The proportion of patients with migraine who, at different annual prices, could be treated with erenumab or fremanezumab without crossing the Institute for Clinical and Economic Review’s annual budget impact threshold of $915 million. Estimates are based on treatment of patients with episodic and chronic migraine with prior failure of at least 1 previous preventive therapy. QALY indicates quality-adjusted life-year; WAC, wholesale acquisition cost.
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Loder E, Renthal W. Calcitonin Gene-Related Peptide Monoclonal Antibody Treatments for Migraine. JAMA Intern Med. Published online January 14, 2019. doi:10.1001/jamainternmed.2018.7536
The Institute for Clinical and Economic Review (ICER) has issued an evidence report on the effectiveness and value of 2 new calcitonin gene-related peptide monoclonal antibody treatments (CGRP mAbs) for migraine.1
Migraine is a disabling condition determined by both genetic and environmental factors. It affects an estimated 32 million people in the United States2 and produces a lifelong predisposition to develop severe headache and associated symptoms spontaneously or in response to triggers. Occasional migraine attacks usually are treated individually with symptomatic medications such as triptans. If attacks are frequent, regularly administered preventive treatment may decrease headache frequency or severity. A variety of US Food and Drug Administration–approved preventive treatments are available, including β-blockers such as propranolol, antiepileptic drugs such as topiramate, and biologics such as onabotulinumtoxinA. In general, these treatments provide modest relief of symptoms and some are poorly tolerated.3
Calcitonin gene-related peptide is released during attacks of migraine and when infused it can trigger migraine. Antibodies to CGRP or its receptor are thought to interfere with CGRP-mediated activation of trigeminal afferent neurons and dilation of meningeal vessels. The US Food and Drug Administration approved erenumab in May 2018 for prevention of episodic and chronic migraine.4 Fremanezumab and galcanezumab were approved for the preventive treatment of migraine in September 2018. A fourth antibody, eptinezumab, is in development.4 Erenumab and galcanezumab are self-administered monthly injections. Fremanezumab can be self-administered as a monthly or quarterly injection.
The objectives of this review were to determine (1) whether fremanezumab and erenumab are associated with improved outcomes in patients with chronic and episodic migraine and (2) whether these monoclonal antibody treatments are cost-effective compared with other migraine treatments.
The ICER review focused on 2 of the 4 CGRP antibodies (erenumab and fremanezumab) for which sufficient published information was available. Erenumab is an antibody to the CGRP receptor, and fremanezumab is an antibody to CGRP. The review used network meta-analysis (NMA) to compare the CGRP antibodies with placebo and with other commonly used preventive treatments for the treatment of episodic and chronic migraine (headache for 15 or more days per month for at least 3 months).
For episodic migraine, NMA found that patients using fremanezumab, erenumab, or galcanezumab had statistically significantly fewer migraine days compared with those using placebo. This was also true for propranolol, 160 mg/d, and topiramate, 100 mg/d and 200 mg/d.1 The CGRP mAbs were not superior to propranolol or topiramate when judged by a change in migraine days from baseline or the proportion of trial participants who had a 50% or more reduction in monthly migraine days.
The NMA estimated that change from baseline ranged from 3.5 fewer migraine days per month with erenumab, 70 mg, to 4.1 fewer migraine days per month with erenumab, 140 mg, and 4 fewer migraine days per month for topiramate, 100 mg/d, and propranolol, 160 mg/d.1 Data on patients who had failed at least 1 preventive therapy were provided in confidence by the manufacturers of erenumab and fremanezumab but are not publicly available.
