Medical Policy

Policy Num:       05.001.035
Policy Name:     Monoclonal Antibody Therapies for Migraine and Cluster Headache
Policy ID:          [05.001.035]  [Ac / B / M+ / P+]  [5.01.29]

Last Review:       January 15, 2025
Next Review:      January 20, 2026
 

Related Policies: 

05.001.004-Botulinum Toxin

Monoclonal Antibody Therapies for Migraine and Cluster Headache

   Population  Reference No.

   Populations

   Interventions

   Comparators

   Outcomes

SUMARRY

Description

Migraine is a headache disorder characterized by recurrent moderate to severe headaches with associated symptoms. For patients who experience more than 4 migraine days per month, preventive treatment may be recommended. Cluster headache is a disabling primary headache disorder that is characterized by attacks of intense headache on 1 side of the head, with associated agitation or restlessness, as well as by cranial autonomic symptoms. Treatment of acute headache is pain relief as well as a preventive therapy at the onset of a cluster episode to reduce the frequency of attacks. Evidence implicates calcitonin gene-related peptide (CGRP) in migraine and cluster headache. Monoclonal antibodies (mAbs) for the CGRP receptor and molecule have been developed for migraine and cluster headache.

Summary of Evidence

For individuals who have episodic migraine who are eligible to receive standard pharmacologic preventative therapy who receive calcitonin gene-related peptide (CGRP) monoclonal antibodies (mAbs) , the evidence includes multiple randomized controlled trials (RCTs) and 1 network meta-analysis. Relevant outcomes are symptoms, change in disease status, quality of life (QOL) , and treatment-related morbidity. The HER-MES trial compared erenumab to topiramate in patients with migraines occurring at least 4 days per month (ie, patients with episodic and chronic migraine). Erenumab demonstrated a reduction in the proportion of patients who discontinued the medication due to an adverse event (AE; 10.6% vs. 38.9%), which was the primary outcome, and an improvement in the proportion of patients with at least 50% reduction in monthly migraine days from baseline over months 4 to 6 (55.4% vs. 31.2%). Also, patients in the erenumab group experienced a significantly greater reduction in mean monthly migraine days versus topiramate (-5.86 days vs. -4.02 days). The applicability of the HER-MES trial is challenging due to the inclusion of a broad migraine population without stratification of results by migraine type (episodic vs. chronic) or prior treatment. Furthermore, the trial enrolled a mostly White race and female population and had a potential for unblinding due to the known side effect profile of topiramate. Seven placebo-controlled RCTs with over 5000 adults showed a reduction of 1 to 2 monthly migraine days with the CGRP mAbs. A network meta-analysis showed no statistical difference in reduction in monthly migraine days or a 50% decrease in monthly migraine days when CGRP mAbs (erunemab, fremanezumab, and galcanezumab) were compared to oral preventive therapies. This meta-analysis did not include data on eptinezumab. The most commonly reported AEs with CGRP mAbs involved injection-site events (injection pain and injection-site reactions including erythema, induration, and pruritus) in up to 30% of patients at 12 or 24 weeks. In the trials of oral preventive therapies, the most commonly reported AEs were fatigue, cognitive symptoms (including cognitive difficulties, difficulty with memory, concentration, and language), paresthesia, taste perversion, and weight change. Such AEs were not observed with CGRP mAbs. No head-to-head studies comparing eptinezumab with oral therapies for prophylaxis of episodic migraine were identified. In the placebo-controlled PROMISE-1 trial, the mean treatment effect (the difference between eptinezumab and placebo) was approximately 0.69 (100 mg dose) to 1.11 (300 mg dose) fewer migraine days per month. A greater proportion of patients receiving 100 and 300 mg eptinezumab experienced at least 50% reduction in migraines compared with placebo (50% and 56% vs. 37%, respectively). Evidence of CGRP mAbs is lacking in a certain group of patients such as children, older adults, and women during pregnancy and lactation as they were excluded from the pivotal RCTs. Given the limited availability of head-to-head trials of CGRP mAbs with currently available oral preventive therapies, lack of superiority of CGRP mAbs (erunemab, fremanezumab, and galcanezumab) versus oral preventive therapies in network meta-analysis, and limited long-term data on efficacy and safety of CGRP mAbs, the ability to ascertain the incremental benefit of CGRP mAbs in patients who are eligible to receive standard oral pharmacologic preventative therapy is limited. The evidence is insufficient to determine that the technology results in an improvement in the net health outcome.

For individuals who have episodic migraine not responsive to standard pharmacologic therapy who receive CGRP mAbs, the evidence includes multiple RCTs and a systematic review. Relevant outcomes are symptoms, change in disease status, QOL, and treatment-related morbidity. Multiple multicenter RCTs evaluating CGRP mAbs (erenumab, eptinezumab, fremanezumab, and galcanezumab) for the prevention of migraine in patients who had failed 2 to 4 other preventative treatments have been published. These trials have consistently demonstrated that CGRP mAbs reduced monthly migraine days in the range of 1.6 to 3.5 days compared to a placebo. A pivotal trial of eptinezumab (PROMISE-1) did not specifically include or exclude patients with a documented failure of previous preventive therapy. In the PROMISE-1 trial, the mean treatment effect (the difference between eptinezumab and placebo) was approximately 0.69 ( 100 mg dose) to 1.11 (300 mg dose) fewer migraine days per month. A systematic review demonstrated that mAbs targeting the CGRP molecule (ie, eptinezumab, fremanezumab, and galcanezumab) are potentially superior to those targeting the CGRP receptor (ie, erenumab) in reducing monthly migraine days (mean difference, -1.55 days) and improving at least 50% response rate (relative risk [RR] , 1.52). While there are uncertainties about long-term efficacy and safety, the observed magnitude of benefit of erunemab, fremanezumab, galcanezumab, and eptinezumab observed in pivotal RCTs represents a potential benefit to patients who have exhausted other preventive treatment options; therefore, CGRP mAbs may be an effective second-line option in these patients. The evidence is sufficient to determine that the technology results in an improvement in the net health outcome.

For individuals who have chronic migraine who are eligible to receive standard pharmacologic preventative therapy who receive CGRP mAbs, the evidence includes multicenter RCTs and a systematic review. Relevant outcomes are symptoms, change in disease status, QOL, and treatment-related morbidity. The HER-MES trial compared erenumab to topiramate in patients with migraines occurring at least 4 days per month (ie, patients with episodic and chronic migraine). Erenumab demonstrated a reduction in the proportion of patients who discontinued the medication due to an AE (10.6% vs. 38.9%), which was the primary outcome, and an improvement in the proportion of patients with at least 50% reduction in monthly migraine days from baseline over months 4 to 6 (55.4% vs. 31.2%). Also, patients in the erenumab group experienced a significantly greater reduction in mean monthly migraine days versus topiramate (-5.86 days vs. -4.02 days). The applicability of the HER-MES trial is challenging due to the inclusion of a broad migraine population without stratification of results by migraine type (episodic vs. chronic) or prior treatment. Furthermore, the trial enrolled a mostly White race and female population and had a potential for unblinding due to the known side effect profile of topiramate.Four placebo-controlled, multicenter RCTs, with a total of nearly 4000 adult patients, have been identified on CGRP mAbs for the preventative treatment of chronic migraine. Compared to controls, CGRP mAbs (erenumab, fremanezumab, galcanezumab, and epitenezumab) decreased the mean number of migraine days by up to 2.6 days. More patients treated with the mAbs had at least 50% reduction in migraines. The most commonly reported AEs with CGRP mAbs involved injection-site events. A network meta-analysis showed no statistical difference in reduction in monthly migraine days or 50% decrease in monthly migraine days when CGRP mAbs were compared to active therapies (onabotulinum toxin A or topiramate). This meta-analysis did not include data on eptinezumab.No head-to-head studies comparing eptinezumab with oral therapies for prophylaxis of chronic migraine were identified. In the placebo-controlled PROMISE-2 trial, the mean treatment effect (the difference between eptinezumab and placebo) was approximately 2 (100 mg dose) to 2.6 (300 mg dose) fewer migraine days/month. A greater proportion of patients receiving 100 and 300 mg eptinezumab experienced ≥50% reduction in migraines compared to placebo (58% and 61% vs 39%). Evidence of CGRP mAbs is lacking in a certain group of patients such as children, older adults, and women during pregnancy and lactation as they were excluded from the pivotal RCTs. Given the limited availability of head-to-head trials of CGRP mAbs with currently available oral preventive therapies, lack of superiority of CGRP mAbs (erenumab, fremanezumab, and galcanezumab) versus oral preventive therapies in network meta-analysis, and limited long-term data on efficacy and safety of CGRP mAbs, it is difficult to ascertain incremental benefit of CGRP mAbs in patients who are eligible to receive standard oral pharmacologic preventative therapy. The evidence is insufficient to determine that the technology results in an improvement in the net health outcome.

For individuals who have chronic migraine not responsive to standard pharmacologic therapy who receive CGRP mAbs, the evidence includes multiple multicenter RCTs. Relevant outcomes are symptoms, change in disease status, QOL, and treatment-related morbidity. Multiple multicenter RCTs for CGRP mAbs (erenumab, fremanezumab, galcanezumab, and eptinezumab) for the prevention of migraine in patients with at least 4 migraine days per month who had failed 2 to 4 other preventative treatments have been published. As previously noted, these trials have consistently demonstrated that a greater proportion of patients in the treated group had a reduction in monthly migraine days compared to the placebo group. The CONQUER and FOCUS trials for galcanezumab and fremanezumab, respectively, published results for the subgroup of patients with chronic migraine and prior treatment failure. In these analyses, galcanezumab and fremanezumab decreased the mean number of migraine days by up to 3.8 days versus control. The pivotal trial of eptinezumab (PROMISE-2) did not specifically include or exclude patients with a documented failure of previous preventive therapy. In the PROMISE-2 trial, the mean treatment effect (the difference between eptinezumab and placebo) was approximately 2 (100 mg dose) to 2.6 (300 mg dose) fewer migraine days per month. Further, a greater proportion of patients receiving eptinezumab 100 and 300 mg experienced at least 50% reduction in migraines compared to placebo (58% and 61% vs. 39%). While there are uncertainties about the durability of efficacy as well as safety, the observed magnitude of benefit of erunemab, fremanezumab, galcanezumab, and eptinezumab observed in pivotal trials represents a potential benefit to patients who have exhausted other preventive treatment options. The evidence is sufficient to determine that the technology results in an improvement in the net health outcome.

For individuals who have episodic cluster headache who receive CGRP mAbs, the evidence includes 1 multicenter RCT. Relevant outcomes are symptoms, change in disease status, QOL, and treatment-related morbidity. No head-to-head studies comparing CGRP mAbs with oral therapies for episodic cluster were identified. One RCT with 106 adult patients reported a reduction in the frequency of weekly cluster headaches by 8.7 days among those treated with galcanezumab versus 5.2 days in the placebo arm over weeks 1 to 3. The proportion of patients with at least 50% reduction in weekly cluster headache attacks at week 3 was 71% and 53%, respectively. The most commonly reported AEs with galcanezumab involved injection-site events. Given the lack of head-to-head trials of CGRP mAbs with currently available oral therapies, and limited long term data on efficacy and safety of galcanezumab, it is difficult to ascertain incremental benefit of galcanezumab in patients who are eligible to receive standard oral pharmacologic preventative therapy. However, galcanezumab may be considered a reasonable second-line option in patients who fail to respond or in whom the standard oral pharmacologic agents are contraindicated. The evidence is sufficient to determine that the technology results in an improvement in the net health outcome.

For individuals who have chronic cluster headache who receive CGRP mAbs, the evidence includes an RCT. Relevant outcomes are symptoms, change in disease status, QOL, and treatment-related morbidity. The RCT reported no significant difference between galcanezumab and placebo in reduction of weekly chronic cluster headaches. The evidence is insufficient to determine that the technology results in an improvement in the net health outcome. update this based on published evidence.

For individuals who have acute migraine who receive CGRP mAbs, the evidence includes a single RCT. Relevant outcomes are symptoms, change in disease status, QOL, and treatment-related morbidity. Results from 1 multicenter RCT comparing eptinezumab with placebo in patients with a history of migraine for >1 year and experienced migraine on 4 to 15 days per month in the previous 3 months were reported. Results showed that eptinezumab administered during the first 6 hours of a migraine attack significantly reduced time to freedom from pain (4 hours vs 9 hours, respectively) and the most bothersome accompanying symptom (2 vs 3 hours, respectively) compared with placebo. The major limitation is the lack of head to head trials of CGRP mAbs with currently available oral therapies for treatment of acute migraine. Use of an intravenous (IV) treatment for acute migraine poses challenges to timely administration of the drug outside of a trial setting. Initiation of IV eptinezumab within 6 hours of headache at an infusion center may not be practical. In addition to limited duration of follow-up, other limitations include lack of QOL data, limited generalizability of the results to many additional patients groups such as children, older adults, and women during pregnancy and lactation. The evidence is insufficient to determine that the technology results in an improvement in the net health outcome.

Additional Information

Not applicable.

OBJECTIVE

The objective of this evidence review is to determine whether treatment with calcitonin gene-related peptide monoclonal antibodies improves the net health outcome in patients with migraine and cluster headaches.

POLICY STATEMENTS

Subcutaneously administered Food and Drug Administration (FDA)-approved monoclonal antibodies for calcitonin gene-related peptide may be considered medically necessary for the preventive treatment of episodic or chronic migraine under the following conditions:

• The individual is ≥ 18 years of age; AND

• Has ≥ 4 migraine headache days per month; AND

• Has failed a trial (eg, not effective or not tolerated) from ≥ 3 classes of prophylactic pharmacologic therapies (eg, anti-depressants, anticonvulsants, and beta-blockers, if not contraindicated) AND;

• Has not received botulinum toxin headache prophylaxis in the past 4 months.

Intravenously administered FDA-approved monoclonal antibody for calcitonin gene-related peptide may be considered medically necessary for the preventive treatment of episodic or chronic migraine under the following conditions:

• The individual is ≥ 18 years of age; AND

• Has ≥ 4 migraine headache days per month; AND

• Has failed a trial (eg, not effective or not tolerated) from ≥ 3 classes of prophylactic pharmacologic therapies (eg, anti-depressants, anticonvulsants, and beta-blockers, if not contraindicated) AND;

• Has not received botulinum toxin headache prophylaxis in the past 4 months.

