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Gepants: updates on current use and future directions for migraine treatment
Recent years have seen a revolution in the development and use of gepants as acute and preventive treatments for migraine. With recent clinical trials and FDA-issued approvals, the implications for this novel class of drugs for patients with migraine continue to expand.
Migraine is a highly prevalent neurological disorder that is characterized by disabling headache and can be accompanied by sensory sensitivities, nausea, vomiting, and aura.1, 2, 3 According to the 2016 Global Burden of Disease Study, migraine is the second leading cause of disability globally, underscoring the acute need for effective, tolerable, and accessible therapeutics.4 Recent developments have led to the U.S. Food and Drug Administration (FDA) approval of a novel intranasal agent, zavegepant, for acute migraine and expanded approval of atogepant for all migraine, offering valuable new therapeutic avenues for patients with migraine.
Over the past decades, a class of non-peptide small molecule calcitonin gene-related peptide (CGRP) receptor antagonists, known more commonly as gepants, emerged in the arena of migraine treatment. CGRP, a vasodilatory neuropeptide, has long been implicated in the pathophysiology of migraine; it is thought that release of CGRP in the trigeminovascular system contributes to the onset of a migraine attack.1 To interrupt the migraine-inducing effects of CGRP in both acute and preventive settings, gepants have been specifically designed to bind CGRP receptors, thus blocking the receptor’s interaction with CGRP and other factors associated with migraine pathophysiology.1
Along with anti-CGRP receptor monoclonal antibodies (mAbs), gepants represent the first therapeutic agents specifically designed to treat migraine.1 Prior to the development of gepants, the most common therapies for migraine were triptans, a class of 5-HT receptor agonists which are thought to interrupt CGRP release.2 Despite receiving FDA approval and being widely prescribed in clinical practice, triptans are associated with drug interactions, contraindications, inefficacy, and low tolerability in many patients.2 The development of novel CGRP receptor antagonists such as gepants thus offered a promising alternative for patients unable to use triptans.
Current Landscape
The first generation of gepants emerged around 15 years ago and underwent early clinical study. Studies on first-generation gepants were halted in the 2010s, however, due to hepatoxicity and poor oral availability.1 Recent studies have now revisited this class of agents to produce the second-generation gepants, namely rimegepant, ubrogepant, and atogepant.1 Numerous clinical studies have individually evaluated these second-generation gepants as acute treatments upon the onset of a migraine attack or as long-term preventive treatment in patients with chronic migraine.2 These trials have yielded positive outcomes in safety and efficacy, and, importantly, no hepatoxicity has been reported in any clinical trials for these drugs.1,2
Rimegepant is the only gepant with confirmed efficacy for both acute and preventive migraine.2 The efficacy of rimegepant in the acute setting was demonstrated in two Phase III studies (NCT03235479, NCT03237845), where freedom from pain two hours post-administration and relief from the most bothersome symptom (MBS) were both improved.5 An additional study (NCT03461757) confirmed the efficacy and safety of rimegepant specifically as an orally disintegrating tablet (ODT), and in February 2020, rimegepant received FDA approval for acute migraine treatment in the form of a 75-mg ODT.2 A 2021 Phase II/III study (NCT03732638) further demonstrated the efficacy of rimegepant in the preventive setting, showing a significant reduction in the mean monthly migraine days (MMD) compared with baseline. This study confirmed efficacy in the form of daily 75-mg oral doses over 12 weeks, however, further data will be necessary to elucidate efficacy with longer-term use.2 Rimegepant received expanded FDA approval as a preventive migraine treatment in May 2021.6
Ubrogepant, a treatment for acute migraine, was granted FDA approval in December 2019.7 An initial 2016 Phase II trial established efficacy and tolerability in the acute setting, demonstrating significant freedom from pain two hours post-administration with 100 mg of ubrogepant compared to placebo and only mild adverse events.2 These results were further supported by the ACHIEVE I (NCT02828020) and ACHIEVE II (NCT02867709) studies, which additionally reported positive outcomes regarding freedom from MBS.2
Atogepant was the first gepant developed specifically as a preventive therapy for episodic migraine, or patients who experience 0–14 migraine attacks per month. Atogepant was evaluated in the Phase III ADVANCE trial (NCT03777059) in patients with episodic migraine. The primary endpoint, change in mean MMD compared to baseline, was met, and no serious adverse events were reported. Long-term use of atogepant for one year was also well tolerated.2 In September 2021, atogepant received FDA approval as a preventive treatment for episodic migraine.8
Approval of Zavegepant for Acute Migraine
Recent and ongoing studies in 2023 have led to the emergence of a third generation of gepants. The second-generation gepants have all been approved as agents for oral administration; however, due to the structure of the third-generation gepants, these novel agents have been under investigation for further routes of administration, such as subcutaneous and intranasal.2
In March 2023, zavegepant was the first member of the third-generation gepants to be granted FDA approval for the treatment of acute migraine in adults with and without aura.9 Furthermore, zavegepant is the first gepant approved for an intranasal route of administration. Prior Phase III (NCT04571060) and Phase II/III (NCT03872453) studies evaluated the efficacy, tolerability, and safety profile of a 10-mg dose of intranasal zavegepant. Patients experienced a significant increase in freedom from pain and MBS two hours post-administration compared with placebo, and only minor side effects were reported.9,10 Results additionally demonstrated freedom from pain as early as 15 minutes post-administration, which may be attributed to the rapid absorption of the agent via the nasal mucosa.9 As an intranasal agent, zavegepant represents a beneficial therapeutic alternative for patients who cannot tolerate the oral administration route of other gepants due to nausea or vomiting.9
Timothy Smith, MD, RPh, FACP, StudyMetrix Research, St. Louis, MO, comments on a post-hoc subgroup analysis of these studies, highlighting that zavegepant shows significant effectiveness in migraine both with and without aura. In this context, Dr Smith emphasizes the need to investigate further migraine agents for their efficacy with and without aura, as this will provide crucial information to clinicians when determining treatment courses for their patients.
