Anti-CGRP treatments for migraine
In recent years, specific treatments that target a key mediator of migraine, the neuropeptide calcitonin gene-related peptide (CGRP), have been approved for prevention of migraine.
Clinical trials have shown these anti-CGRP treatments, including CGRP monoclonal antibodies (CGRP mAbs), are effective and safe for prevention of migraine. But how effective and safe are CGRP mAbs in more complex, real-world patients with comorbidities who have often failed multiple prior treatments?
Join Professor Mario Peres, founder of the Sao Paulo Headache Center in Sao Paulo, Brazil, in exploring emerging real-world evidence for CGRP mAbs in preventing migraine.
CGRP is a potent vasodilator produced by neurons in both the central nervous system (CNS) and peripheral nervous system, and strong evidence supports it playing a key causative role in development of migraine and cluster headaches1.
To inhibit the role of CGRP in development of migraine, anti-CGRP treatments have been developed including small molecule CGRP receptor antagonists (gepants) and CGRP monoclonal antibodies (CGRP mAbs). The 2021 European Consensus Statement for diagnosis and management of migraine recommends gepants as an option for acute treatment of migraine, and CGRP mAbs as an option for preventative treatment for episodic and chronic migraine2.
Of the four CGRP mAbs available worldwide (erenumab, fremanezumab, galcanezumab and eptinezumab):
- Three (erenumab, fremanezumab and galcanezumab) have been EMA-approved for prophylaxis of migraine in adults who have at least 4 migraine days per month3–5, and
- All are FDA-approved for preventative treatment of migraine in adults6–9
Note eptinezumab remains under review by the EMA for prophylaxis of migraine in adults and is not yet approved for use in Europe10.
This article will focus on CGRP mAbs, and will provide a brief summary of emerging real-world evidence for their use in prevention of migraine.
Meet Professor Mario Peres and hear about his experience in managing migraine, and listen to an overview of findings from emerging real-world evidence for CGRP mAbs in preventing migraines.
While results from blinded, randomised clinical trials are highly valuable to inform the efficacy and safety of CGRP mAbs for migraine, many clinical trials of CGRP mAbs for migraine restricted use of concomitant migraine preventative medications11–17, and some featured exclusion criteria for comorbidities (such as pain-, psychiatric- or cardiovascular-related conditions)13,14,16–18.
Real-world evidence comes from real-world patients, who may have failed multiple prior migraine preventative treatments, may have various comorbidities and who may also be taking concomitant acute and/or other preventative migraine medications19–23
What is the real-world evidence showing for CGRP mAbs in preventing migraines?
Professor Peres describes some implications of real-world evidence on the prescribing of CGRP mAbs for migraine.
As the first FDA/EMA-approved CGRP mAb in 20184,7, there is comparatively more real-world evidence published for erenumab, with multiple peer-reviewed published retrospective analyses and observational studies to support the effectiveness of erenumab in real-world patients with chronic migraine (CM), episodic migraine (EM) or high-frequency episodic migraine (HFEM)20–30, and good rates of adherence23,26 (Table 1).
However, real-world safety findings and post-market data have prompted updates to the prescribing information for erenumab.
Evidence from real-world patients treated with erenumab and the post-market setting indicate a higher-than-expected rate of constipation occurring in 8.8% to 23.8% of patients in each study20,22,24,25,27–29, and an increased risk of hypertension31–33.
Constipation is listed as a warning/precaution in erenumab prescribing information in both the US and Europe4,7. Hypertension has also been included in the 2021 update of erenumab prescribing information in the US7.
This update includes:
- An increased risk of constipation particularly in patients with a history of constipation and in those who are concurrently using other medications which decrease gastrointestinal motility7,34. Constipation was most commonly reported after the first dose, and usually resolves in 3 months7
- Hypertension was reported in patients with or without pre-existing hypertension and most frequently occurred within one week after the first dose7. Note this safety signal has not yet been demonstrated with other CGRP mAbs33
There is limited real-world published evidence available for galcanezumab35, and emerging preliminary unpublished findings for fremanezumab36–39 and eptinezumab40 remain to be confirmed in peer-reviewed publications. Brief findings are summarised in Table 1.