Galcanezumab may be considered medically necessary for the treatment of episodic cluster headaches under the following conditions:

• The individual is ≥ 18 years of age; AND

• Individual has been diagnosed with episodic cluster headaches as defined as having at least 2 cluster periods lasting from 7 days to 1 year, separated by pain-free remission periods lasting at least 1 month;

• Individua has been unable to achieve a reduction in weekly cluster headache attack frequency with preventative medication(s).

Treatment with monoclonal antibodies for calcitonin gene-related peptide is considered investigational in all other situations including treatment of acute migraine.

POLICY GUIDELINES

Botulinum toxin is an approved treatment for migraine headache prophylaxis (see policy No. 5.01.05). Evidence is lacking on combined treatment with botulinum toxin and monoclonal antibodies for calcitonin gene-related peptide.

Pharmacologic therapies that have demonstrated efficacy in the preventive treatment of migraine are described in the Supplemental Information section.

Coding

See the Codes table for details./p>

BENEFIT APPLICATION

BlueCard/National Account Issues

State or federal mandates (eg, Federal Employee Program) may dictate that certain U.S. Food and Drug Administration-approved devices, drugs, or biologics may not be considered investigational, and thus these devices may be assessed only by their medical necessity.

Benefits are determined by the group contract, member benefit booklet, and/or individual subscriber certificate in effect at the time services were rendered. Benefit products or negotiated coverages may have all or some of the services discussed in this medical policy excluded from their coverage.

BACKGROUND

Migraine and Cluster Headache

Migraine is a headache disorder characterized by recurrent moderate to severe headaches with associated symptoms. Approximately 15% of the population have migraines, with a higher prevalence in women than in men.^1, The typical migraine headache is throbbing, unilateral, and aggravated by motion. Migraines are frequently associated with nausea, vomiting, photophobia, and phonophobia, although other neurological symptoms may occur. Migraine attacks can last from several hours to several days and are often preceded by transient neurological symptoms (eg, visual disturbance) known as migraine aura.

Migraines are categorized as episodic or chronic depending on the frequency of attacks. Episodic migraine is defined as migraine or headache for less than 15 days per month and accounts for more than 90% of cases of migraine. Chronic migraine is defined as 15 or more headache days each month, of which at least 8 are migraine days.

Migraine was previously thought to be primarily vascular, but recent evidence suggests that sensitization of pain pathways in the central nervous system may be involved.^2,At least 3 messenger molecules are thought to be involved during migraine attacks: nitric oxide, 5-hydroxytryptamine, and calcitonin gene-related peptide (CGRP). CGRP is produced in both peripheral and central neurons and is a potent vasodilator. Some preclinical studies suggest that during a migraine, sensory neurons in the trigeminal ganglion release CGRP from their peripherally projecting nerve endings in the meninges.

Cluster headache is a disabling primary headache disorder that is characterized by attacks of intense headache on 1 side of the head, with associated agitation or restlessness, as well as by cranial autonomic symptoms, such as lacrimation, conjunctival injection, and nasal congestion. Attacks last 15 to 180 minutes when untreated and can occur once or several times per day during cluster headache periods that can last for weeks to months.^3, Cluster headaches, like migraines, are categorized as episodic or chronic depending on the frequency of the attacks. Episodic cluster headache is defined as at least 2 cluster periods lasting 7 to 365 days and separated by pain-free remission periods of 1 month or longer. Chronic cluster headache attacks occur for 1 year or longer without remission, or with remission periods lasting less than 1 month.

Treatment

Symptomatic treatment is available for both migraine attacks and cluster headaches. Initial treatment for migraine is the use of oral pain relievers, but those with severe disease typically try multiple therapies, including both non-drug (eg, exercise, diet, relaxation techniques) and drug therapies. Acute drug therapies, such as triptans, treat symptoms after they’ve started. For patients who experience more than 4 migraine days per month, preventive treatment may be recommended and include certain antidepressants, anti-seizure medications, beta-blockers, and, for those with chronic migraine, onabotulinum toxin A (see evidence review 5.01.50). Oral medications approved by the U.S. Food and Drug Administration (FDA) for migraine prophylaxis include topiramate, propranolol, timolol, and valproate. All of these medications have contraindications and side effects that limit their use. For many people, preventive therapies are not effective or have intolerable side effects.

For acute management of cluster headache, oxygen and sumatriptan are typically recommended. Intranasal dihydroergotamine, intranasal lidocaine, and intranasal capsaicin are less studied alternatives in place of the first-line recommendations. Oral sumatriptan, verapamil, divalproex, and prednisone are among the agents that can be used for episodic cluster headache prophylaxis, either reducing the frequency of episodic cluster headaches or severity. Verapamil and lithium are agents used in chronic cluster headache treatment. None of these agents, however, are FDA approved for the treatment of cluster headache.

This evidence review addresses humanized monoclonal antibodies (mAbs) that bind to the CGRP receptor or CGRP molecule and are designed for the prevention or treatment of migraine or cluster headache (see Table 1). The role of CGRP in cluster headache provided the rationale for utilizing humanized mAbs in preventing migraine and cluster headache. Unlike oral drug therapy, mAbs are not metabolized by the liver can remain in the body for weeks or months.

REGULATORY STATUS

Table 1 summarizes the CGRP mAbs that have been approved by the FDA. Gepants are a pharmacologically distinct class of drugs that also work via the CGRP pathway. These are small molecules that work by acting as CGRP receptor antagonists and are given orally. Gepants are utilized for acute treatment of migraine and are not within the scope of this policy. In December 2019, ubrogepant (Ubrelvy^®) was the first-in-class oral CGRP antagonist approved by FDA for the acute treatment of migraine with or without aura in adults. In February 2020, rimegepant (Nurtec^® ODT) was the second FDA gepant approved for the acute treatment of migraine with or without aura in adults. In May 2021, rimegepant (Nurtec ODT) was approved for preventive treatment of episodic migraine in adults. In September 2021, atogepant (Qulipta™) was approved for the preventive treatment of episodic migraine in adults.

Table 1. Monoclonal Antibody CGRP Antagonists Approved by FDA

   BLA: biologics license application; CGRP: calcitonin gene-related peptide; FDA: U.S. Food and Drug Administration.

RATIONALE

This evidence review was created in December 2018 with a search of the PubMed database and has been updated regularly with searches of the PubMed database. The most recent literature update was performed through November 4, 2024.

Evidence reviews assess the clinical evidence to determine whether the use of technology improves the net health outcome. Broadly defined, health outcomes are the length of life, quality of life (QOL), and ability to function¾including benefits and harms. Every clinical condition has specific outcomes that are important to patients and managing the course of that condition. Validated outcome measures are necessary to ascertain whether a condition improves or worsens; and whether the magnitude of that change is clinically significant. The net health outcome is a balance of benefits and harms.

To assess whether the evidence is sufficient to draw conclusions about the net health outcome of technology, two domains are examined: the relevance, and quality and credibility. To be relevant, studies must represent 1 or more intended clinical use of the technology in the intended population and compare an effective and appropriate alternative at a comparable intensity. For some conditions, the alternative will be supportive care or surveillance. The quality and credibility of the evidence depend on study design and conduct, minimizing bias and confounding that can generate incorrect findings. The randomized controlled trial (RCT) is preferred to assess efficacy; however, in some circumstances, nonrandomized studies may be adequate. RCTs are rarely large enough or long enough to capture less common adverse events (AEs) and long-term effects. Other types of studies can be used for these purposes and to assess generalizability to broader clinical populations and settings of clinical practice.

Promotion of greater diversity and inclusion in clinical research of historically marginalized groups (e.g., People of Color [African-American, Asian, Black, Latino and Native American]; LGBTQIA (Lesbian, Gay, Bisexual, Transgender, Queer, Intersex, Asexual); Women; and People with Disabilities [Physical and Invisible]) allows policy populations to be more reflective of and findings more applicable to our diverse members. While we also strive to use inclusive language related to these groups in our policies, use of gender-specific nouns (e.g., women, men, sisters, etc.) will continue when reflective of language used in publications describing study populations.

Population Reference No. 1 

Episodic Migraine Who Are Eligible to Receive Standard Pharmacologic Preventative Therapy

Clinical Context and Therapy Purpose

The purpose of monoclonal antibodies (mAbs) targeting the calcitonin gene-related peptide (CGRP) receptor (erenumab) and CGRP molecule (eptinezumab, fremanezumab, and galcanezumab) in patients who have episodic migraine who are eligible to receive standard pharmacologic preventative therapy is to provide a treatment option that is an alternative to or an improvement on existing therapies.

The following PICO was used to select literature to inform this review.

Populations

The relevant population of interest is patients with episodic migraine who are eligible to receive standard pharmacologic preventative therapy.

Interventions

The therapy being considered is mAbs targeting the CGRP molecule or the CGRP receptor. Subcutaneous injections in the abdomen, thigh, or upper arm are self-administered with prefilled syringes or automatic injectors. Intravenous (IV) injections are administered by a healthcare provider in a healthcare setting. The U.S. Food and Drug Administration (FDA)-approved CGRP mAbs are described in Table 1.

Comparators

The following therapies are currently used for migraine prevention: oral medications approved by the FDA for migraine prophylaxis include topiramate, propranolol, timolol, and valproate. The decrease in migraine days per month with oral prophylactic treatments ranges from 1.2 to 1.8 after subtracting the placebo response.^2,

For patients who have failed or cannot tolerate oral prophylactic treatments, management involves supportive care.

Outcomes

The general outcomes of interest are migraine intensity and frequency, and the effect on function and QOL (see Table 2). The most common outcome measures are a decrease in migraine/headache days per month compared with baseline and the proportion of responders to the treatment (typically 12 weeks treatment duration), defined as those patients who report a more than a 50%, 75%, or 100% decrease in migraine days per month compared to pre-treatment. The acute effect of mAbs on migraine severity and frequency should be measured over 3 to 6 months. Safety and long-term efficacy may be observed at 1 to 2 years.

Table 2. Patient-Reported Outcome Measures

Study Selection Criteria

Methodologically credible studies were selected using the following principles:

• To assess efficacy outcomes, comparative controlled prospective trials were sought, with a preference for RCTs;

• In the absence of such trials, comparative observational studies were sought, with a preference for prospective studies.

• To assess long-term outcomes and adverse events, single-arm studies that capture longer periods of follow-up and/or larger populations were sought.

• Consistent with a 'best available evidence approach,' within each category of study design, studies with larger sample sizes and longer durations were sought.

• Studies with duplicative or overlapping populations were excluded.

Review of Evidence

Meta-Analysis

The Institute for Clinical and Economic Review conducted a network meta-analysis that included 18 trials: 8 placebo-controlled trials of CGRP mAbs and 10 trials assessing oral preventive therapies.^8, Overall, there were greater reductions in monthly migraine days, higher odds of 50% response, and greater reductions in days using acute medication per month for all interventions including CGRP mAbs versus placebo. Results comparing CGRP mAbs to oral preventive therapies were not statistically different. Compared to placebo, reduction in monthly migraine days with erunemab was 1.3 (70 mg monthly) to 1.9 days (140 mg monthly), fremanezumab 1.2 (675 mg quarterly) to 1.6 days (225 mg monthly), galcanezumab 1.8 days (120 as well as 240 mg monthly), topiramate 1.2 (100 mg/day) to 1.0 (200 mg/day), amitriptyline 1.1 days (25-100 mg/day) and 1.2 days (160 mg/day). This review was published prior to the FDA approval of eptinezumab and therefore does not include data on epitenuzumab.

Across the CGRP trials, there were no differences in the meta-analyzed odds of discontinuing for any cause, discontinuing due to AEs, or experiencing serious AEs with the CGRP mAbs versus other preventive therapies. The most commonly reported AEs involved injection-site events (injection pain and injection-site reactions including erythema, induration, and pruritus) in up to 30% of patients at 12 or 24 weeks. In the trials of other preventive therapies, the most commonly reported AEs were fatigue, cognitive symptoms (including cognitive difficulties, difficulty with memory, concentration, language), paresthesia, taste perversion, and weight change. These AEs were not frequently observed in the CGRP mAbs trials.

Randomized Controlled Trials

The first RCT to compare the efficacy of a mAb targeting the CGRP pathway to that of a standard care oral preventive drug was published by Reuter et al in 2022 (see Table 3).^9, The HER-MES trial (head-to-head study of erenumab against topiramate – migraine study to assess tolerability and efficacy in a patient-centered setting) was a 24-week, double-blind, double-dummy, phase 4 trial in which 777 patients with migraines occurring ≥4 days per month were randomized to erenumab 70 or 140 mg once monthly (n=389) or topiramate 50 to 100 mg per day (n=388). Patients were eligible if they had not received prior prophylactic migraine treatment or, due to lack of efficacy or tolerability, had failed or had not been suitable for 3 or fewer prior prophylactic treatments. In the initial protocol, only patients with episodic migraine (4 to 14 monthly migraine days over the last 3 months prior to screening) were eligible. However, in order to implement the recommendation of the health technology assessment body to include a full migraine population, a protocol amendment permitted patients with chronic migraine to be enrolled. At the time of the protocol change, 43.8% of the total study population, all of whom had episodic migraine, had been randomized. At baseline, 64.7% of patients had 8 to 14 monthly migraine days, 24% had 4 to 7 monthly migraine days, and 11% had ≥15 monthly migraine days; the mean number of monthly headache days and monthly migraine days was 11.4 and 10.3, respectively.

Seven additional multi-center pivotal trials with over 5000 adults with episodic migraine have been published that compared erenumab, fremanezumab, galcanezumab, and eptinezumab with placebo (see Table 3). The average number of migraine days per month ranged from 4 to 14 in these studies (see Table 4). In ARISE and STRIVE (phase 3, randomized, double-Blind, placebo-controlled studies to evaluate the efficacy and safety of AMG 334 in migraine prevention), about 40% of patients had a history of preventive treatment failure, while in EVOLVE-1 (a phase 3, randomized, double-Blind, placebo-controlled study of LY2951742 in patients with episodic migraine),18% of patients had failed preventive treatment. All of the studies with erenumab, fremanezumab, and galcanezumab excluded patients who had failed ≥2 or 3 classes of preventive treatments. In the PROMISE-1 trial (a parallel group, double-blind, randomized, placebo controlled, trial to evaluate the efficacy and safety of ALD403 administered intravenously in patients with frequent episodic migraines) with eptinezumab, patients were allowed to use concurrent acute migraine or headache medications, including migraine-specific medications (i.e., triptans, ergotamine derivatives), during the trial. Further, the trial protocol did not specify the inclusion of patients based on failure of any previous preventive therapy nor specify exclusion of patients who had failed ≥2 or 3 classes of preventive treatments. As per the protocol, eligible patients did not regularly use (>7 days) preventive headache medication within 2 months prior to screening and during the 28-day period prior to randomization; short-term (<7 days/month) prophylactic treatment for menstrual migraine was allowed.

