic migraine, erenumab at a dosage of 70mg monthly significantly reduced migraine frequency and acute migraine-specific medication use (Dodick et al.; ARISE trial) The primary outcome measure was change in MMD from baseline in the last 4 weeks of the 12-week double-blind treatment phase. Aimovig 70 mg and 140 mg reduced MMD versus placebo (both doses days vs placebo -4.2 days; difference -2.5, 95% CI -3.5 to -1.4, P<0 0001). Study (Tepper et al., 2017) 2) Clinical rationale and documentation supporting therapy with a higher dose (140 mg), including ALL of the following: [ALL] 2. Authorization Limit [ALL] Response to therapy as defined by 50% reduction in monthly migraine days has not been attained, however positive response has been documented by at least TWO (2) of the following: [TWO] o Severity of headaches and migraines o Reduction in acute pharmacological medication o Reduction in monthly acute migraine-specific medication treatment days o Improvement in Migraine Physical Function Impact Diary (MPFID) physical impairment and impact on everyday activities domain scores o Health-related quality of life; Objective quality of life improvement measures (MIDAS, HIT-6, MSQ) [Refer to Appendix 1] Member has not experienced ANY of the following: [ANY] o Intolerable adverse effects or absence of unacceptable toxicity from the drug o Poor response to treatment as evidenced by physical findings and/or clinical symptoms C. Quantity limit: [ONE] 70 mg subcutaneously (SC) once monthly: 1 autoinjector per 30 days 140 mg injected SC once monthly: 2 autoinjectors/prefilled syringes per 30 days [NOTE: Criteria for 140mg must be met] D. Dispensing Limit: One One-month supply per fill E. Duration of initial authorization: 3 months F. Continuation of treatment: Re-authorization is required every 6 months to determine effectiveness of therapy and continued need based on documented positive clinical response. Refer to Continuation of Therapy section. Page 11 of 20

12 3. Route of Administration [ALL] G. Aimovig (erenumab) is considered a self-administered medication for subcutaneous use only H. 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. COVERAGE EXCLUSIONS All other uses of Aimovig (erenumab) that are not an FDA-approved indication or not included in the Coverage Criteria section of this policy are considered experimental/investigational or not a covered benefit of this policy. This subject to change based on research and medical literature, or at the discretion of Molina Healthcare. Non-FDA approved indication Younger than 18 years of age Non-FDA approved dosing regimen(s) Individuals who have had previous anaphylactic reaction to Aimovig (Erenumab) Aimovig (Erenumab) therapy initiated with samples and the member does not meet policy criteria for coverage (as outlined above) prior to the start of therapy. Coverage will not be authorized upon completion of samples. Administration in any manner other that which is FDA-approved (for subcutaneous injection) will not be authorized SUMMARY OF CLINICAL EVIDENCE Erenumab is a human immunoglobulin G2 (IgG2) monoclonal antibody. Erenumab is specific and selective to CGRP receptors, exerting action by full competitive inhibition of the receptor. Maximum concentrations of erenumab did not demonstrate antagonist or agonist activity on human adrenomedullin, calcitonin, and amylin receptors. Animal studies have determined the trigeminal ganglion is not protected by the blood-brain barrier, so it may not be necessary for a drug like erenumab to cross the blood-brain barrier to be effective. Calcitonin gene-related peptide (CGRP) is a peptide expressed in the peripheral and central nervous systems. At nerve endings located on cerebral vascular smooth muscle, CGRP is a potent pro-inflammatory peptide that is released from the trigeminal ganglia neurons, resulting in vasodilation of the cranial vasculature. CGRP receptors are found in the vasculature, trigeminal sensory afferents, trigeminal ganglion, and trigeminal nucleus caudalis. Elevated blood and salivary CGRP levels occur in patients with migraines, cluster headaches, facial pain disorders, trigeminal neuralgia, chronic paroxysmal hemicrania, trigeminal neuralgia, and rhinosinusitis. Levels are elevated during a migraine attack and between migraine attacks in patients with chronic migraines. In studies to determine the role of elevated CGRP levels in patients with migraine headaches (i.e., causative or secondary to migraine), exogenous CGRP infusions were shown to trigger migraine attacks. In addition, elevated CGRP levels predict patient response to treatment with triptans and dihydroergotamine mesylate in those with acute migraine attacks, and to onabotulinumtoxina in those with chronic migraines. Monoclonal antibody therapies targeting the CGRP receptor have shown efficacy in episodic and chronic migraine prevention. Page 12 of 20

