Headache Medicine Update: What’s New in CGRP Functional Blocking Agents

Migraine remains one of the most common and debilitating neurologic disorders, affecting more than a billion individuals globally.¹ Despite being common and debilitating, migraine remains underdiagnosed and undertreated.² A headache is considered a migraine when it is associated with 2 of the following criteria: moderate to severe intensity, throbbing quality, exacerbated by activity, or unilateral location. In addition, migraine headaches are associated with photophobia, phonophobia, nausea, or vomiting.³ Migraine is characterized by debilitating attacks of varying frequency and duration, and treating attacks acutely is necessary.

For many individuals with frequent migraines, routinely administered preventive treatment is as important as treating acute exacerbations. The American Headache Society suggests that individuals with 4 or more headache days per month associated with disability should be offered preventive treatment. Migraine has been described as early as 400 BCE and is common worldwide; however, treatment has remained relatively elusive until recently. Preventive migraine treatment, the mainstay for individuals with the most debilitating forms of migraine, has often consisted of off-label medications initially used for other neurologic conditions and repurposed for individuals with migraine. Although effective in varying capacities, these treatments have been associated with a wide spectrum of side effects such that 80% of people discontinued preventive treatments within the first year.⁴ Although triptans have been the mainstay of prescribed acute migraine treatment, they also are associated with high discontinuation rates.⁵ This left an unmet need for effective and tolerable acute and preventive medications. Perhaps the most important recent advancement in fulfilling this unmet need consists of inhibiting the calcitonin gene-related peptide (CGRP) nociceptive pathway.

The pathophysiology of migraine is intimately linked with CGRP. First, CGRP receptors are found ubiquitously along migraine nociceptive pathways.⁶ Second, individuals who have a known history of migraine have higher baseline levels of CGRP than others, and their CGRP levels increase further during migraine attack.^6a In addition, infusion of CGRP precipitates a migraine headache and inhibiting CGRP aborts migraine, which is believed to be the mechanism by which triptans abort migraine headache. The subsequent advent of small molecule gepants inhibiting the CGRP receptor and peripherally acting large molecule monoclonal antibodies ushered in an exciting new era of headache treatment for both individuals and providers.

Over the past several years, CGRP monoclonal antibodies (mAbs) and gepants have been studied in several landmark clinical trials have been associated with both qualitative and quantitative improvements in migraine outcomes.⁷ As a result, CGRP-inhibiting treatments are used in an increasing variety of settings, including in different combinations and for different headache conditions. The purpose of this article is to summarize some of these more recent advances.

Data Supporting Gepant Use With Other CGRP-Inhibiting Agents

Gepants are small molecules that target the CGRP receptor. Their shorter half-lives allow for their use as rescue treatments or, in the case of atogepant, as an oral, daily dosed preventive alternative to the monthly injectable CGRP mAb. There are 3 rescue gepant options: ubrogepant (Ubrevly; Allergan, Irvine, CA), rimegepant (Nurtec; Pfizer, New York, NY), and zavegepant (Zavzpret; Pfizer, New York, NY). Rimegepant has been approved by the Food and Drug Administration (FDA) for episodic migraine prevention in addition to its rescue treatment indication. Atogepant is approved by the FDA for both episodic and chronic migraine prevention. A multicenter open-label trial studying the combination of ubrogepant and atogepant in 26 participants found that the C_max of ubrogepant increased in the setting of concomitant ubrogepant without any serious side effects reported.⁸ A single nonserious treatment-emergent side effect of palpitations was determined to be not related to study drug. Additional studies are underway to evaluate the efficacy of the ubrogepant and atogepant combination (Study to Assess Adverse Events When Ubrogepant Tablets in Combination With Atogepant Tablets Are Used to Treat Adult Participants With Migraine [TANDEM]; NCT05264129). In theory, any rescue gepant may be used with the preventive atogepant, but neither safety nor efficacy data are available for using rimegepant or zavegepant with atogepant. There are also no data available to support using ubrogepant or zavegepant with the preventive q48h rimegepant dosing (Table 1).

Small studies establishing the pharmacokinetics and safety of gepants with CGRP mAbs have paved the way for larger real world evidence studies. A study evaluating 40 participants treated with ubrogepant in the setting of either erenumab (Aimovig; Amgen, Thousand Oaks, CA) 140 mg or galcanezumab (Emgality; Eli Lilly, Indianapolis, IN) 120 mg preventive therapy found no significant differences in ubrogepant C_max compared with treatment with ubrogepant alone.^8a In addition, treatment-emergent side effects were similar between individuals treated with ubrogepant along with and CGRP mAbs compared with those treated with ubrogepant alone. A smaller study evaluating 13 individuals treated with rimegepant and CGRP mAbs reported no serious side effects in participants taking both treatments concurrently.^8b Only 3 nonserious adverse effects were reported among 234 people using rimegepant or ubrogepant with a CGRP mAb in a retrospective, real-world study,⁹ none of which led to discontinuation of the treatments. In the COURAGE (Clinical Outcomes Utilizing Revascularization and Aggressive Drug Evaluation; NCT00007657) study, researchers prospectively evaluated 245 participants who were treated with ubrogepant in the setting of CGRP mAb preventive use. Results across 10 acute attacks found meaningful pain relief in 61.6% and 80.4% of individuals at 2 and 4 hours, respectively. In addition, by 2 and 4 hours, 34.7% and 55.5% of individuals had returned to normal function, respectively.¹⁰ The data support the use of gepants concurrently with a CGRP mAb; additional prospective randomized control trials will be helpful to establish efficacy and safety.