In 2024, Pozo-Rosich et al published an active-controlled RCT (APPRAISE) investigating the use of erenumab versus oral migraine preventative therapies (see Table 3).^17, The APPRAISE study was a 12-month, prospective, open-label, multicenter, active-controlled, Phase 4 RCT comparing sustained benefits of erenumab and oral prophylactic medications in adults with episodic migraines in which 621 patients with migraines occurring ≥4 days per month but <15 days per month were randomized to erenumab 70 or 140 mg once monthly (n=413) or nonspecific oral migraine preventive medications, including beta-blockers, topiramate, and tricyclic antidepressants (n=208). Patients were eligible if they had episodic migraine, as defined above, and had, due to lack of efficacy or tolerability, failed 1 or 2 prior prophylactic treatments. The primary endpoint was a composite of the proportion of patients completing 1 year of the randomized treatment while also achieving 50% or greater reduction from baseline in monthly migraine days at month 12.

Table 3. Summary of Key RCT Characteristics in Patients with Episodic Migraine

  FDA: US Food and Drug Administration; IV: intravenous; RCT: randomized controlled trial; TCA: tricyclic antidepressants. a Dose of 30 mg is not FDA approved and results are not summarized for this dose group

Table 4. Summary of Clinical Characteristics in Patients with Episodic Migraine

  RCT: randomized controlled trial; SD: standard deviation. a Reported only for prior topiramate use b Number of migraine days per month reported as a range between 4 treatment groups

In the active-controlled trial (Reuter et al 2022) comparing erenumab with topiramate, results demonstrated that the primary outcome of the proportion of patients who discontinued the medication due to an AE was lower with erenumab (10.6%) versus topiramate (38.9%; p<.001). A secondary outcome of the proportion of patients with ≥50% reduction in monthly migraine days from baseline over months 4 to 6 of the double-blind treatment phase was 55.4% with erenumab versus 31.2% with topiramate (p<.001). Also, patients in the erenumab group experienced a significantly greater reduction in mean monthly migraine days versus topiramate (-5.86 days vs. -4.02 days, respectively; p<.001).

In the active-controlled trial (Pozo-Rosich et al 2024) comparing erenumab with nonspecific oral preventive medications, results demonstrated that the primary outcome of the proportion of patients completing 1 year of the randomized treatment while also achieving ≥50% reduction from baseline in monthly migraine days at month 12 was greater with erenumab (56.2%) versus oral preventive medications (16.8%; p<.001). A secondary outcome showed that significantly more patients in the erenumab group completed the 12-month study taking the initially randomized treatment (86.9%) versus those in the oral medications arm (37.5%; p<.001). The mean change from baseline in cumulative average monthly migraine days was significantly greater with erenumab compared to the oral medications group. At month 12, the mean change from baseline in monthly migraine days was -4.32 days with erenumab and -2.65 days with oral medications (mean treatment difference, -1.67; p<.001). The incidence of AEs leading to treatment discontinuation was approximately 8 times lower in patients treated with erenumab (2.9%) versus oral medications (23.3%).

In the placebo-controlled studies with erenumab, fremanezumab, and galcanezumab, patients receiving injections of a CGRP mAb had an average decrease of 2.9 to 4.8 monthly migraine days, while the placebo group had a decrease of an average of 1.8 to 3.2 monthly migraine days (see Table 5). This resulted in an improvement of 1.0 to 2.0 monthly migraine days with the mAbs. The odds ratio for a 50% decrease in monthly migraine days ranged from 1.6 to 2.8. The decrease in monthly migraine-specific medication days was 0.6 to 4 days greater with mAb treatment. The most common AE was injection site pain. Serious AEs ranged from 0.6% to 2.9%.

Smith et al (2020) reported extended data on eptinezumab from the PROMISE-1 trial at 1 year of follow-up. The reduction in mean monthly migraine days at weeks 1 to 12, weeks 13 to 24, weeks 25 to 36, and weeks 37 to 48 with eptinezumab 100 mg dose was −3.9, −4.5, −4.7, and −4.5 days, respectively; with 300 mg dose was −4.3, −4.8, −5.1, and −5.3 days, respectively; and with placebo was −3.2, −3.8, −4.0, and −4.0 days, respectively. The proportions of patients with ≥50% reduction in migraines (ie, migraine responder rate) were similar across the eptinezumab groups during each 12-week dosing interval, ranging from 50% to 56% (vs 37% with placebo) during the first dosing interval (weeks 1 to 12) and from 65% to 70% (vs. 55% with placebo) during the fourth interval (weeks 37 to 48).^18,

Goadsby et al (2020) reported long-term results of fremanezumab in episodic and chronic migraine from the pivotal HALO trials as well as new patients. The 52-week, multicenter, randomized, double-blind, parallel-group study enrolled 1890 patients; 394 and 386 patients with episodic migraine received quarterly or monthly fremanezumab, respectively. Extended data at 52 weeks showed sustained efficacy of fremanezumab from baseline.^19, In patients with episodic migraine, fremanezumab reduced monthly migraine days (quarterly dosing -5.2 days, monthly dosing -5.1 days) and headache days of at least moderate severity (quarterly dosing -4.4 days, monthly dosing -4.2 days) from baseline to 12 months. Approximately two-thirds of patients with episodic migraine (quarterly dosing 66%, monthly dosing 68%) had a ≥50% reduction in the monthly average number of migraine days from baseline to 12 months.

Table 5. Summary of Key RCT Results in Patients with Episodic Migraine

  AE: adverse event; CI: confidence interval; COPD: chronic obstructive pulmonary disease; Diff: difference; OR: odds ratio; mAbs: monoclonal antibody; MPFID-PI: Migraine Physical Function Impact Diary-Physical Impairment domain; MSQRFR, Migraine Specific Quality of Life questionnaire, version 2.1, Role-Function Restrictive; RCT: randomized controlled trial; SE: standard error.

The applicability of the HER-MES trial is challenging due to the inclusion of a broad migraine population without stratification of results by migraine type (episodic vs. chronic) or prior treatment. Furthermore, the trial enrolled a mostly White race and female population (99.2% and 85.8%, respectively) and had a potential for unblinding due to the known side effect profile of topiramate (paresthesia, etc). No major limitations were identified in the study design and conduct for the placebo-controlled trials (see Tables 6 and 7). All trials had comparable arms at baseline, did not have differential attrition, were patient and physician/investigator blinded, had clear definitions of intervention and outcomes, and used an intent-to-treat analysis or a modified version. In terms of relevance limitations of this evidence base, the trials compared CGRP mAbs to placebo, in most trials restricted the patient population to those for whom ≤2 or 3 other preventive therapies had failed, were short-term in duration, and enrolled a majority White race and female population. QOL outcomes measures are considered critical in migraine and patients seek improvement in the QOL measures. However, such QOL measures were reported infrequently in the trials and when reported, the follow-up period was short. Generalizability of the results generated from the RCTs is limited and may not apply to many patients who are likely be treated with CGRP mAbs, such as those who have tried >3 preventive therapies, those with comorbidities and other groups of patients such as children, older adults, and women during pregnancy and lactation. Further, as these agents have a novel mechanism of action, there is limited certainty about the durability of benefit as well safety beyond 1 to 2 years. There are concerns, particularly AEs which may manifest after a longer duration of treatment such as cardiovascular events or those that are rare. CGRP is involved in multiple physiological processes and some concerns exist about the long-term effects of continuous blocking of CGRP or its receptor due to CGRP’s cardiovascular protective role.^19,20,21,

No major limitations were identified in the study design and conduct for the placebo-controlled trials (see Tables 6 and 7). All trials had comparable arms at baseline, did not have differential attrition, were patient and physician/investigator blinded, had clear definitions of intervention and outcomes, and used an intent-to-treat analysis or a modified version. In terms of relevance limitations of this evidence base, the trials compared CGRP mAbs to placebo, in most trials restricted the patient population to those for whom ≤2 or 3 other preventive therapies had failed, were short-term in duration, and enrolled a majority White race and female population. Quality-of-life outcomes measures are considered critical in migraine and patients seek improvement in the QOL measures. However, such QOL measures were reported infrequently in the trials and when reported, the follow-up period was short. Generalizability of the results generated from the RCTs is limited and may not apply to many patients who are likely be treated with CGRP mAbs, such as those who have tried >3 preventive therapies, those with comorbidities and other groups of patients such as children, older adults, and women during pregnancy and lactation. Further, as these agents have a novel mechanism of action, there is limited certainty about the durability of benefit as well safety beyond 1 to 2 years. There are concerns, particularly AEs which may manifest after a longer duration of treatment such as cardiovascular events or those that are rare. CGRP is involved in multiple physiological processes and some concerns exist about the long-term effects of continuous blocking of CGRP or its receptor due to CGRP’s cardiovascular protective role.^20,21,22,

Table 6. Study Relevance Limitations

  RCT: randomized controlled trial.  The study limitations stated in this table are those notable in the current review; this is not a comprehensive gaps assessment. a Population key: 1. Intended use population unclear; 2. Study population is unclear; 3. Study population not representative of intended use; 4, Enrolled populations do not reflect relevant diversity; 5. Other. b Intervention key: 1. Not clearly defined; 2. Version used unclear; 3. Delivery not similar intensity as comparator; 4. Not the intervention of interest (e.g., proposed as an adjunct but not tested as such); 5: Other. c Comparator key: 1. Not clearly defined; 2. Not standard or optimal; 3. Delivery not similar intensity as intervention; 4. Not delivered effectively; 5. Other. d Outcomes key: 1. Key health outcomes not addressed; 2. Physiologic measures, not validated surrogates; 3. Incomplete reporting of harms; 4. Not establish and validated measurements; 5. Clinically significant difference not prespecified; 6. Clinically significant difference not supported; 7. Other. e Follow-Up key: 1. Not sufficient duration for benefit; 2. Not sufficient duration for harms; 3. Other

Table 7. Study Design and Conduct Limitations

  RCT: randomized controlled trial.  The study limitations stated in this table are those notable in the current review; this is not a comprehensive gaps assessment. a Allocation key: 1. Participants not randomly allocated; 2. Allocation not concealed; 3. Allocation concealment unclear; 4. Inadequate control for selection bias; 5. Other. b Blinding key: 1. Participants or study staff not blinded; 2. Outcome assessors not blinded; 3. Outcome assessed by treating physician; 4. Other. c Selective Reporting key: 1. Not registered; 2. Evidence of selective reporting; 3. Evidence of selective publication; 4. Other. d Data Completeness key: 1. High loss to follow-up or missing data; 2. Inadequate handling of missing data; 3. High number of crossovers; 4. Inadequate handling of crossovers; 5. Inappropriate exclusions; 6. Not intent to treat analysis (per protocol for noninferiority trials); 7. Other. e Power key: 1. Power calculations not reported; 2. Power not calculated for primary outcome; 3. Power not based on clinically important difference; 4. Other. f Statistical key: 1. Analysis is not appropriate for outcome type: (a) continuous; (b) binary; (c) time to event; 2. Analysis is not appropriate for multiple observations per patient; 3. Confidence intervals and/or p values not reported; 4. Comparative treatment effects not calculated; 5. Other.

Section Summary: Episodic Migraine Who Are Eligible to Receive Standard Pharmacologic Therapy

The HER-MES trial compared erenumab to topiramate in patients with migraines occurring ≥4 days per month (ie, patients with episodic and chronic migraine). Erenumab demonstrated a reduction in the proportion of patients who discontinued the medication due to an AE (10.6% vs. 38.9%), which was the primary outcome, and an improvement in the proportion of patients with ≥50% reduction in monthly migraine days from baseline over months 4 to 6 (55.4% vs. 31.2%). Also, patients in the erenumab group experienced a significantly greater reduction in mean monthly migraine days versus topiramate (-5.86 days vs. -4.02 days). The applicability of the HER-MES trial is challenging due to the inclusion of a broad migraine population without stratification of results by migraine type (episodic vs. chronic) or prior treatment. Furthermore, the trial enrolled a mostly White race and female population and had a potential for unblinding due to the known side effect profile of topiramate. Seven placebo-controlled RCTs with over 5000 adults showed a reduction of 1 to 2 monthly migraine days with the CGRP mAbs. A network meta-analysis showed no statistical difference in reduction in monthly migraine days or a 50% decrease in monthly migraine days when CGRP mAbs (erunemab, fremanezumab, and galcanezumab) were compared to oral preventive therapies. This meta-analysis did not include data on eptinezumab. The most commonly reported AEs with CGRP mAbs involved injection-site events (injection pain and injection-site reactions including erythema, induration, and pruritus) in up to 30% of patients at 12 or 24 weeks. In the trials of oral preventive therapies, the most commonly reported AEs were fatigue, cognitive symptoms (including cognitive difficulties, difficulty with memory, concentration, and language), paresthesia, taste perversion, and weight change. Such AEs were not observed with oral CGRP inhibitors. Evidence of CGRP mAbs is lacking in a certain group of patients such as children, older adults, and women during pregnancy and lactation as they were excluded from the pivotal RCTs. Given the limited availability of head-to-head trials of CGRP mAbs with currently available oral preventive therapies, lack of superiority of CGRP mAbs (erunemab, fremanezumab and galcanezumab) versus oral preventive therapies in network meta-analysis, and limited long-term data on efficacy and safety of CGRP mAbs, the ability to ascertain the incremental benefit of CGRP mAbs in patients who are eligible to receive standard oral pharmacologic preventative therapy is limited. No head-to-head studies comparing eptinezumab with oral therapies for prophylaxis of episodic migraine were identified. In the placebo-controlled PROMISE-1 trial, the mean treatment effect (the difference between eptinezumab and placebo) was approximately 0.69 ( 100 mg dose) to 1.11 (300 mg dose) fewer migraine days/month. A greater proportion of patients receiving 100 and 300 mg eptinezumab experienced ≥50% reduction in migraines compared to placebo (50%, 56% versus 37% respectively).