13 PIVOTAL TRIALS The effectiveness of erenumab for the preventive treatment of migraine was evaluated in three clinical trials, comparing erenumab to placebo in 3 major clinical trials: ARISE, STRIVE, and LIBERTY. STRIVE Phase III (6 months) A Phase 3, Randomized, Double-blind, Placebo-controlled Study to Evaluate the Efficacy and Safety of AMG 334 in Migraine Prevention (Goadsby PJ, et al, 2017) A randomized, multi-center, 6-month, placebo-controlled, double-blind study evaluating Aimovig for the preventive treatment of episodic migraine. Patients were allowed to use acute headache treatments including migraine-specific medications (i.e., triptans, ergotamine derivatives) and NSAIDs during the study. Subjects: A total of 955 patients with a history of episodic migraine were randomized to receive either Aimovig 70 mg (N = 317), Aimovig 140 mg (N = 319), or placebo (N = 319) by subcutaneous injection once monthly (QM) for 6 months. Patients experienced between four and 14 migraine days each month, with an average of 8.3 migraine days per month at baseline. Inclusion Criteria History of migraine (with or without aura) for 12 months prior to screening according to the IHS Classification ICHD-3 (Headache Classification Committee of the International Headache Society, 2013) Migraine frequency: 4 and < 15 migraine days per month on average across the 3 months prior to screening and during baseline Headache frequency: < 15 headache days per month on average across the 3 months prior to screening and baseline Demonstrated at least 80% compliance with the ediary Exclusion Criteria Elderly patients (> 65 years) Older than 50 years of age at migraine onset Received botulinum toxin within 4 months before or during the baseline phase Used devices or procedures for migraine prevention within 2 months before the baseline phase No therapeutic response to more than two migraine-preventive treatment categories Patients with medication overuse headache History of cluster headache or hemiplegic migraine headache Unable to differentiate migraine from other headache No therapeutic response to > 2 previous migraine preventive migraine treatment categories after an adequate therapeutic trial Used a prohibited medication, device, or procedure within 2 months prior to the start of the baseline phase or during the baseline phase Concomitant use of 2 or more medications with possible migraine prophylactic effects within 2 months prior to the start of the baseline phase or during the baseline phase. If only 1 prophylactic medication is used, the dose must be stable within 2 months prior to the start of the baseline phase and throughout the study Intervention Patients were randomized 1:1:1 to receive subcutaneous injections of erenumab 70 mg, erenumab 140 mg, or placebo once a month for 6 months. Patients were allowed to use acute headache treatments, including triptans, ergotamine derivatives, and NSAIDs, during the study. The study allowed enrollment of patients with concomitant use of 1 migraine preventative medication at a stable dose. Primary Outcome Measures The primary endpoint was change in mean monthly migraine days from baseline over the last three months of the doubleblind treatment phase of the study (months 4, 5 and 6) Page 13 of 20