For chronic migraine, the NMA found that patients using the mAbs as a preventive treatment for migraine had fewer migraine or headache days per month and fewer days requiring acute symptomatic headache treatment compared with placebo but only the results for acute symptomatic treatments were statistically significant.1 Compared with patients who used placebo, participants receiving erenumab had a reduction of 2.4 migraine days per month at both the 70-mg and 140-mg doses, and participants receiving fremanezumab, 675 mg quarterly or 225 mg monthly, had a reduction of 1.3 and 1.7 migraine days per month, respectively. There was insufficient evidence that the mAbs for chronic migraine resulted in a clinical benefit comparable to other preventive agents such as topiramate or botulinum toxin. The Institute for Clinical and Economic Review also reviewed unpublished data on patients who had failed at least 1 previous preventive therapy and found that the mAbs were “comparable or better compared to no treatment” in this subgroup but did not publicly report the effect size or statistical significance of this analysis.1
Participants in clinical trials tolerated the mAbs well. The most common adverse effect was injection-site pain in up to 30% of patients and nasopharyngitis in 12% of patients.1 The NMA did not identify any statistically significant differences in discontinuation rates between the mAbs and placebo. The odds ratio for discontinuation from adverse events was 1.4 for erenumab, 70 mg/mo and 140 mg/mo, 1.4 for propranolol, 120 to 160 mg/d, and 2.5 for topiramate, 100 mg/d, compared with discontinuations owing to adverse events from placebo. The report noted that the long-term safety of mAbs is unknown.
The list price of erenumab is $6900 per year.4 As the Figure shows, price reductions of 75% or more would be needed to achieve coverage of all potentially eligible patients at a reasonable cost. The cost-effectiveness ratios for the mAbs for treatment of chronic migraine were between $90 000 and $120 000 per quality-adjusted life-year (QALY) gained ($100-$140 per migraine-free day) and were $150 000 per QALY gained ($150-$160 per migraine-free day) for episodic migraine. The estimated annual budget impact for all migraine patients ranged from $2.1 billion to $8.9 billion, depending on the magnitude of pricing discounts.
There were no head-to-head trials of CGRP mAbs and standard preventive treatment, and the duration of trials was short.1 The quality of older trials of comparative agents was variable. The headache frequency at which patients should be encouraged to use preventive treatment was not based on firm evidence.5 Trials of the mAbs excluded patients most likely to receive these treatments in clinical practice, namely those with daily migraine in whom all existing preventive treatments have failed or who have severe comorbidity. The optimal duration of treatment is uncertain. The long-term safety of the mAbs and their safety for use during pregnancy are unknown. The good tolerability of the mAbs is difficult to capture in clinical trial outcomes, as are other intangible but important benefits such as the convenience and adherence advantages of periodic injections.
In its economic model, ICER focused on the benefits of the antibodies compared with placebo.1 This is not an appropriate comparator given the availability of other preventive treatments of established efficacy. Compared with commonly used doses of propranolol or topiramate, the antibodies’ cost per QALY exceeds reasonable thresholds, and the overall budget impact is likely to be substantial. Other key inputs that drive the results of the model, such as safety or the durability of treatment response with the CGRP antibodies, may change over time as more data are gathered.
Fremanezumab and erenumab seem to improve outcomes in patients with chronic and episodic migraine relative to no treatment, but the magnitude of benefit is similar to existing, less expensive treatments.1 Therefore, given their unknown long-term safety, these mAbs are not to be used as first-line treatments. It is possible that the mAbs, because of a different mechanism of action, might be useful for patients who have not benefited from or cannot tolerate existing therapies.
The cost of the CGRP mAbs is likely to exacerbate existing treatment inequities because people of low socioeconomic status are more likely to experience migraine but have less access to treatment.4
The CGRP mAbs are better than placebo for preventing both episodic and chronic migraine, but are far more expensive than comparable existing treatments. Therefore, the mAbs should be reserved for patients with disabling high-frequency episodic migraine or chronic migraine who have not benefited from or cannot tolerate first-line preventive treatments such as propranolol or topiramate for episodic migraine or botulinum toxin for chronic migraine.
Corresponding Author: Elizabeth Loder, MD, MPH, Division of Headache, Department of Neurology, Harvard Medical School, Brigham and Women’s Hospital, 1153 Centre St, Boston, MA 02130 (email@example.com).
Published Online: January 14, 2019. doi:10.1001/jamainternmed.2018.7536
Conflict of Interest Disclosures: Dr Loder is a past president of the American Headache Society. Dr Renthal reports an investigator-initiated grant from Teva Pharmaceutical Industries to conduct research unrelated to calcitonin gene-related peptide antibodies.
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