For individuals who have episodic migraine who are eligible to receive standard pharmacologic preventative therapy who receive CGRP mAbs, the evidence includes multiple randomized controlled trials (RCTs) and 1 network meta-analysis. Relevant outcomes are symptoms, change in disease status, quality of life (QOL), and treatment-related morbidity. The HER-MES trial compared erenumab to topiramate in patients with migraines occurring at least 4 days per month (ie, patients with episodic and chronic migraine). Erenumab demonstrated a reduction in the proportion of patients who discontinued the medication due to an adverse event (AE; 10.6% vs. 38.9%), which was the primary outcome, and an improvement in the proportion of patients with at least 50% reduction in monthly migraine days from baseline over months 4 to 6 (55.4% vs. 31.2%). Also, patients in the erenumab group experienced a significantly greater reduction in mean monthly migraine days versus topiramate (-5.86 days vs. -4.02 days). The applicability of the HER-MES trial is challenging due to the inclusion of a broad migraine population without stratification of results by migraine type (episodic vs. chronic) or prior treatment. Furthermore, the trial enrolled a mostly White race and female population and had a potential for unblinding due to the known side effect profile of topiramate. Seven placebo-controlled RCTs with over 5000 adults showed a reduction of 1 to 2 monthly migraine days with the CGRP mAbs. A network meta-analysis showed no statistical difference in reduction in monthly migraine days or a 50% decrease in monthly migraine days when CGRP mAbs (erunemab, fremanezumab, and galcanezumab) were compared to oral preventive therapies. This meta-analysis did not include data on eptinezumab. The most commonly reported AEs with CGRP mAbs involved injection-site events (injection pain and injection-site reactions including erythema, induration, and pruritus) in up to 30% of patients at 12 or 24 weeks. In the trials of oral preventive therapies, the most commonly reported AEs were fatigue, cognitive symptoms (including cognitive difficulties, difficulty with memory, concentration, and language), paresthesia, taste perversion, and weight change. Such adverse events were not observed with CGRP mAbs. No head-to-head studies comparing eptinezumab with oral therapies for prophylaxis of episodic migraine were identified. In the placebo-controlled PROMISE-1 trial, the mean treatment effect (the difference between eptinezumab and placebo) was approximately 0.69 (100 mg dose) to 1.11 (300 mg dose) fewer migraine days per month. A greater proportion of patients receiving 100 and 300 mg eptinezumab experienced at least 50% reduction in migraines compared with placebo (50% and 56% vs. 37%, respectively). Evidence of CGRP mAbs is lacking in a certain group of patients such as children, older adults, and women during pregnancy and lactation as they were excluded from the pivotal RCTs. Given the limited availability of head-to-head trials of CGRP mAbs with currently available oral preventive therapies, lack of superiority of CGRP mAbs (erunemab, fremanezumab, and galcanezumab) versus oral preventive therapies in network meta-analysis, and limited long-term data on efficacy and safety of CGRP mAbs, the ability to ascertain the incremental benefit of CGRP mAbs in patients who are eligible to receive standard oral pharmacologic preventative therapy is limited. The evidence is insufficient to determine that the technology results in an improvement in the net health outcome.

Population Reference No. 2

Episodic Migraine Not Responsive to Standard Pharmacologic Preventive Therapy

Clinical Context and Therapy Purpose

The purpose of mAbs targeting the CGRP receptor (erenumab) and CGRP molecule (eptinezumab, fremanezumab, and galcanezumab) in patients who have episodic migraine not responsive to standard pharmacologic preventive therapy is to provide a treatment option that is an alternative to or an improvement on existing therapies.

The following PICO was used to select literature to inform this review.

Populations

The relevant population of interest is patients with episodic migraine not responsive to standard pharmacologic preventive therapy.

Interventions

The therapy being considered is mAbs targeting the CGRP molecule or the CGRP receptor (see Table 1). Subcutaneous injections in the abdomen, thigh, or upper arm are self-administered with prefilled syringes or automatic injectors. Intravenous injections are administered by a healthcare provider in a healthcare setting.

Comparators

The following therapies are currently used for episodic migraine not responsive to standard pharmacologic preventive therapy: supportive care.

Outcomes

The general outcomes of interest are migraine intensity and frequency, the effect of the migraines or treatment on QOL as measured by instruments such as the 12-Item Short Form Health Survey, hospitalizations due to migraine, and adverse effects of the mAbs (see Table 2). Migraine severity and frequency are measured over 3 to 6 months.

Study Selection Criteria

Methodologically credible studies were selected using the following principles:

• To assess efficacy outcomes, comparative controlled prospective trials were sought, with a preference for RCTs;

• In the absence of such trials, comparative observational studies were sought, with a preference for prospective studies.

• To assess long-term outcomes and adverse events, single-arm studies that capture longer periods of follow-up and/or larger populations were sought.

• Consistent with a 'best available evidence approach,' within each category of study design, studies with larger sample sizes and longer durations were sought.

• Studies with duplicative or overlapping populations were excluded.

Review of Evidence

Systematic Reviews

Wang et al (2022) published a systematic review of placebo-controlled RCTs evaluating the effectiveness of CGRP mAbs for patients with migraines with prior treatment failure.^22, In total, 9 RCTs (N=3052) were included for the following agents: eptinezumab (DELIVER [summarized below]), erenumab (LIBERTY [summarized below], STRIVE [summarized above], and Hirata et al 2021 [not detailed in this review as only Japanese patients were enrolled], fremanezumab (FOCUS [summarized below]), and galcanezumab (CONQUER [summarized below], EVOLVE-1 and -2 [summarized above], and REGAIN [summarized below]). Five trials (55.6%) had follow-up until 24 weeks, and the others had follow-up until 12 weeks. Results demonstrated a greater reduction in mean monthly migraine days with mAbs targeting the CGRP molecule (mean difference [MD], -3.29 days; 95% credible interval [CrI], -3.97 to -2.76) and CGRP receptor (MD, -1.74 days; 95% CrI, -2.72 to -1.11), when compared to placebo. Furthermore, the mAbs targeting the CGRP molecule were superior to those targeting the CGRP receptor in reducing monthly migraine days (MD, -1.55 days; 95% CrI, -2.43 to -0.44) and improving ≥50% response rates (relative risk [RR], 1.52; 95% CrI, 1.04 to 2.21). Ranking probabilities suggest that galcanezumab 240 mg has the highest probability of being the best agent for reducing monthly migraine days (MD, -4.40 days), followed by fremanezumab (MD, -3.50 days), eptinezumab 300 mg (MD, -3.20 days), galcanezumab 120 mg (MD, -3.09 days), quarterly fremanezumab (MD, -3.11 days), eptinezumab 100 mg (MD, -2.70 days), erenumab 140 mg (MD, -1.81 days), and erenumab 70 mg (MD, -1.64 days).

Randomized Controlled Trials

One multicenter RCT (n=246), LIBERTY,evaluated erenumab for the prevention of migraine in patients who had failed 2 to 4 other preventative treatments (see Table 8). The characteristics of the patients are shown in Table 9. More patients in the mAb group had a 50% or greater and 75% or greater reduction in monthly migraine days compared to the placebo group (see Table 10), with an odds ratio of 2.7 (p=.002) and 3.2 (p=.025), respectively. The mAb-treated group had a reduction of 1.8 monthly migraine days compared to a 0.2-day reduction in the placebo group (p=.004). Patient-reported physical impairment on the Migraine Physical Function Impact Diary (MPFID) was significantly reduced compared to a placebo (-3.5, p=.003).^23, Goadsby et al 2021 reported long-term results at 64 weeks from the open-label extension phase of the LIBERTY trial that was completed by 204 of 240 (85.0%) patients. Among patients continuing erenumab, the 50% responder rate increased from 29.9% at weeks 9 to 12 to 44.3% at weeks 61 to 64.^24, The 50% responder rate in patients who initially received placebo and then switched to erenumab in the open-label extension phase increased to 50.0% at week 61 to 64 compared to 14.2% during the double-blind phase. Ferrari et al (2022) reported long-term results at 112 weeks from the open-label extension phase of the LIBERTY trial that was completed by 181 of 240 (75.4%) patients.^25, Reasons for discontinuation at this time point were mainly due to lack of efficacy (44.0%) and participant decision (37.0%). At 112 weeks, the 50% responder rate was 57.2% and the change from baseline in mean (standard deviation) monthly migraine days was -4.2 (5.0) days. Adverse events occurring in ≥10% of patients were nasopharyngitis, influenza, and back pain.

Ferrari et al (2019) reported the results of a randomized, double-blind, placebo-controlled trial (FOCUS). ^26, The trial enrolled 838 participants aged 18 to 70 years with episodic or chronic migraine (episodic n=329 [39%] or chronic n=509 [61%]) who had documented failure to 2 to 4 classes of migraine preventive medications in the past 10 years. Participants were randomized to fremanezumab (month 1, 675 mg; months 2 and 3: placebo), monthly fremanezumab (month 1: 225 mg in episodic migraine and 675 mg in chronic migraine; months 2 and 3: 225 mg in both migraine subgroups), or matched monthly placebo for 12 weeks. The primary outcome was mean change from baseline in the monthly average number of migraine days during the 12-week treatment period. Study characteristics, patient characteristics, and results of the total cohort including episodic or chronic migraine are reported in Tables 8, 9, and 10, respectively. Among the sub-group of episodic migraine, mean reduction from baseline in the monthly average number of migraine days during the 12 weeks after the first dose was greater versus placebo in participants with episodic migraine treated with quarterly fremanezumab (least squares mean [LSM] difference, -3.1 [95% CI, -3.9 to -2.2], p<.0001) and monthly fremanezumab (-3.1 [95% CI -4.0 to -2.3], p<.0001). Ashina et al (2021) reported the results of the open-label extension phase of the FOCUS trial. Episodic migraine and chronic migraine patients completing the 12-week double-blind period of the FOCUS trial entered the 12-week open-label extension and received 3 monthly doses of fremanezumab (225 mg) ^27, with 772 patients completing the open-label extension. Patients had fewer average monthly migraine days in the placebo, quarterly fremanezumab, and monthly fremanezumab dosing regimens, respectively, (mean [standard deviation] change from baseline: -4.7 [5.4]; -5.1 [4.7]; -5.5 [5.0]) and monthly headache days of at least moderate severity (-4.5 [5.0]; -4.8 [4.5]; -5.2 [4.9]). During the 12-week open-label extension, 38%, 45%, and 46% of patients, respectively, achieved a ≥50% reduction, and 16%, 15%, and 20%, respectively, achieved a ≥75% reduction in monthly migraine days

Mulleners et al (2020) reported the results of a multicenter, randomized, double-blind, placebo-controlled trial that enrolled 462 patients 18 to 75 years of age with episodic or chronic migraine who had a documented failure of preventive medications from 2 to 4 drug categories in the past 10 years owing to lack of efficacy or tolerability, or both (CONQUER).^28, Patients were randomized 1:1 to receive subcutaneous placebo or galcanezumab 120 mg per month (with a 240 mg loading dose administered as two 120 mg injections) for 3 months (see Tables 8 and 9). The primary outcome was the mean change from baseline in number of monthly migraine headache days during the 3-month treatment period. The results of this trial are summarized in Table 10. Furthermore, a total of 432 of 449 patients (96%) entered and completed a 6-month open-label extension phase of the CONQUER trial.^29, At 6 months, the mean change in monthly migraine days was -5.2 and -5.6, with placebo and galcanezumab, respectively, in the total population (episodic and chronic migraine). Among patients with episodic migraine, the mean change in monthly migraine headache days was -4.5 with placebo and -3.8 with galcanezumab. Among patients with chronic migraine, the mean change in monthly migraine headache days was -6.5 with placebo and -8.2 with galcanezumab. Adverse events were similar to those observed during the double-blind treatment phase.

Ashina et al (2022) evaluated eptinezumab for migraine prevention in adults with migraine and 2 to 4 previous preventive treatment failures in a multicenter, randomized trial comprising a 24-week double-blind, placebo-controlled period, and a 48-week dose-blinded extension period (DELIVER).^30, Patients with episodic or chronic migraine with ≥4 monthly migraine days were eligible for enrollment (see Tables 8 to 9). Enrolled patients were randomized to 1:1:1 to receive an IV infusion of eptinezumab (100 mg or 300 mg) or placebo every 12 weeks. The primary outcome was mean change from baseline in the monthly average number of migraine days during weeks 1 to 12. The results from weeks 1 to 12 of the double­ blind, placebo­-controlled study treatment period are summarized in Table 10. Results favoring eptinezumab 100 mg or 300 mg over placebo continued between weeks 13 to 24 with regards to reduction in mean monthly migraine days and 50% and 75% responder rates. The extension period of this trial is ongoing.

Goadsby et al (2023) reported on self-reported QOL measures from adults included in the DELIVER trial.^34, Investigators found that eptinezumab improved patient-reported outcomes more than placebo, starting at week 4 after treatment initiation and at all subsequent time points up to week 24. At week 12, overall health, measured by the EQ-5D-5L visual analog scale score, improved with eptinezumab treatment compared to placebo (difference from placebo in change from baseline: 100 mg, 5.1; 95% CI, 2.2 to 8.1; p<.001; 300 mg, 7.5; 95% CI, 4.5 to 10.4; p<.0001). Additionally, eptinezumab improved headache-related QOL, per the Headache Impact Test total score (difference from placebo in change from baseline: 100 mg, -3.8; 95% CI, -5.0 to -2.5; p<.0001; 300 mg, -5.4; 95% Ci, -6.7 to -4.2; p<.0001), including all Migraine-Specific QOL Questionnaire domains (p<.0001 for all comparisons). Both doses of eptinezumab improved patient-identified most bothersome symptoms compared to placebo at weeks 12 and 24 (p<.0001 for both comparisons). Results from this QOL trial are not included in the tables below.

Table 8. Summary of Key RCT Characteristics in Patients with Refractory Episodic Migraine

   IV: intravenous; LIBERTY: 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; RCT: randomized controlled trial.