14 Primary Endpoint Met: Subjects in the erenumab 70 mg and 140 mg treatment arms experienced reductions of 3.2 and 3.7 days from baseline in monthly migraine days, respectively, as compared to a 1.8-day reduction in the placebo arm. Secondary End Point(s) Reduction in MMD of 50% or more was achieved by 43%, 50%, and 27% of patients in the erenumab 70 mg, erenumab 140 mg, and placebo groups, respectively (P<0.001 for both erenumab groups vs placebo). The number needed to treat was 6.3 for erenumab 70 mg versus placebo and was 4.4 for erenumab 140 mg versus placebo. Monthly acute migraine-specific medication days were reduced by 1.1, 1.6, and 0.2 days per month in the erenumab 70 mg, erenumab 140 mg, and placebo groups, respectively (P<0.001 for both erenumab groups vs placebo) Change in scores for physical impairment and impact on everyday activities, as measured using the Migraine Physical Function Impact Diary (MPFID): Physical impairment scores were improved compared to placebo ( 4.2, 4.8, and 2.4 points in erenumab 70 mg, erenumab 140 mg, and placebo groups, respectively [P<0.001 for both erenumab groups vs placebo]). Everyday activities scores were also improved ( 5.5, 5.9, and 3.3 points in erenumab 70 mg, erenumab 140 mg, and placebo groups, respectively [P<0.001 vs placebo]) End Point(s): Exploratory patient-reported outcome values showed improvements from baseline in quality of life, disability, and migraine-related impact on life. In addition, there was a trend towards better numerical changes in these parameters with erenumab 140 mg compared to erenumab 70 mg. Summary The study was conducted in Austria, Belgium, Canada, Czechia, Finland, Germany, the Netherlands, Poland, Slovakia, Sweden, Turkey, the United Kingdom, and the United States. Erenumab adverse reactions and tolerability were similar to placebo. The efficacy results from this study confirmed the results in phase 2 studies with once-monthly administration of erenumab 70 mg or 140 mg. Limitations: Study results are only available in the form of a meeting abstract. ClinicalTrials.gov Identifier: NCT ARISE Phase III Study (3 months) A Phase 3, Randomized, Double-blind, Placebo-controlled Study to Evaluate the Efficacy and Safety of AMG 334 in Migraine Prevention (followed by open-label treatment phase) Adults with a history of migraine with or without aura for 12 months and who experience 4 to < 15 migraine days per month with < 15 headache days per month will be randomized 1:1 to placebo or AMG 334. Double-blind AMG 334 or placebo will be administered during the 12-week double-blind treatment phase and open-label AMG 334 will be administered during the 28-week open-label treatment phase. Investigational product doses are fixed and will not be adjusted for individual subjects during the study. Inclusion Criteria History of Migraines High migraine frequency Demonstrated compliance with the ediary Exclusion Criteria Older than 50 years of age at migraine onset History of cluster headache or hemiplegic migraine headache Page 14 of 20

15 Unable to differentiate migraine from other headaches No therapeutic response with > 2 categories for prophylactic treatment of migraine after an adequate therapeutic trial Concomitant use of 2 or more medications with possible migraine prophylactic effects within 2 months prior to the start of the baseline phase or during the baseline phase. If only 1 prophylactic medication is used, the dose must be stable within 2 months prior to the start of the baseline phase and throughout the study Used a prohibited medication, device, or procedure within 2 months prior to the start of the baseline phase or during the baseline phase Received botulinum toxin Anticipated to require any excluded medication, device, or procedure during the study Active chronic pain syndromes (such as fibromyalgia and chronic pelvic pain) History of major psychiatric disorder History of seizure disorder or other significant neurological conditions other than migraine Human immunodeficiency virus (HIV) infection by history Myocardial infarction (MI), stroke, transient ischemic attack (TIA), unstable angina, or coronary artery bypass surgery or other revascularization procedure within 12 months prior to screening The subject is at risk of self-harm or harm to others Unlikely to be able to complete all protocol required study visits or procedures, and/or to comply with all required study procedures. Primary Outcome Measures Change from baseline in mean monthly migraine days: To evaluate the effect of AMG 334 compared to placebo on the change from baseline in monthly migraine days, in subjects with episodic migraine Primary Endpoint Met: -2.9 migraine days per month with erenumab 70mg, -1.8 migraine days per month for placebo (p<0.001 vs. placebo) Secondary Outcome Measures Proportion of subjects with at least a 50% reduction from baseline in monthly migraine days (MMD): To evaluate the