In addition, findings from a small retrospective cohort study indicate caution may be warranted when prescribing CGRP mAbs for migraine in patients with Raynaud’s phenomenon41. In this study, of the 169 patients with Raynaud’s phenomenon who were taking CGRP mAbs for migraine, microvascular complications were reported in 9 patients41. These complications included worsening Raynaud’s phenomenon, gangrene and autonecrosis that required distal digit amputation41.
Table 1. Real-world evidence for safety and effectiveness of CGRP mAbs for the prevention of migraine20–29,31–33,35–50. AEs, adverse events; BMI, body mass index; CM, chronic migraine; EM, episodic migraine; HFEM, high frequency episodic migraine; HIT-6, headache impact test; MHD, mean headache days; MIDAS, migraine disability assessment questionnaire; MMD, mean migraine days; MPI, monthly painkiller intake; NRS, numerical rating score; NS, non-significant; PDC, proportion of days covered; VAS, visual analogue scores.
Real-world evidence – key limitations and future directions
Prof Peres discusses some key limitations of real-world evidence, and how these might be addressed in future studies.
Further studies in progress
With additional real-world studies underway, further real-world evidence for CGRP mAbs will continue to accumulate in the coming years. Further real-world studies that are in progress and yet to share preliminary findings include the TRIUMPH and PEARL studies, outlined below.
The TRIUMPH study will further evaluate the real-world effectiveness of galcanezumab in comparison to other preventive treatments for migraine51,52. It is a prospective observational study with a planned enrolment of approximately 2,850 patients from sites across the US, Europe and Asia, with up to 2 years of follow up52. This study will also evaluate prescribing and treatment choices related to migraine preventive treatment use, including switching patterns and discontinuation rates between galcanezumab and approved CGRP antibodies, oral migraine preventive treatments and botulinum toxin A or B52.
PEARL is a prospective, observational, multicentre Phase 4 study of fremanezumab in real-world patients with EM or CM53. The study will run for 24 months, and will evaluate effectiveness, adherence and persistence with fremanezumab treatment in European clinical practice, including effectiveness in patients switching from another CGRP mAb53. In this study, concomitant treatment with other acute and preventative treatments for migraine is permitted, and up to 30% of the study population may have previously received preventive migraine treatment with other mAbs targeting the CGRP pathway53. The study will assess effectiveness, adherence and persistence, tolerability and safety53.
Overall, real-world evidence is emerging to support the effectiveness of CGRP mAbs for prevention of migraine, including treatment-refractory patients with EM or CM, those with comorbidities, and those taking concomitant acute and/or preventative migraine medications. Erenumab and galcanezumab were well-tolerated, although an increased risk of constipation and new-onset/worsening hypertension were reported with erenumab in real-world patients.
Are anti-CGRP treatments robust in the long run? Stay tuned for the second article in this 3-part article series on managing migraine, where we will explore the longer-term evidence on the safety and efficacy of anti-CGRP treatments.
Professor Mario Peres is the Founder of the Sao Paulo Headache Center, President of ABRACES (Brazilian Headache Advocacy Association), Chair of the membership committee of the International Headache Society, and Professor of Postgraduation at the Psychiatry Institute, Sao Paulo State University Medical School.
Professor Peres has been involved in consulting/advisory board activities for Ache, Abbvie/Allergan, Daiichi Sankyo, Eli Lilly, Eurofarma, Hefesto Medtech, Libbs, Lundbeck, Novartis, Pfizer, Sanofi, and Teva Pharmaceuticals.
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- Committee for Medicinal Products for Human Use (CHMP). Aimovig (erenumab), Summary of Product Characteristics. EPAR. Novartis Europharm Limited. 2018 https://www.ema.europa.eu/en/documents/product-information/aimovig-epar-product-information_en.pdf. Accessed 26 October 2021.
- Committee for Medicinal Products for Human Use (CHMP). Emgality (galcanezumab), Summary of Product Characteristics. EPAR. Eli Lilly Nederland B.V. 2018 https://www.ema.europa.eu/en/documents/product-information/emgality-epar-product-information_en.pdf. Accessed 26 October 2021.
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- Pharmacovigilance Risk Assessment Committee (PRAC). Draft Meeting Agenda, 30 August to 2 September 2021. 2021 https://www.ema.europa.eu/en/documents/agenda/agenda-prac-draft-agenda-meeting-30-august-2-september-2021_en.pdf. Accessed 26 October 2021.
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