Table 9. Summary of Clinical Characteristics in Patients with Refractory Episodic Migraine

   SD: standard deviation.

Table 10. Summary of Key RCT Results in Patients with Refractory Episodic Migraine

   CI: confidence interval; Diff: difference; MPFID: Migraine Physical Function Impact Diary; NR: not reported; OR: odds ratio; RCT: randomized controlled trial; SE: standard error. 1 Include number analyzed, effect in each group, and measure of effect (absolute or relative) with CI, 2 Describe the range of sample sizes, effects, and other notable features in text.

Relevance and design and conduct limitations of this trial are described in Tables 11 and 12. QOL outcomes measures are considered critical in migraine and patients seek improvement in the QOL measures. However, such QOL measures were not reported. Generalizability of the results generated from the RCTs is limited and may not apply to many patient groups such as children, older adults, and women during pregnancy and lactation. Further, as these agents have a novel mechanism of action, there is limited certainty about the durability of benefit as well safety beyond 1 to 2 years. There are concerns, particularly AEs which may manifest after a longer duration of treatment such as cardiovascular events or those that are rare. CGRP is involved in multiple physiological processes and some concerns exist about the long-term effects of continuous blocking of CGRP or its receptor due to CGRP’s cardiovascular protective role.^19,20,21,

Table 11. Study Relevance Limitations

   The study limitations stated in this table are those notable in the current review; this is not a comprehensive gaps assessment. a Population key: 1. Intended use population unclear; 2. Study population is unclear; 3. Study population not representative of intended use; 4, Enrolled populations do not reflect relevant diversity; 5. Other. b Intervention key: 1. Not clearly defined; 2. Version used unclear; 3. Delivery not similar intensity as comparator; 4. Not the intervention of interest (e.g., proposed as an adjunct but not tested as such); 5: Other. c Comparator key: 1. Not clearly defined; 2. Not standard or optimal; 3. Delivery not similar intensity as intervention; 4. Not delivered effectively; 5. Other. d Outcomes key: 1. Key health outcomes not addressed; 2. Physiologic measures, not validated surrogates; 3. Incomplete reporting of harms; 4. Not establish and validated measurements; 5. Clinically significant difference not prespecified; 6. Clinically significant difference not supported; 7. Other. e Follow-Up key: 1. Not sufficient duration for benefit; 2. Not sufficient duration for harms; 3. Other

Table 12. Study Design and Conduct Limitations

   The study limitations stated in this table are those notable in the current review; this is not a comprehensive gaps assessment. a Allocation key: 1. Participants not randomly allocated; 2. Allocation not concealed; 3. Allocation concealment unclear; 4. Inadequate control for selection bias. b Blinding key: 1. Not blinded to treatment assignment; 2. Not blinded outcome assessment; 3. Outcome assessed by treating physician. c Selective Reporting key: 1. Not registered; 2. Evidence of selective reporting; 3.Evidence of selective publication. d Data Completeness key: 1. High loss to follow-up or missing data; 2. Inadequate handling of missing data; 3. High number of crossovers; 4. Inadequate handling of crossovers; 5. Inappropriate exclusions; 6. Not intent to treat analysis (per protocol for noninferiority trials). e Power key: 1. Power calculations not reported; 2. Power not calculated for primary outcome; 3. Power not based on clinically important difference. f Statistical key: 1. Analysis is not appropriate for outcome type: (a) continuous; (b) binary; (c) time to event; 2. Analysis is not appropriate for multiple observations per patient; 3. Confidence intervals and/or p values not reported; 4.Comparative treatment effects not calculated.

Section Summary: Episodic Migraine Not Responsive to Standard Pharmacologic Preventive Therapy

Multiple multicenter RCTs and a systematic reviewevaluating CGRP mAbs (erenumab, eptinezumab, fremanezumab, and galcanezumab) for the prevention of migraine in patients who had failed 2 to 4 other preventative treatments have been published. These trials have consistently demonstrated that CGRP mAbs reduced monthly migraine days in the range of 1.6 to 3.5 days compared to a placebo. A pivotal trial of eptinezumab (PROMISE-1) did not specifically include or exclude patients with a documented failure of previous preventive therapy. In the PROMISE-1 trial, the mean treatment effect (the difference between eptinezumab and placebo) was approximately 0.69 ( 100 mg dose) to 1.11 (300 mg dose) fewer migraine days/month. A systematic review demonstrated that mAbs targeting the CGRP molecule are potentially superior to those targeting the CGRP receptor in reducing monthly migraine days (MD, -1.55 days) and improving ≥50% response rate (RR, 1.52). While there are uncertainties about the durability of efficacy as well as safety, the observed magnitude of benefit of erunemab, fremanezumab, galcanezumab, and eptinezumab observed in pivotal RCTs represents a potential benefit to patients who have exhausted other preventive treatment options.

For individuals who have episodic migraine not responsive to standard pharmacologic therapy who receive CGRP mAbs, the evidence includes multiple RCTs and a systematic review. Relevant outcomes are symptoms, change in disease status, QOL, and treatment-related morbidity. Multiple multicenter RCTs evaluating CGRP mAbs (erenumab, eptinezumab, fremanezumab, and galcanezumab) for the prevention of migraine in patients who had failed 2 to 4 other preventative treatments have been published. These trials have consistently demonstrated that CGRP mAbs reduced monthly migraine days in the range of 1.6 to 3.5 days compared to a placebo. A pivotal trial of eptinezumab (PROMISE-1) did not specifically include or exclude patients with a documented failure of previous preventive therapy. In the PROMISE-1 trial, the mean treatment effect (the difference between eptinezumab and placebo) was approximately 0.69 ( 100 mg dose) to 1.11 (300 mg dose) fewer migraine days per month. A systematic review demonstrated that mAbs targeting the CGRP molecule (ie, eptinezumab, fremanezumab, and galcanezumab) are potentially superior to those targeting the CGRP receptor (ie, erenumab) in reducing monthly migraine days (mean difference, -1.55 days) and improving at least 50% response rate (relative risk, 1.52). While there are uncertainties about long-term efficacy and safety, the observed magnitude of benefit of erunemab, fremanezumab, galcanezumab, and eptinezumab observed in pivotal RCTs represents a potential benefit to patients who have exhausted other preventive treatment options; therefore, CGRP mAbs may be an effective second-line option in these patients. The evidence is sufficient to determine that the technology results in an improvement in the net health outcome.

Population Reference No. 3 

Chronic Migraine Who Are Eligible to Receive Standard Pharmacologic Preventative Therapy

Clinical Context and Therapy Purpose

The purpose of mAbs targeting the CGRP receptor (erenumab) and CGRP molecule (eptinezumab, fremanezumab, and galcanezumab) in patients who have chronic migraine who are eligible to receive standard pharmacologic preventative therapy is to provide a treatment option that is an alternative to or an improvement on existing therapies.

The following PICO was used to select literature to inform this review.

Populations

The relevant population of interest is patients with chronic migraine who are eligible to receive standard pharmacologic preventative therapy

Interventions

The therapy being considered is mAbs targeting the CGRP molecule or the CGRP receptor (see Table 1). Subcutaneous injections in the abdomen, thigh, or upper arm are self-administered with prefilled syringes or automatic injectors. Intravenous injections are administered by a healthcare provider in a healthcare setting.

The following therapies are currently used for migraine prevention: oral medications approved by the FDA for migraine prophylaxis include topiramate, propranolol, timolol, and valproate. The decrease in migraine days per month with oral prophylactic treatments ranges from 1.2 to 1.8 after subtracting the placebo response.^2,

For patients who have failed or cannot tolerate oral prophylactic treatments, management involves supportive care.

Outcomes

The general outcomes of interest are migraine intensity and frequency, the effect of the migraines or treatment on function and QOL (see Table 2). The most common outcome measures are a decrease in migraine/headache days per month compared with baseline and the proportion of responders to the treatment (typically 12 weeks treatment duration), defined as those patients who report more than a 50%, 75% or 100% decrease in migraine days per month compared to pre-treatment. Migraine severity and frequency are measured in the last month of 3 to 6 months of treatment.

Study Selection Criteria

Methodologically credible studies were selected using the following principles:

• To assess efficacy outcomes, comparative controlled prospective trials were sought, with a preference for RCTs;

• In the absence of such trials, comparative observational studies were sought, with a preference for prospective studies.

• To assess long-term outcomes and adverse events, single-arm studies that capture longer periods of follow-up and/or larger populations were sought.

• Consistent with a 'best available evidence approach,' within each category of study design, studies with larger sample sizes and longer durations were sought.

• Studies with duplicative or overlapping populations were excluded.

Review of Evidence

Meta-Analysis

The Institute for Clinical and Economic Review conducted a network meta-analysis that included 11 trials: 3 placebo-controlled trials of CGRP mAbs and 8 trials assessing onabotulinum toxin A or topiramate.^8, Overall, there were greater reductions in monthly migraine days, higher odds of 50% response, and greater reductions in days using acute medication per month for all interventions including CGRP mAbs versus placebo. Results comparing CGRP mAbs to other preventive therapies were not statistically different. Compared to placebo, reduction in monthly migraine days was 2.4 days with erunemab (70 or 140 mg monthly), 1.3 and 1.7 days with fremanezumab (675 mg quarterly and 675/225 mg monthly, respectively), 1.7 days with topiramate (100 mg/day), and 2 days with onabotulinum toxin A (155 IU quarterly). Results comparing CGRP mAbs to active therapies were not statistically different. This review was published prior to the FDA approval of eptinezumab and therefore does not include data on epitenuzumab.

Randomized Controlled Trials

Four multicenter RCTs with 4 different mAbs, 3 of which had over 1000 patients, have been identified on CGRP mAbs for the preventive treatment of chronic migraine (see Table 13). In the studies with erenumab, fremanezumab, galcanezumab and epitenezumab, the mean number of migraine days per month ranged from 16. 1 to 19.5 days at baseline (see Table 14). Three of the studies specified exclusion of patients who had failed 2 or 3 or more classes of preventive treatments. Two of the studies allowed concurrent use of prophylactic medications. Compared to placebo injections, mAbs for CGRP resulted in a decrease of 1.8 to 2.6 monthly migraine days, a higher percentage of patients (13% to 23% higher) who had ≥50% reduction in monthly migraine days, and a decrease of 1.8 to 2.6 migraine-specific medication days compared to patients treated with placebo (all p<.001, see Table 15).

In the PROMISE-2 trial, treatment with eptinezumab during the primary 12-week treatment period led to a reduction in approximately 7 to 8 migraine days/month, whereas placebo treated patients had a reduction of approximately 6 migraine days/month, both groups improving on average, from a baseline rate of 16 migraine days/month. The mean treatment effect (the difference between eptinezumab and placebo) was approximately 1 to 2 fewer migraine days/month. Silberstein et al (2020) reported extended data for the PROMISE-2 trial at 24 weeks. In this analysis, the magnitude of efficacy that eptinezumab achieved during the first dosing interval at 12 weeks was sustained through 24 weeks.^35, The reduction in mean monthly migraine days at 12 weeks (100 mg, -7.7 days; 300 mg, -8.2 days; placebo, -5.6 days) was further decreased at 24 weeks (100 mg, -8.2 days; 300 mg, -8.8 days; placebo, -6.2 days) with both doses of eptinezumab demonstrating consistently greater reductions from baseline compared to placebo. The ≥50% and ≥75% migraine responder rates increased after a second dose, with more eptinezumab-treated patients experiencing migraine response than placebo patients (≥50% response rate at weeks 13 to 24: 100 mg, 61.0%; 300 mg, 64.0%; placebo, 44.0%; and ≥75% response rate at weeks 13 to 24: 100 mg, 39.3%; 300 mg, 43.1%; placebo, 23.8%).

Goadsby et al (2020) reported long-term results of fremanezumab in episodic and chronic migraine from the pivotal HALO trials as well as new patients. The 52-week, multicenter, randomized, double-blind, parallel-group study enrolled 1,890 patients; 551 and 559 patients with episodic migraine received quarterly or monthly fremanezumab, respectively. Extended data at 52 weeks showed sustained efficacy of fremanezumab from baseline.^19, In patients with chronic migraine, fremanezumab reduced monthly migraine days (quarterly dosing -7.2 days, monthly dosing -8.0 days) and headache days of at least moderate severity (quarterly dosing -6.4 days, monthly dosing -6.8 days) from baseline to 12 months. More than half of the patients with chronic migraine (quarterly dosing 53%, monthly dosing 57%) had a ≥50% reduction in monthly average number of migraine days from baseline to 12 months.

Pozo-Rosich et al (2022) reported on a 9-month open-label extension of the REGAIN trial.^36, A total of 1022 of 1033 patients (99%) opted to enter the open-label extension and 825 patients (81%) completed this phase of the trial. The mean change in the number of monthly migraine days decreased 8.5 days with placebo, 9.0 days with galcanezumab 120 mg, and 8.0 days with galcanezumab 240 mg; the proportion of patients with ≥50% response was 57%, 57%, and 53%, respectively.

The HER-MES trial was previously introduced (see Tables 3 and 4). In this 24-week, double-blind, double-dummy, Phase 4 trial, 777 patients with migraines occurring ≥4 days per month were randomized to erenumab 70 or 140 mg once monthly (n=389) or topiramate 50 to 100 mg per day (n=388). Patients were eligible if they had not received prior prophylactic migraine treatment or, due to lack of efficacy or tolerability, had failed or had not been suitable for 3 or fewer prior prophylactic treatments. In the initial protocol, only patients with episodic migraine (4 to 14 monthly migraine days over the last 3 months prior to screening) were eligible. However, in order to implement the recommendation of the health technology assessment body to include a full migraine population, a protocol amendment permitted patients with chronic migraine to be enrolled. At the time of the protocol change, 43.8% of the total study population, all of whom had episodic migraine, had been randomized. At baseline, 64.7% of patients had 8 to 14 monthly migraine days, 24% had 4 to 7 monthly migraine days, and 11% had ≥15 monthly migraine days; the mean number of monthly headache days and monthly migraine days was 11.4 and 10.3, respectively. Results of this trial are summarized in the section focused on the use of CGRP mAbs in patients with episodic migraine who are eligible to receive standard pharmacologic preventative therapy (see Table 5).

Table 13. Summary of Key RCT Characteristics in Chronic Migraine

   IV: intravenous; RCT: randomized controlled trial.