effect of AMG 334 compared to placebo on the proportion of subjects with at least 50% reduction from baseline in MMD Change from baseline in monthly acute migraine-specific medication treatment days: To evaluate the effect of AMG 334 compared to placebo on the change from baseline in monthly acute migraine-specific medication treatment days Change from baseline in physical impairment: To evaluate the effect of AMG 334 compared to placebo on the proportion of subjects with at least a 5-point reduction from baseline in mean physical impairment domain score as measured by the MPFID Change from baseline in impact on everyday activities: To evaluate the effect of AMG 334 compared to placebo on the proportion of subjects with at least a 5-point reduction from baseline in mean impact on everyday activities domain score as measured by the Migraine Physical Function Impact Diary (MPFID) CHRONIC MIGRAINE: Phase II Study (3 months) A Study to Evaluate the Efficacy and Safety of AMG 334 in Chronic Migraine Prevention (Tepper S, et al.) Page 15 of 20

16 Phase 2, multicenter, randomized, double-blind, placebo-controlled study of patients with chronic migraine. Enrolled 667 people with an average of 18 migraine days per month at baseline. Subjects were randomized to receive either placebo, or one of two AMG 334 subcutaneous doses every month for the duration of the 12-week double-blind treatment phase. Subjects were allowed to use acute headache treatments, including triptans, ergotamine derivatives, and NSAIDs, during the study Inclusion Criteria History of at least 5 attacks of migraine without aura and/or migraine with visual sensory, speech and/or language, retinal or brainstem aura History of migraine, with or without aura and 15 headache days/month, of which 8 were migraine days 4 distinct headache episodes, each lasting 4 hours OR if shorter, associated with use of a triptan or ergotderivative on the same calendar day based on the ediary calculations Demonstrated at least 80% compliance with the ediary Exclusion Criteria Elderly patients (> 65 years) Myocardial infarction, stroke, transient ischemic attacks, unstable angina, coronary artery bypass surgery, or other revascularization procedures within 12 months prior to screening History of cluster headache or hemiplegic migraine headache Unable to differentiate migraine from other headaches No therapeutic response to > 3 previous migraine preventative migraine treatment categories due to lack of efficacy, whereas there was no limit to the number of previous failures for poor tolerability Received botulinum toxin head or neck region within 4 months prior to screening Used a prohibited migraine prophylactic medication, device or procedure within 2 months prior to the start of the baseline phase Primary Endpoint Met: -6.6 migraine days per month with erenumab at both doses (70mg and 140mg), -4.2 migraine days per month for placebo (p<0.001 for both doses vs. placebo) LIBERTY A Study Evaluating the Effectiveness of AMG 334 Injection in Preventing Migraines in Adults Having Failed Other Therapies A 12-week Double-blind, Randomized, Multicenter Study Comparing the Efficacy and Safety of Once Monthly Subcutaneous AMG 334 Against Placebo in Adult Episodic Migraine Patients Who Have Failed Prophylactic Migraine Treatments LIBERTY is a Phase 3b, multicenter, randomized 12-week, double-blind, placebo-controlled study evaluating the safety and efficacy of Aimovig in patients with episodic migraine (defined in the trial as four to 14 migraine days per month at baseline) who have failed up to four prior preventive treatments for migraine. In the study, 246 participants with episodic migraine who had two to four previous treatment failures were randomized to receive Aimovig 140 mg or placebo during the 12-week double-blind treatment phase. Inclusion Criteria Documented history of migraine in the 12 months prior to screen 4-14 days per month of migraine symptoms > 80% diary compliance during the Baseline period Failure of previous migraine prophylactic treatments Exclusion Criteria > 50 years old at migraine onset Pregnant or nursing Page 16 of 20