CGRP-Inhibiting Treatments in Combination With OnabotulinumtoxinA

A combination of preventive medications is commonly used for individuals with difficult-to-treat refractory migraine. Given the known benefit of onabotulinumtoxinA and the established benefit of CGRP-inhibiting treatments, it is natural to consider their combination in those who have had partial benefit with either treatment alone. There is a clear scientific rationale supporting the use of both treatments in concert. CGRP mAbs are believed to interrupt pain mediation along the Aδ-meningeal nociceptors, but not the unmyelinated C-fibers. OnabotulinumtoxinA inhibits the unmyelinated C-fibers.¹¹ Both pain fibers are implicated in migraine pain. Because of the mediation of these different pain pathways, there exists a rationale for a synergistic or additive effect of both treatments used together for the treatment of migraine pain.

Several studies have evaluated the use of CGRP mAbs with concurrent onabotulinumtoxinA (Table 2).^12-17 The studies range in sample size from 17 to 257 participants and evaluated reduction in monthly migraine days, reduction in pain, and side effects. Overall, the data support the combined use of CGRP mAbs with onabotulinumtoxinA. The most dramatic improvement with combination therapy was noted by Hennessy et al¹³ in a study evaluating 194 participants who had been started individually on CGRP mAb or onabotulinumtoxinA. Baseline monthly migraine days were 28 before the onset of either treatment. After initiation of the first treatment (either CGRP mAb or onabotulinumtoxinA), monthly migraine days were reduced by 10. After the initiation of combination therapy, monthly migraine days improved with an additional reduction of 6 days per month. Most individuals in this study had been treated with erenumab (78%), likely because it was the first CGRP mAb that was approved by the FDA. No side effects were documented, but other studies have reported no major side effects with this treatment. The most common side effect reported by a single study was constipation (9%).¹⁵ This is a known side effect of erenumab and is similar to what is noted in real-world studies and clinical trials. Limitations across these studies are similar, including small sample sizes limited to single institutions with a retrospective study design. An apparent challenge in implementing the combination of these treatments is that both treatments are costly, and combination therapy would magnify the costs.¹¹

The rationale for combination therapy with CGRP mAb and onabotulinumtoxinA is sound, and the preliminary data appear promising. More robust data from randomized controlled trials are necessary to establish efficacy and safety for this combination.

Evidence for Broadening the Use of CGRP-Inhibiting Treatments

CGRP mAbs have been evaluated in various migraine spectrum disorders, including hemiplegic migraine, vestibular migraine, and menstrually related migraine, and as a migraine prophylactic during pregnancy.^18-21 Although the data often are limited to case reports or case series, the data reflect broadening use of CGRP inhibitors to treat various migraine-related conditions. The most promising data appear to be for treatment of vestibular migraine. Vestibular migraine can be debilitating and difficult to treat. Preventive treatments include acetazolamide, Β-blockers, and calcium channel blockers.¹⁹ However, treatments are often limited by their side effects. A prospective observational study evaluating 50 participants who were treated with CGRP mAbs for vestibular migraine reported that 78% of individuals had 50% improvement in headache frequency, 50% improvement in vertigo frequency, and 50% improvement in quality of life.²² Additional prospective, well-conducted studies are necessary, but these preliminary results are promising.

Posttraumatic headache (PTH) is often debilitating and resistant to treatment. Whereas an infusion of CGRP precipitates a migraine-like headache in individuals with PTH, preclinical models appear to suggest that there are both CGRP-dependent and CGRP-independent mechanisms responsible for the headache pain associated with PTH.^23,24 As a result, conflicting data exist on the use of CGRP mAbs for the treatment of PTH. The most robust clinical trial (A Study to Test if Fremanezumab Reduces Headache in Participants With Posttraumatic Headache, NCT03347188) evaluated fremanezumab (Ajovy; Teva Pharmaceuticals, Parsippany–Troy Hills, NJ) for PTH treatment. There was no difference in benefit between the fremanezumab-treated and placebo cohorts. However, a smaller retrospective study that included 63 participants found improvement in headache severity and reduction in headache frequency in individuals treated with CGRP mAbs.²⁵ Data are limited, but this is another area in which CGRP inhibitors may be used and hold promise.

Conclusion

The era of CGRP inhibitors has been an exciting period in the history of migraine treatment. As the pivotal clinical trials established safety and efficacy, real-world studies corroborated the benefits noted by clinicians and individuals, leading to a natural progression for the use of CGRP inhibitors in combination with various treatments to bolster efficacy further. Based on early data, the combination of gepants with CGRP mAbs appears to be a safe treatment option. A reduction in migraine frequency, particularly in individuals with high headache burden, appears to occur with a combination of CGRP mAbs and onabotulinumtoxinA. In addition to combination therapy, broadening the use of CGRP inhibitors to headache conditions in which CGRP plays an important role may help individuals with debilitating headache disorders, including vestibular migraine, PTH, and hemiplegic migraine. Although the data are in their infancy, the indications and use of CGRP inhibitors in these settings and beyond are likely to increase.