Table 14. Summary of Clinical Characteristics in Chronic Migraine

   SD: standard deviation. a Previous use of topiramate b Patients taking prescription or over-the counter medication for acute or preventive treatment of migraine were eligible only if the medications had been prescribed or recommended by a healthcare professional; migraine preventive medication use had to be stable for ≥3 months before screening. A total of 479 patients (44.7%) used concomitant prophylactic medication at the baseline.

Table 15. Summary of Key RCT Results in Chronic Migraine

   CI: confidence interval; Diff: difference; HIT-6: Headache Impact Test; MSQL: Migraine-specific quality of lfe; OR: odds ratio; RCT: randomized controlled trial; SE: standard error. a A total of 10 patients (<1%) experienced a serious treatment emergent adverse event (7 patients who received eptinezumab and 3 who received placebo). These were nervous system disorders (eptinezumab n = 4 [<1%], placebo n = 1 [<1%]); injury, poisoning, and procedural complications (eptinezumab n = 2 [<1%], placebo n = 0); and psychiatric disorders (eptinezumab n = 2 [<1%], placebo n = 0)

The applicability of the HER-MES trial is challenging due to the inclusion of a broad migraine population without stratification of results by migraine type (episodic vs chronic) or prior treatment (see Tables 6 and 7). No major limitations were identified in study design and conduct for the placebo-controlled trials. In terms of relevance limitations of this evidence base, the trials compared CGRP mAbs to placebo and restricted the patient population to those for whom no ≥2 or 3 other preventive therapies had failed (See Table 16). QOL outcomes measures are considered critical in migraine and patients seek improvement in the QOL measures. However, such QOL measures were reported infrequently in the trials and when reported, the follow-up period was short. Generalizability of the results generated from the RCTs is limited and may not apply to many patients who are likely be treated with CGRP mAbs, such as those who have tried >3 preventive therapies, those with comorbidities and other groups of patients such as children, older adults, and women during pregnancy and lactation. Further, as these agents have a novel mechanism of action, there is limited certainty about the durability of benefit as well safety beyond 1 to 2 years. There are concerns, particularly AEs which may manifest after a longer duration of treatment such as cardiovascular events or those that are rare. CGRP is involved in multiple physiological processes and some concerns exist about the long-term effects of continuous blocking of CGRP or its receptor due to CGRP’s cardiovascular protective role.^19,20,21,

Table 16. Study Relevance Limitations

   The study limitations stated in this table are those notable in the current review; this is not a comprehensive gaps assessment. a Population key: 1. Intended use population unclear; 2. Clinical context is unclear; 3. Study population is unclear; 4. Study population not representative of intended use. b Intervention key: 1. Not clearly defined; 2. Version used unclear; 3. Delivery not similar intensity as comparator; 4.Not the intervention of interest. c Comparator key: 1. Not clearly defined; 2. Not standard or optimal; 3.Delivery not similar intensity as intervention; 4. Not delivered effectively. d Outcomes key: 1. Key health outcomes not addressed; 2. Physiologic measures, not validated surrogates; 3. No CONSORT reporting of harms; 4. Not establish and validated measurements; 5. Clinical significant difference not prespecified; 6. Clinical significant difference not supported. e Follow-Up key: 1. Not sufficient duration for benefit; 2. Not sufficient duration for harms.

Section Summary: Chronic Migraine Who Are Eligible to Receive Standard Pharmacologic Preventative Therapy

The HER-MES trial compared erenumab to topiramate in patients with migraines occurring at least 4 days per month (ie, patients with episodic and chronic migraine). Erenumab demonstrated a reduction in the proportion of patients who discontinued the medication due to an AE (10.6% vs. 38.9%), which was the primary outcome, and an improvement in the proportion of patients with at least 50% reduction in monthly migraine days from baseline over months 4 to 6 (55.4% vs. 31.2%). Also, patients in the erenumab group experienced a significantly greater reduction in mean monthly migraine days versus topiramate (-5.86 days vs. -4.02 days). The applicability of the HER-MES trial is challenging due to the inclusion of a broad migraine population without stratification of results by migraine type (episodic vs. chronic) or prior treatment. Furthermore, the trial enrolled a mostly White race and female population and had a potential for unblinding due to the known adverse effect profile of topiramate. Four placebo-controlled, multicenter RCTs, with a total of nearly 4000 adult patients, have been identified on CGRP mAbs for the preventative treatment of chronic migraine. Compared to controls, CGRP mAbs (erenumab, fremanezumab, galcanezumab, and epitenezumab) decreased the mean number of migraine days by up to 2.6 days. More patients treated with the mAbs (erenumab, fremanezumab, galcanezumab, and epitenezumab) had at least 50% reduction in migraines. The most commonly reported AEs with CGRP mAbs involved injection-site events. A network meta-analysis showed no statistical difference in reduction in monthly migraine days or 50% decrease in monthly migraine days when CGRP mAbs were compared to active therapies (onabotulinum toxin A or topiramate). This meta-analysis did not include data on eptinezumab. No head-to-head studies comparing eptinezumab with oral therapies for prophylaxis of chronic migraine were identified. In the placebo-controlled PROMISE-2 trial, the mean treatment effect (the difference between eptinezumab and placebo) was approximately 2 (100 mg dose) to 2.6 (300 mg dose) fewer migraine days/month. A greater proportion of patients receiving 100 and 300 mg eptinezumab experienced ≥50% reduction in migraines compared to placebo (58% and 61% vs 39%). Given the limited availability of head-to-head trials of CGRP mAbs with currently available oral preventive therapies, lack of superiority of CGRP mAbs (erunemab, fremanezumab, and galcanezumab) versus oral preventive therapies in network meta-analysis, and limited long term data on efficacy and safety of CGRP mAbs, it is difficult to ascertain incremental benefit of CGRP mAbs in patients who are eligible to receive standard oral pharmacologic preventative therapy.

For individuals who have chronic migraine who are eligible to receive standard pharmacologic preventative therapy who receive CGRP mAbs, the evidence includes multicenter RCTs and a systematic review. Relevant outcomes are symptoms, change in disease status, QOL, and treatment-related morbidity. The HER-MES trial compared erenumab to topiramate in patients with migraines occurring at least 4 days per month (ie, patients with episodic and chronic migraine). Erenumab demonstrated a reduction in the proportion of patients who discontinued the medication due to an AE (10.6% vs. 38.9%), which was the primary outcome, and an improvement in the proportion of patients with at least 50% reduction in monthly migraine days from baseline over months 4 to 6 (55.4% vs. 31.2%). Also, patients in the erenumab group experienced a significantly greater reduction in mean monthly migraine days versus topiramate (-5.86 days vs. -4.02 days). The applicability of the HER-MES trial is challenging due to the inclusion of a broad migraine population without stratification of results by migraine type (episodic vs. chronic) or prior treatment. Furthermore, the trial enrolled a mostly White race and female population and had a potential for unblinding due to the known side effect profile of topiramate.Fourplacebo-controlled, multicenter RCTs, with a total of nearly 4000 adult patients, have been identified on CGRP mAbs for the preventative treatment of chronic migraine. Compared to controls, CGRP mAbs (erenumab, fremanezumab, galcanezumab, and epitenezumab) decreased the mean number of migraine days by up to 2.6 days. More patients treated with the mAbs had at least 50% reduction in migraines. The most commonly reported AEs with CGRP mAbs involved injection-site events. A network meta-analysis showed no statistical difference in reduction in monthly migraine days or 50% decrease in monthly migraine days when CGRP mAbs were compared to active therapies (onabotulinum toxin A or topiramate). This meta-analysis did not include data on eptinezumab.No head-to-head studies comparing eptinezumab with oral therapies for prophylaxis of chronic migraine were identified. In the placebo-controlled PROMISE-2 trial, the mean treatment effect (the difference between eptinezumab and placebo) was approximately 2 (100 mg dose) to 2.6 (300 mg dose) fewer migraine days/month. A greater proportion of patients receiving 100 and 300 mg eptinezumab experienced at least 50% reduction in migraines compared to placebo (58% and 61% vs 39%). Evidence of CGRP mAbs is lacking in a certain group of patients such as children, older adults, and women during pregnancy and lactation as they were excluded from the pivotal RCTs. Given the limited availability of head-to-head trials of CGRP mAbs with currently available oral preventive therapies, lack of superiority of CGRP mAbs (erenumab, fremanezumab, and galcanezumab) versus oral preventive therapies in network meta-analysis, and limited long-term data on efficacy and safety of CGRP mAbs, it is difficult to ascertain incremental benefit of CGRP mAbs in patients who are eligible to receive standard oral pharmacologic preventative therapy. The evidence is insufficient to determine that the technology results in an improvement in the net health outcome.

Population Reference No. 4

Chronic Migraine Not Responsive to Standard Pharmacologic Preventive Therapy

Clinical Context and Therapy Purpose

The purpose of mAbs targeting the CGRP receptor (erenumab) and CGRP molecule (eptinezumab, fremanezumab, and galcanezumab) in patients who have chronic migraine not responsive to standard pharmacologic preventive therapy is to provide a treatment option that is an alternative to or an improvement on existing therapies.

The following PICO was used to select literature to inform this review.

Populations

The relevant population of interest is patients with chronic migraine not responsive to standard pharmacologic preventive therapy

Interventions

The therapy being considered is mAbs targeting the CGRP molecule or the CGRP receptor (see Table 1). Subcutaneous injections in the abdomen, thigh, or upper arm are self-administered with prefilled syringes or automatic injectors. Intravenous injections are administered by a healthcare provider in a healthcare setting.

Comparators

The following therapies are currently used for chronic migraine not responsive to standard pharmacologic preventive therapy: supportive care.

Outcomes

The general outcomes of interest are migraine intensity and frequency, the effect of the migraines or treatment on QOL as measured by instruments such as the 12-Item Short Form Health Survey, hospitalizations due to migraine, and adverse effects of the treatment (see Table 2). Migraine severity and frequency are measured over 6 to 12 months.

Study Selection Criteria

Methodologically credible studies were selected using the following principles:

• To assess efficacy outcomes, comparative controlled prospective trials were sought, with a preference for RCTs;

• In the absence of such trials, comparative observational studies were sought, with a preference for prospective studies.

• To assess long-term outcomes and adverse events, single-arm studies that capture longer periods of follow-up and/or larger populations were sought.

• Consistent with a 'best available evidence approach,' within each category of study design, studies with larger sample sizes and longer durations were sought.

• Studies with duplicative or overlapping populations were excluded.

Review of Evidence

Randomized Controlled Trials

The LIBERTY, FOCUS, CONQUER, and DELIVER trials evaluating erunemab, fremanezumab, galcanezumab, and eptinezumab, respectively, were previously introduced and included patients with ≥4 migraine days per month who had failed 2 to 4 other preventative treatments. The CONQUER and FOCUS trials for galcanezumab and fremanezumab, respectively, published results for the subgroup of patients with chronic migraine (see Tables 17 to 19). The remainder of the trials did not specifically analyze results for the subgroup of patients with chronic migraine, and are therefore not further discussed in this section.

Ferrari et al (2019) reported the results of a randomized, double-blind, placebo-controlled trial (FOCUS). ^26, The trial enrolled 838 participants aged 18-70 years with episodic or chronic migraine (episodic n=329 [39%] or chronic n=509 [61%] who had documented failure to 2 to 4 classes of migraine preventive medications in the past 10 years. Participants were randomized to fremanezumab (month 1: 675 mg; months 2 and 3: placebo), monthly fremanezumab (month 1: 225 mg in episodic migraine and 675 mg in chronic migraine; months 2 and 3: 225 mg in both migraine subgroups), or matched monthly placebo for 12 weeks. The primary outcome was mean change from baseline in the monthly average number of migraine days during the 12-week treatment period. A

Mulleners et al (2020) reported results of multicenter, randomized, double-blind, placebo-controlled that enrolled 462 patients 18 to 75 years of age with episodic or chronic migraine who had a documented failure of preventive medications from 2 to 4 drug categories in the past 10 years owing to lack of efficacy or tolerability, or both (CONQUER).^28, Patients were randomized 1:1 to receive subcutaneous placebo or galcanezumab 120 mg per month (with a 240 mg loading dose administered as two 120 mg injections) for 3 months.. The primary outcome was the mean change from baseline in number of monthly migraine headache days during the 3-month treatment period.

Table 17. Summary of Key RCT Characteristics in Patients with Refractory Chronic Migraine

   RCT: randomized controlled trial.

Table 18. Summary of Clinical Characteristics in Patients with Refractory Chronic Migraine

   SD: standard deviation.

Table 19. Summary of Key RCT Results in Patients with Refractory Chronic Migraine

   CI: confidence interval; HR: hazard ratio; MPFID: Migraine Physical Function Impact Diary; OR: odds ratio; RCT: randomized controlled trial; SE: standard error.

Relevance and design and conduct limitations are described in Tables 20 and 21. QOL outcomes measures are considered critical in migraine and patients seek improvement in the QOL measures. However, such QOL measures were not reported. Generalizability of the results generated from the RCTs is limited and may not apply to many patients groups such as children, older adults, and women during pregnancy and lactation. Further, as these agents have a novel mechanism of action, there is limited certainty about the durability of benefit as well safety beyond 1 to 2 years. There are concerns, particularly AEs which may manifest after a longer duration of treatment such as cardiovascular events or those that are rare. CGRP is involved in multiple physiological processes and some concerns exist about the long-term effects of continuous blocking of CGRP or its receptor due to CGRP’s cardiovascular protective role.^19,20,21,

Table 20. Study Relevance Limitations

   The study limitations stated in this table are those notable in the current review; this is not a comprehensive gaps assessment. a Population key: 1. Intended use population unclear; 2. Clinical context is unclear; 3. Study population is unclear; 4. Study population not representative of intended use. b Intervention key: 1. Not clearly defined; 2. Version used unclear; 3. Delivery not similar intensity as comparator; 4.Not the intervention of interest. c Comparator key: 1. Not clearly defined; 2. Not standard or optimal; 3.Delivery not similar intensity as intervention; 4. Not delivered effectively. d Outcomes key: 1. Key health outcomes not addressed; 2. Physiologic measures, not validated surrogates; 3. No CONSORT reporting of harms; 4. Not establish and validated measurements; 5. Clinical significant difference not prespecified; 6. Clinical significant difference not supported. e Follow-Up key: 1. Not sufficient duration for benefit; 2. Not sufficient duration for harms.