17 History of cluster or hemiplegic headache Evidence of seizure or psychiatric disorder Score of 19 or higher on BDI Active chronic pain syndrome Cardiac or hepatic disease Primary endpoint: The percentage of patients with at least a 50 percent reduction of monthly migraine days from baseline over the last four weeks of the double-blind treatment phase of the study (weeks 9-12). The study includes an ongoing 52- week open-label extension study. Secondary endpoints assessed during the same time period included: Change from baseline in monthly migraine days Change from baseline in the number of monthly acute migraine-specific medication treatment days, and Change from baseline in the *Migraine Physical Function Impact Diary (MPFID) physical impairment and impact on everyday activities domain scores *The MPFID assessed the impact of migraine on physical function and everyday activities as secondary endpoints 75 percent and 100 percent responder rates (number of patients experiencing at least a 75 percent or 100 percent reduction in monthly migraine days compared to placebo) Summary LIBERTY is the first migraine prevention trial of its kind conducted specifically in patients who have tried multiple therapies without success, and are in need of additional treatment options The trial met its primary endpoint of percentage of patients on Aimovig achieving at least a 50 percent reduction of migraine days versus placebo, and all secondary endpoints Results add to the consistent efficacy, safety and tolerability profile of Aimovig across the spectrum of migraine, even in more difficult to treat patients ClinicalTrials.gov Identifier: NCT CLINICAL PRACTICE GUIDELINES American Headache Society/American Academy of Neurology (AHS/AAN) Guidelines for prevention of episodic migraine: a summary and comparison with other recent clinical practice guidelines (AHS/AAN 2012) AAN s 2012 guidelines were jointly developed with the American Headache Society (AHS) Updated AHS/AAN guidelines for the preventive treatment of episodic migraine summarize and compare key recommendations of 2 other recent migraine prevention guidelines from the Canadian Headache Society and the European Federation of Neurological Societies. The 3 guidelines provide similar recommendations and support use of topiramate, divalproex/sodium valproate, propranolol, and metoprolol as first-line therapies based on the highest level of evidence. For the prevention of episodic migraine, the AAN/AHS recommends that clinicians offer antiepileptic drugs (divalproex sodium, sodium valproate, topiramate) or beta blockers (metoprolol, propranolol, timolol). Several other medications were probably effective, including antidepressants (amitriptyline, venlafaxine) and other beta blockers (atenolol, nadolol). Additional medications are considered possibly effective (lisinopril, candesartan, guanfacine, carbamazepine, and nebivolol), and may be offered to patients. NOTE: Erenumab has not been addressed in the guidelines. AAN Guideline for Pharmacologic Episodic Migraine Prevention (2012) The AAN guideline for pharmacologic treatment for episodic migraine prevention in adults recommends that preventive treatment should be considered for those patients whose migraine headaches have a substantial impact Page 17 of 20

18 on their lives and have not responded to acute care, or where the frequency of migraine attacks is such that the reliance on acute care medications would increase the potential for drug-induced (rebound) headache. The guideline notes that the use of divalproex sodium, sodium valproate, topiramate, metoprolol, propranolol, or timolol for migraine prevention is supported by strong evidence and should be offered for migraine prevention. NOTE: The guideline does not address use of CGRP inhibitors for migraine prevention. DEFINITIONS N/A APPENDIX APPENDIX 1: QUALITY OF LIFE DATA Headache Impact Test (HIT-6): A six-item questionnaire developed to measure the burden and level of disability in migraine patients. The questionnaire asks patients about their head pain, social, work and cognitive functioning, vitality, and psychological distress. An overall severity level is generated, with scores ranging from 36 to 78 and higher scores indicate more severe impact. The HIT-6 can be found online ( Migraine Disability Assessment (MIDAS): A five-item questionnaire developed to help patients measure the number of days that migraines impacted their lives. The questionnaire asks patients about the number of days during last three months that they were inhibited by their headaches in different forms. An overall level of disability is generated based on the total number of days affected. The specific questions are: 1. On how many days in the last three months did you miss work or school because of your headaches? 