Expanded Indication of Atogepant as a Preventive for Chronic Migraine
Ongoing research has also been investigating further applications for the existing second-generation gepants. To this effect, in April 2023, atogepant received expanded FDA approval as a preventive treatment for adults with chronic migraine.11 This approval was issued in accordance with results from the Phase III PROGRESS (NCT03855137) and the ADVANCE (NCT03777059) trials, demonstrating safety, tolerability, and efficacy of a 60-mg daily dose of atogepant in adults with chronic migraine. Atogepant is available to patients in doses of 10 mg, 30 mg, and 60 mg; however, only the 60-mg dose has received approval from the FDA.8 With this recent expansion of approval, atogepant is now approved for chronic and episodic migraine with and without aura.11
The PROGRESS study for atogepant in chronic migraine was the pivotal study that ultimately led to its expanded approval. Stewart Tepper, MD, Dartmouth-Hitchcock Medical Center, Lebanon, NH, explains that the outcomes from this study were highly positive: patients experienced a mean MMD reduction of seven days for three total months.
Dr Tepper further cites a post-hoc analysis of the ADVANCE study, which has associated atogepant treatment with a decrease in body weight.12 However, follow-up studies will be necessary to understand the implications of this finding.
Ongoing Clinical Trials and the Future of Gepants
Numerous ongoing clinical trials are evaluating gepants in further contexts for patients with migraine. For instance, older patients have been historically excluded from trials for migraine agents, despite the increasing prevalence of migraine in this patient group.1 This exclusion has historically limited the therapeutic options for older patients. As a result, patients aged over 65 years are now being actively included in trials for migraine treatments, including gepants, to develop appropriate targets. Pediatric and pregnant patients also experience limited access to migraine treatments due to concerns of severe adverse events; trials are currently being designed to evaluate the use of gepants in these patient groups as well.1
Though gepants have been subject to rigorous preclinical and clinical testing over the past decades, many open questions remain. Significantly, there is minimal evidence regarding side effects with long-term use of gepants.1 Human CGRP receptors are found systemically and are of particular importance in the cardiovascular system, raising the question of cardiovascular or other off-target effects in the long term.1,3 Though many studies have confirmed the safety of gepants, further research will be necessary to ascertain the occurrence or risk of such off-target effects with continued use of gepants.
Furthermore, no head-to-head clinical trials have been conducted thus far to compare the second and third generation gepants with triptans.1 Studies on gepants alone have demonstrated the high efficacy and safety of these agents to treat patients who are unable to use triptans, however, clinical studies will be needed to directly compare the efficacy, safety, benefits, and risks conferred by each class of medications.1,2 Evidence has also suggested that rimegepant may offer benefits to patients who experience medication overuse headache from triptan use.1,2 This finding will require systematic evaluation, but if validated, may have crucial implications for treatment selection in clinical practice.2
Through the successes and failures in the development of migraine therapies, gepants have emerged as a safe, tolerable, and effective treatment option for many patients. Recent approvals and ongoing clinical trials for second and third generation gepants support the expanded applications of these therapies, promising a bright future for this novel class of agents.
Written by Alexandra Ertman
Reviewed by Juliet Lawrence
References
1. Rissardo JP, Caprara ALF. Gepants for Acute and Preventive Migraine Treatment: A Narrative Review. Brain Sci. Nov 2022;12(12):1612.
2. Moreno-Ajona D, Villar-Martínez MD, Goadsby PJ. New Generation Gepants: Migraine Acute and Preventive Medications. J Clin Med. Mar 2022;11(6):1656.
3. de Boer I, Verhagen IE, Souza MNP, et al. Place of next generation acute migraine specific treatments among triptans, non-responders and contraindications to triptans and possible combination therapies. Cephalalgia. Feb 2023;43(2):3331024221143773.
4.GBD 2016 Headache Collaborators. Global, regional, and national burden of migraine and tension-type headache, 1990–2016: a systematic analysis for the Global Burden of Disease Study 2016. Lancet Neurol. Nov 2018;17(11):954-976.
5. Lipton RB, Croop R, Stock EG, et al. Rimegepant, an Oral Calcitonin Gene-Related Peptide Receptor Antagonist, for Migraine. The New England Journal of Medicine. July 2019;381(2):142-149.
6. American Headache Society. NURTEC® ODT (rimegepant) receives additional approval for preventive treatment for adult patients with episodic migraine. [Press Release] 1st June 2023. Accessed 8th June 2023.
7. U.S. Food and Drug Administration. FDA approves new treatment for adults with migraine. [Press Release] 23 Dec 2019. Accessed 9th June 2023.
8. American Headache Society. Atogepant receives FDA approval for the preventive treatment of episodic migraine in adults. [Press Release]. 4 October 2021. Accessed 8th June 2023.
9. Pfizer. Pfizer’s ZAVZPRET™ (zavegepant) Migraine Nasal Spray Receives FDA Approval. [Press Release]. 10 March 2023. Accessed 8th June 2023.
10. Dhillon, S. Zavegepant: First Approval. Drugs. May 2023;83(9): 825–831.
11. AbbVie. U.S. FDA Approves QULIPTA® (atogepant) for Adults With Chronic Migraine. [Press Release]. 17 April 2023. Accessed 08/06/23
12. Dodick DW, Hay DL, Walker CS, et al. Decrease in Body Weight With Once-Daily Atogepant for the Preventive Treatment of Migraine: A Post Hoc Analysis (P1-2.002). Neurology. May 2022;98(18 Supplement):17.