Table 21. Study Design and Conduct Limitations

   The study limitations stated in this table are those notable in the current review; this is not a comprehensive gaps assessment. a Allocation key: 1. Participants not randomly allocated; 2. Allocation not concealed; 3. Allocation concealment unclear; 4. Inadequate control for selection bias. b Blinding key: 1. Not blinded to treatment assignment; 2. Not blinded outcome assessment; 3. Outcome assessed by treating physician. c Selective Reporting key: 1. Not registered; 2. Evidence of selective reporting; 3.Evidence of selective publication. d Data Completeness key: 1. High loss to follow-up or missing data; 2. Inadequate handling of missing data; 3. High number of crossovers; 4. Inadequate handling of crossovers; 5. Inappropriate exclusions; 6. Not intent to treat analysis (per protocol for noninferiority trials). e Power key: 1. Power calculations not reported; 2. Power not calculated for primary outcome; 3. Power not based on clinically important difference. f Statistical key: 1. Analysis is not appropriate for outcome type: (a) continuous; (b) binary; (c) time to event; 2. Analysis is not appropriate for multiple observations per patient; 3. Confidence intervals and/or p values not reported; 4.Comparative treatment effects not calculated.

Section Summary: Chronic Migraine Not Responsive to Standard Pharmacologic Preventive Therapy

Multiple multicenter RCTs for CGRP mAbs (erenumab, fremanezumab, galcanezumab, and eptinezumab) for the prevention of migraine in patients with ≥4 migraine days per month who had failed 2 to 4 other preventative treatments have been published. These trials have consistently demonstrated that a greater proportion of patients in the treated group had a reduction in monthly migraine days compared to the placebo group.. The CONQUER and FOCUS trials for galcanezumab and fremanezumab, respectively, published results for the subgroup of patients with chronic migraine and prior treatment failure. In these analyses, galcanezumab and fremanezumab decreased the mean number of migraine days by up to 3.8 days versus control. The pivotal trial of eptinezumab (PROMISE-2) did not specifically include or exclude patients with a documented failure of previous preventive therapy. In the PROMISE-2 trial, the mean treatment effect (the difference between eptinezumab and placebo) was approximately 2 ( 100 mg dose) to 2.6 (300 mg dose) fewer migraine days/month. Further a greater proportion of patients receiving eptinezumab 100 and 300 mg experienced ≥50% reduction in migraines compared to placebo (58% and 61% vs. 39%). While there are uncertainties about the durability of efficacy as well as safety, the observed magnitude of benefit of erunemab, fremanezumab, galcanezumab, and eptinezumab observed in pivotal trials represents a potential benefit to patients who have exhausted other preventive treatment options.

For individuals who have chronic migraine not responsive to standard pharmacologic therapy who receive CGRP mAbs, the evidence includes multiple multicenter RCTs. Relevant outcomes are symptoms, change in disease status, QOL, and treatment-related morbidity. Multiple multicenter RCTs for CGRP mAbs (erenumab, fremanezumab, galcanezumab, and eptinezumab) for the prevention of migraine in patients with at least 4 migraine days per month who had failed 2 to 4 other preventative treatments have been published. As previously noted, these trials have consistently demonstrated that a greater proportion of patients in the treated group had a reduction in monthly migraine days compared to the placebo group. The CONQUER and FOCUS trials for galcanezumab and fremanezumab, respectively, published results for the subgroup of patients with chronic migraine and prior treatment failure. In these analyses, galcanezumab and fremanezumab decreased the mean number of migraine days by up to 3.8 days versus control. The pivotal trial of eptinezumab (PROMISE-2) did not specifically include or exclude patients with a documented failure of previous preventive therapy. In the PROMISE-2 trial, the mean treatment effect (the difference between eptinezumab and placebo) was approximately 2 ( 100 mg dose) to 2.6 (300 mg dose) fewer migraine days/month. Further, a greater proportion of patients receiving eptinezumab 100 and 300 mg experienced at least 50% reduction in migraines compared to placebo (58% and 61% vs. 39%). While there are uncertainties about the durability of efficacy as well as safety, the observed magnitude of benefit of erunemab, fremanezumab, galcanezumab, and eptinezumab observed in pivotal trials represents a potential benefit to patients who have exhausted other preventive treatment options. The evidence is sufficient to determine that the technology results in an improvement in the net health outcome.

Population Reference No. 5 Policy Statement

Episodic Cluster Headache

Clinical Context and Therapy Purpose

The purpose of mAbs targeting the CGRP receptor (erenumab) and CGRP molecule (eptinezumab, fremanezumab, and galcanezumab) in patients who have episodic cluster headache is to provide a treatment option that is an alternative to or an improvement on existing therapies.

The following PICO was used to select literature to inform this review.

Populations

The relevant population of interest is patients with episodic cluster headache.

Interventions

The therapy being considered is the human mAb galcanezumab. Subcutaneous injections in the abdomen, thigh, or upper arm are self-administered with prefilled syringes or automatic injectors.

Comparators

The following therapies are currently used for episodic cluster headache: oral and intranasal triptans and high flow oxygen. Verapamil and lithium have been used for prophylaxis, although they are associated with many side effects.

Outcomes

The general outcomes of interest are cluster headache intensity and frequency and the effect of the cluster headaches or treatment on QOL on a self-reported basis.

Study Selection Criteria

Methodologically credible studies were selected using the following principles:

• To assess efficacy outcomes, comparative controlled prospective trials were sought, with a preference for RCTs;

• In the absence of such trials, comparative observational studies were sought, with a preference for prospective studies.

• To assess long-term outcomes and adverse events, single-arm studies that capture longer periods of follow-up and/or larger populations were sought.

• Consistent with a 'best available evidence approach,' within each category of study design, studies with larger sample sizes and longer durations were sought.

• Studies with duplicative or overlapping populations were excluded.

Review of Evidence

Randomized Controlled Trials

One multicenter RCT (n=106) randomized 106 adults who met the International Classification of Headache Disorders 3rd edition (beta version) diagnostic criteria for episodic cluster headache and had a maximum of 8 attacks per day, a minimum of 1 attack every other day, and≥4 attacks during the prospective 7-day baseline period.^38, All patients were randomized in a 1:1 ratio to receive once-monthly subcutaneous injections of galcanezumab 300 mg or placebo. Patients were allowed to use certain specified acute/abortive cluster headache treatments, including triptans, oxygen, acetaminophen, and NSAIDs during the study. The study excluded patients on other treatments intended to reduce the frequency of cluster headache attacks; patients with medication overuse headache; patients with ECG abnormalities compatible with an acute cardiovascular event or conduction delay; and patients with a history of myocardial infarction, unstable angina, percutaneous coronary intervention, coronary artery bypass grafting, deep vein thrombosis, or pulmonary embolism within 6 months of screening. In addition, patients with any history of stroke, intracranial or carotid aneurysm, intracranial hemorrhage, or vasospastic angina; clinical evidence of peripheral vascular disease; or diagnosis of Raynaud’s disease were excluded. The primary efficacy endpoint was the mean change from baseline in weekly cluster headache attack frequency across weeks 1 to 3. A secondary endpoint was the percentage of patients who achieved a response (defined as a reduction from baseline of 50% or greater in the weekly cluster headache attack frequency) at week 3. Out of 106 patients randomized, 90 patients completed the 8-week double-blind phase. There was a greater decrease in the least-squares mean from baseline in the weekly frequency of cluster headache attacks across weeks 1 to 3 (see Table 23) in the treatment group compared to placebo. The percentage of patients with a reduction of ≥50% in the weekly frequency of cluster headaches at week 3 was greater in the treatment group compared to placebo. Beginning at week 4 and through the remainder of the 8 week double-blind period, there was no difference in the outcomes between galcanezumab and placebo arm suggesting spontaneous improvement or remission (reflecting the typical course of a bout of cluster headache) or that the treatment effect with galcanezumab no longer differed substantially from that with placebo at those time points. The incidence of discontinuation of the trial regimen was higher in the placebo group (21%) than in the galcanezumab group (8%), whereas the incidence of discontinuation due to an AE did not differ substantially between the groups.

Rieseberg et al (2022) published an open-label study that evaluated the long-term safety of galcanezumab in patients (N=164) with cluster headache who completed one of two double-blind RCTs (episodic cluster headache: NCT02397473 [Goadsby et al, 2019]; chronic cluster headache: NCT02438826).^39, The mean duration of exposure was 475 days (range, 28 to 1211). Of the 119 patients (72.6%) who reported ≥1 treatment-emergent AE, 79.8% reported the event as mild or moderate. Nasopharyngitis and influenza were the most frequently reported treatment-emergent AEs (22% and 9.8%, respectively).

Table 22. Summary of Key RCT Characteristics in Episodic Cluster Headache

   RCT: randomized controlled trial.

Table 23. Summary of Key RCT Results in Episodic Cluster Headache

   CI: confidence interval; RCT: randomized controlled trial; SD: standard deviation.

No major limitations were identified in study design and conduct. In terms of relevance limitations of this evidence base, the trials compared CGRP mAbs to placebo and were short-term in duration (See Table 24). QOL outcomes measures are considered critical in episodic cluster headache and patients seek improvement in the QOL measures. However, such QOL measures were not reported. Generalizability of the results is limited and may not apply to many patients such as patients with cardiovascular comorbidities, children and pregnant women. Further, as these agents have a novel mechanism of action, the short-term trials limit our certainty about the durability of benefit as well safety, particularly those AEs which may manifest after a longer duration of treatment such as cardiovascular or those that are rare. CGRP is involved in multiple physiological processes and some concerns exist about the long-term effects of continuous blocking of CGRP or its receptor due to CGRP’s cardiovascular protective role.^19,20,21,

Table 24. Study Relevance Limitations

   The study limitations stated in this table are those notable in the current review; this is not a comprehensive gaps assessment. a Population key: 1. Intended use population unclear; 2. Clinical context is unclear; 3. Study population is unclear; 4. Study population not representative of intended use. b Intervention key: 1. Not clearly defined; 2. Version used unclear; 3. Delivery not similar intensity as comparator; 4.Not the intervention of interest. c Comparator key: 1. Not clearly defined; 2. Not standard or optimal; 3.Delivery not similar intensity as intervention; 4. Not delivered effectively. d Outcomes key: 1. Key health outcomes not addressed; 2. Physiologic measures, not validated surrogates; 3. No CONSORT reporting of harms; 4. Not establish and validated measurements; 5. Clinical significant difference not prespecified; 6. Clinical significant difference not supported. e Follow-Up key: 1. Not sufficient duration for benefit; 2. Not sufficient duration for harms.

Section Summary: Episodic Cluster Headache

No head-to-head studies comparing CGRP mAbs with oral therapies for episodic cluster headache were identified. One RCT with 106 adult patients reported a reduction in the frequency of weekly cluster headache attacks by 8.7 days among those treated galcanezumab versus 5.2 days in the placebo arm over weeks 1 to 3. The proportion of patients with ≥50% reduction in weekly cluster headache attacks at week 3 was 71% and 53%, respectively. The most commonly reported AEs with galcanezumab involved injection-site events. Given the lack of head-to-head trials of CGRP mAbs with currently available oral therapies, and limited long-term data on efficacy and safety of galcanezumab, it is difficult to ascertain the incremental benefit of galcanezumab in patients who are eligible to receive standard oral pharmacologic preventative therapy. However, it may be considered a reasonable second-line option in patients who fail to respond or in whom the standard oral pharmacologic agents are contraindicated.

For individuals who have episodic cluster headache who receive CGRP mAbs, the evidence includes 1 multicenter RCT. Relevant outcomes are symptoms, change in disease status, QOL, and treatment-related morbidity. No head-to-head studies comparing CGRP mAbs with oral therapies for episodic cluster were identified. One RCT with 106 adult patients reported a reduction in the frequency of weekly cluster headaches by 8.7 days among those treated with galcanezumab versus 5.2 days in the placebo arm over weeks 1 to 3. The proportion of patients with at least 50% reduction in weekly cluster headache attacks at week 3 was 71% and 53%, respectively. The most commonly reported AEs with galcanezumab involved injection-site events. Given the lack of head-to-head trials of CGRP mAbs with currently available oral therapies, and limited long term data on efficacy and safety of galcanezumab, it is difficult to ascertain incremental benefit of galcanezumab in patients who are eligible to receive standard oral pharmacologic preventative therapy. However, galcanezumab may be considered a reasonable second-line option in patients who fail to respond or in whom the standard oral pharmacologic agents are contraindicated. The evidence is sufficient to determine that the technology results in an improvement in the net health outcome.

Population Reference No. 6 Policy Statement

Chronic Cluster Headache

Clinical Context and Therapy Purpose

The purpose of mAbs targeting the CGRP receptor (erenumab) and CGRP molecule (eptinezumab, fremanezumab, and galcanezumab) in patients who have chronic cluster headache is to provide a treatment option that is an alternative existing therapy.

The following PICO was used to select literature to inform this review.

Populations

The relevant population of interest is patients with chronic cluster headache.

Interventions

The therapy being considered is the human mAb galcanezumab. Subcutaneous injections in the abdomen, thigh, or upper arm are self-administered with prefilled syringes or automatic injectors.

Comparators

The following therapies are currently used for chronic cluster headache: verapamil and lithium ^3,

Outcomes

The general outcomes of interest are cluster headache intensity and frequency and the effect of the cluster headaches or treatment on QOL on a self-reported basis.

Study Selection Criteria

Methodologically credible studies were selected using the following principles:

• To assess efficacy outcomes, comparative controlled prospective trials were sought, with a preference for RCTs;

• In the absence of such trials, comparative observational studies were sought, with a preference for prospective studies.

• To assess long-term outcomes and adverse events, single-arm studies that capture longer periods of follow-up and/or larger populations were sought.

• Consistent with a 'best available evidence approach,' within each category of study design, studies with larger sample sizes and longer durations were sought.

• Studies with duplicative or overlapping populations were excluded.