2. How many days in the last three months was your productivity at work or school reduced by half or more because of your headaches? (Do not include days you counted in question one where you missed work or school.) 3. On how many days in the last three months did you not do household work (such as housework, home repairs and maintenance, shopping, caring for children and relatives) because of your headaches? 4. How many days in the last three months was your productivity in household work reduced by half of more because of your headaches? (Do not include days you counted in question three where you did not do household work.) 5. On how many days in the last three months did you miss family, social or leisure activities because of your headaches? Migraine-Specific Quality of Life Questionnaire version 2.1 (MSQ v2.1) A 14-item questionnaire used to assess the limitations in daily performance due to migraine MSQ v2.1 is composed of three domains: role function- restrictive (RR), role function-preventive (RP), and emotional function (EF). The first two of these domains are used to access the reduction and prevention of daily social- and work-related activities The last domain is used to evaluate emotions associated with migraine. CODING INFORMATION The codes listed in the policy are for reference purposes only. Listing of a service or device code in this policy does not imply that the service described by this code is covered or non-covered. Coverage is determined by the benefit document. This list of codes may not be all inclusive. Page 18 of 20

19 HCPCS J3590 Description Aimovig (erenumab-aooe) REFERENCES Package Insert, FDA, Drug Compendia Aimovig (erenumab-aooe) [prescribing information]. Thousand Oaks, CA: Amgen Inc; May Drug Facts and Comparisons. Facts and Comparisons eanswers [online]. Clinical Drug Information LLC, Available from Wolters Kluwer Health, Inc. [via subscription only] Clinical Pharmacology [database online]. Tampa, FL: Gold Standard, Inc.; Available at: [via subscription only] CLINICAL TRIALS, DEFINITIONS, PEER-REVIEWED PUBLICATIONS Study to Evaluate the Efficacy and Safety of AMG 334 Compared to Placebo in Migraine Prevention (ARISE). Dodick DW, Ashina M, et al. ARISE: A Phase 3 randomized trial of erenumab for episodic migraine. Cephalalgia May;38(6): doi: / Epub 2018 Feb 22. ClinicalTrials.gov Identifier: NCT Accessed May Study to Evaluate the Efficacy and Safety of AMG 334 in Migraine Prevention (STRIVE). Goadsby PJ, Reuter U, Hallström Y, et al. A Controlled Trial of Erenumab for Episodic Migraine. N Engl J Med Nov 30;377(22): doi: /NEJMoa ClinicalTrials.gov Identifier: NCT Accessed May Phase 2, Multicenter, Randomized, Double-blind, Placebo-controlled Study of Patients with Chronic Migraine. Tepper S, Ashina M, et al. Safety and efficacy of erenumab for preventive treatment of chronic migraine: a randomised, double-blind, placebo-controlled phase 2 trial. Lancet Neurol Jun;16(6): doi: /S (17) Epub 2017 Apr 28. ClinicalTrials.gov Identifier: NCT Accessed May GOVERNMENT AGENCIES, PROFESSIONAL SOCIETIES, OTHER AUTHORITATIVE PUBLICATIONS American Headache Society/American Academy of Neurology (AHS/AAN). Evidence-based guideline update: Pharmacologic treatment for episodic migraine prevention in adults. S.D. Silberstein, S. Holland, F. Freitag, et al. Neurology Apr 2012, 78 (17) ; DOI: /WNL.0b013e d20 Available at: Accessed May AHS/AAN guidelines for prevention of episodic migraine: a summary and comparison with other recent clinical practice guidelines. Headache 2012; 52:930. Available at: Accessed May American Academy of Neurology (AAN). Practice guideline update summary: Botulinum neurotoxin for the treatment of blepharospasm, cervical dystonia, adult spasticity, and headache: Report of the Guideline Development Subcommittee of the American Academy of Neurology. Neurology. 2016;86(19): Institute for Clinical and Economic Review (ICER). Evidence Report. Calcitonin Gene-Related Peptide (CGRP) Inhibitors as Preventive Treatments for Patients with Episodic or Chronic Migraine: Effectiveness and Value. May 31, Available at: Accessed May Page 19 of 20