Review of Evidence

Randomized Controlled Trials

Dodick et al (2020) published results of a 12-week double-blind, placebo-controlled RCT of galcanezumab 300 mg in patients with chronic cluster headaches (N=237), followed by a 52-week open-label period.^44, The investigators reported a reduction in the number of weekly chronic cluster headaches with galcanezumab compared to placebo (mean change in weekly attack frequency, -5.4 galcanezumab vs -4.6 placebo), however, the results were not statistically significant (p=.334).

Section Summary: Chronic Cluster Headache

One RCT reported no significant difference between galcanezumab and placebo in reduction of weekly chronic cluster headaches. No trials were identified that included a significant difference in chronic cluster headache response from galcanezumab compared to placebo.

For individuals who have chronic cluster headache who receive CGRP mAbs, the evidence includes an unpublished, multicenter RCT. Relevant outcomes are symptoms, change in disease status, QOL, and treatment-related morbidity. No published trials were identified on mAbs for the treatment of chronic cluster headache. Results of a recently completed RCT published on ClinicalTrials.gov reports a reduction in the number of weekly chronic cluster headaches. However, the results were not statistically significant. The evidence is insufficient to determine that the technology results in an improvement in the net health outcome.

Population Reference No. 7

Acute Treatment of Migraine

Clinical Context and Therapy Purpose

The purpose of mAbs targeting the CGRP receptor (erenumab) and CGRP molecule (eptinezumab, fremanezumab, and galcanezumab) in patients who have acute migraine is to provide a treatment option that is an alternative to or an improvement on existing therapies.

The following PICO was used to select literature to inform this review.

Populations

The relevant population of interest is patients with acute migraine.

Interventions

The therapy being considered is mAbs targeting the CGRP molecule or the CGRP receptor. Subcutaneous injections in the abdomen, thigh, or upper arm are self-administered with prefilled syringes or automatic injectors. Intravenous injections are administered by a healthcare provider in a healthcare setting.

Comparators

The following therapies are currently used for acute migraine: pharmacological agents such as triptans, nonsteroidal anti-inflammatory drugs (such as diclofenac, aspirin, ibuprofen, and ketorolac) and combinations of these agents. In addition, small-molecule oral CGRP antagonists (gepants) and 5-HT receptor agonist (ditans) are also approved for acute treatment of migraine. Among devices, remote electrical neuromodulation and external vagus nerve stimulation are in use.

Outcomes

The general outcomes of interest are relief from pain and the associated symptoms of migraine such as photophobia, phonophobia, and nausea. In addition, effective acute treatment of migraine should restore function, reduce migraine-related disability, reduce health care utilization, and improve quality of life.

Study Selection Criteria

Methodologically credible studies were selected using the following principles:

• To assess efficacy outcomes, comparative controlled prospective trials were sought, with a preference for RCTs;

• In the absence of such trials, comparative observational studies were sought, with a preference for prospective studies.

• To assess long-term outcomes and adverse events, single-arm studies that capture longer periods of follow-up and/or larger populations were sought.

• Consistent with a 'best available evidence approach,' within each category of study design, studies with larger sample sizes and longer durations were sought.

• Studies with duplicative or overlapping populations were excluded.

Review of Evidence

Randomized Controlled Trials

Winner et al (2021) reported the findings of a randomized clinical trial in which 480 participants (mean age, 44 years; range, 18-75 years; 84% women) who had a history of migraine for >1 year and experienced migraine on 4 to 15 days per month in the previous 3 months were treated during a moderate to severe migraine attack with eptinezumab,100 mg (n = 238) or placebo (n = 242) (See Table 25 to 27). Results showed that eptinezumab administered during the first 6 hours of a migraine attack significantly reduced time to freedom from pain and the most bothersome accompanying symptom compared with placebo.^40, The median time to headache freedom after treatment with eptinezumab was 4 hours versus 9 hours after placebo, and median time to absence of most bothersome symptom was 2 hours in the eptinezumab group versus 3 hours in the placebo group. Of the 238 participants who received eptinezumab, 5 had hypersensitivity reactions (1 severe), all of which occurred within 40 minutes of infusion completion. None of the 242 patients who received placebo had a similar reaction.

Table 25. Summary of Key RCT Characteristics in Patients with Active Moderate to Severe Migraine Attack

   IV: intravenous; RCT: randomized controlled trial. 

Table 26. Summary of Clinical Characteristics in Patients with Active Moderate to Severe Migraine Attack

   SD: standard deviation.

Table 27. Summary of Key RCT Results in Patients with Active Moderate to Severe Migraine Attack

   CI: confidence interval; HR: hazard ratio; IQR: inter-quartile range; OR: odds ratio; RCT: randomized controlled trial

Relevance and design and conduct limitations of this trial are described in Tables 28 and 29. The major limitation is the lack of head-to-head trials of parenteral CGRP mAbs with currently available oral therapies for treatment of acute migraine. Further, the clinical context of using an IV treatment for acute migraine attack poses challenges to timely administration of the drug outside of a trial setting. Initiation of IV eptinezumab within 6 hours of headache at an infusion center may not be practical. The investigators of the RELIEF trial note that eptinezumab is not an acute migraine treatment and the purpose of RELIEF trial was to capture same-day infusion efficacy data with eptinezumab, which was not possible with the design of the previous prophylaxis studies. Data generated from the RELIEF trial may be be most helpful for patients who need rapid onset of preventive treatment due to frequent or severe migraine headaches. Other limitations include lack of QOL data, limited generalizability of the results to many patients groups such as children, older adults, and women during pregnancy and lactation and lastly, the trial follow-up was limited.

Table 28. Study Relevance Limitations

  The study limitations stated in this table are those notable in the current review; this is not a comprehensive gaps assessment. a Population key: 1. Intended use population unclear; 2. Clinical context is unclear; 3. Study population is unclear; 4. Study population not representative of intended use. b Intervention key: 1. Not clearly defined; 2. Version used unclear; 3. Delivery not similar intensity as comparator; 4.Not the intervention of interest. c Comparator key: 1. Not clearly defined; 2. Not standard or optimal; 3.Delivery not similar intensity as intervention; 4. Not delivered effectively. d Outcomes key: 1. Key health outcomes not addressed; 2. Physiologic measures, not validated surrogates; 3. No CONSORT reporting of harms; 4. Not establish and validated measurements; 5. Clinical significant difference not prespecified; 6. Clinical significant difference not supported. e Follow-Up key: 1. Not sufficient duration for benefit; 2. Not sufficient duration for harms.

Table 29. Study Design and Conduct Limitations

  The study limitations stated in this table are those notable in the current review; this is not a comprehensive gaps assessment. a Allocation key: 1. Participants not randomly allocated; 2. Allocation not concealed; 3. Allocation concealment unclear; 4. Inadequate control for selection bias. b Blinding key: 1. Not blinded to treatment assignment; 2. Not blinded outcome assessment; 3. Outcome assessed by treating physician. c Selective Reporting key: 1. Not registered; 2. Evidence of selective reporting; 3.Evidence of selective publication. d Data Completeness key: 1. High loss to follow-up or missing data; 2. Inadequate handling of missing data; 3. High number of crossovers; 4. Inadequate handling of crossovers; 5. Inappropriate exclusions; 6. Not intent to treat analysis (per protocol for noninferiority trials). e Power key: 1. Power calculations not reported; 2. Power not calculated for primary outcome; 3. Power not based on clinically important difference. f Statistical key: 1. Analysis is not appropriate for outcome type: (a) continuous; (b) binary; (c) time to event; 2. Analysis is not appropriate for multiple observations per patient; 3. Confidence intervals and/or p values not reported; 4.Comparative treatment effects not calculated.

Section Summary: Acute Treatment of Migraine

No head-to-head studies comparing parenteral CGRP mABs with oral therapies for treatment of acute migraine were identified. Results from one multicenter RCT comparing eptinezumab with placebo in patients with a history of migraine for >1 year and experienced migraine on 4 to 15 days per month in the previous 3 months were reported. Results showed that eptinezumab administered during the first 6 hours of a migraine attack significantly reduced time to freedom from pain (4 hours vs 9 hours respectively) and the most bothersome accompanying symptom (2 versus 3 hours respectively) compared with placebo. The major limitation is the lack of lack of head to head trials of parenteral CGRP mAbs to oral therapies for treatment of acute migraine. Use of an IV treatment for acute migraine poses challenges to timely administration of the drug outside of a trial setting. Initiation of IV eptinezumab within 6 hours of headache at an infusion center may not be practical. In addition to limited duration of follow-up, other limitations include lack of QOL data, limited generalizability of the results to many additional patients groups such as children, older adults, and women during pregnancy and lactation limited.

For individuals who have acute migraine who receive CGRP mAbs, the evidence includes a single RCT. Relevant outcomes are symptoms, change in disease status, QOL, and treatment-related morbidity. Results from one multicenter RCT comparing eptinezumab with placebo in patients with a history of migraine for >1 year and experienced migraine on 4 to 15 days per month in the previous 3 months were reported. Results showed that eptinezumab administered during the first 6 hours of a migraine attack significantly reduced time to freedom from pain (4 hours vs 9 hours, respectively) and the most bothersome accompanying symptom (2 hours vs 3 hours, respectively) compared with placebo. The major limitation is the lack of head to head trials of CGRP mAbs with currently available oral therapies for treatment of acute migraine. Use of an intravenous (IV) treatment for acute migraine poses challenges to timely administration of the drug outside of a trial setting. Initiation of IV eptinezumab within 6 hours of headache at an infusion center may not be practical. In addition to limited duration of follow-up, other limitations include lack of QOL data, limited generalizability of the results to many additional patients groups such as children, older adults, and women during pregnancy and lactation. The evidence is insufficient to determine that the technology results in an improvement in the net health outcome.

SUPPLEMENTAL INFORMATION

The purpose of the following information is to provide reference material. Inclusion does not imply endorsement or alignment with the evidence review conclusions.

Practice Guidelines and Position Statements

Guidelines or position statements will be considered for inclusion in ‘Supplemental Information’ if they were issued by, or jointly by, a US professional society, an international society with US representation, or National Institute for Health and Care Excellence (NICE). Priority will be given to guidelines that are informed by a systematic review, include strength of evidence ratings, and include a description of management of conflict of interest.

American Headache Society

The American Headache Society (AHS) published a position statement on integrating new migraine treatments into clinical practice in 2018;^46, an update to this statement was published in 2021.^47, The AHS provides comprehensive criteria for initiating treatment with monoclonal antibodies (mAbs) targeting calcitonin gene-related peptide (CGRP). Per the 2021 update, CGRP mAbs are recommended for the prevention of migraine in adults with either episodic or chronic migraine with an inability to tolerate (due to side effects) or inadequate response to an 8-week trial of ≥2 conventional pharmacologic treatments for migraine prevention with established efficacy (ie, classified as having Level A ["Established as Effective"] or B [Probably Effective"] supportive evidence per the American Academy of Neurology [AAN]; see Table 30). Additional agents that are established as effective or probably effective per the 2021 AHS position statement include candasartan (established efficacy), lisinopril (probably effective), and memantine (probably effective). For patients with chronic migraine, CGRP mAbs are also recommended for patients with an inability to tolerate or inadequate response to a minimum of 2 quarterly injections (6 months) of onabotulinumtoxinA therapy. The 2021 position statement also provides criteria for continuation of CGRP mAbs after an initial trial (defined as 3 months for treatments administered monthly and 6 months [2 cycles of treatment] for treatments delivered quarterly). However, in their most recent position statement, AHS removed the qualifier for treatment as failure of previous therapies, and recommend CGRP-targeting treatments as first-line therapy.

In 2024, AHS published a position statement specifically regarding therapies targeting CGRP for the prevention of migraine.^48, Within this position statement, AHS states that CGRP-targeting treatments, which include mAbs (erenumab, fremanezumab, galcanezumab, and eptinezumab) and gepants (rimegepant and atogepant), should be considered first-line agents for the prevention of migraine along with previous first-line therapies without a requirement for prior failure of other classes of migraine preventive treatment. This updated consensus is based on the clinical trial evidence existing for CGRP-targeting treatments and its similar efficacy in indirect comparisons to topiramate. A head-to-head study of topiramate and erenumab found adherence to erenumab was significantly better than topiramate and found that erenumab was statistically superior in terms of efficacy. Additionally, AHS cites "real-world" experience as useful in confirming results of randomized controlled trials regarding efficacy, tolerability, and safety.

American Academy of Neurology/American Headache Society

In 2012, the AAN and the AHS published guidelines on therapies for migraine prevention.^43, Recommended pharmacologic treatments for episodic migraine prevention are described in Table 30. These guidelines were reaffirmed in 2022 and an update is in progress.

Table 30. Recommended Pharmacologic Treatments for Episodic Migraine Prevention

   MAM: menstrually associated migraines

Institute for Clinical and Economic Review

The Institute for Clinical and Economic Review (ICER) assessed the comparative clinical effectiveness and value of CGRP inhibitors as preventive treatments for patients with episodic or chronic migraine.^8,

• Among patients with chronic migraine who are eligible to receive preventive therapy, ICER Report rated the evidence on the net benefit of erenumab and fremanezumab as insufficient (“I”) compared to oral agents or to onabotulinum toxin A.

• Among patients with chronic migraine for whom prior preventive therapy has failed, ICER Report rated the net benefit of erenumab and fremanezumab as comparable or better (“C+”) compared to no treatment, weighing uncertainties about potential harms of CGRP inhibitors against the need for therapy in patients with frequent migraine and no other preventive treatment options.

• Among patients with episodic migraine who are eligible to receive preventive therapy, ICER Report rated the evidence on the net benefit of erenumab, fremanezumab, and galcanezumab as insufficient (“I”) compared to oral agents.

• Among patients with episodic migraine for whom oral preventive therapies have failed, ICER Report rated the net benefit of erenumab and fremanezumab as promising but inconclusive (“P/I”) compared to no treatment, again weighing uncertainties about potential harms of CGRP inhibitors against the need for therapy in patients without other preventive treatment options but with less frequent migraine than in the chronic migraine population.

U.S. Preventive Services Task Force Recommendations

Not applicable.

Medicare National Coverage

There is no national coverage determination. In the absence of a national coverage determination, coverage decisions are left to the discretion of local Medicare carriers.

Ongoing and Unpublished Clinical Trials

Some currently unpublished trials that might influence this review are listed in Table 31.

Table 31. Summary of Key Trials

  NCT: national clinical trial. a Denotes industry-sponsored or cosponsored trial.    

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