This site is intended for healthcare professionals
Headache migraine woman
  • Home
  • /
  • News
  • /
  • News trends
  • /
  • Migraine
  • /
  • Anti-CGRP treatments for migraine
News

Anti-CGRP treatments for migraine

Are they holding their promise?
Read time: 20 mins
Last updated:23rd Dec 2021
Published:23rd Dec 2021

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.

Anti-CGRP treatments and their role in migraine prevention and treatment

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.

Real-world evidence for CGRP mAbs 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

Migraine_Article1_NOV21_Fig1.png

Figure 1: Typical migraine clinical trial participants versus real-world migraine patients 19–23.

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.

Migraine_Article1_NOV21_Fig2.png

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.

Summary

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.

About Professor Mario Peres

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.

Disclosures

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.

References

  1. Charles A, Pozo-Rosich P. Targeting calcitonin gene-related peptide: a new era in migraine therapy. The Lancet. 2019;394(10210):1765–1774.
  2. Eigenbrodt AK, Ashina H, Khan S, Diener HC, Mitsikostas DD, Sinclair AJ, et al. Diagnosis and management of migraine in ten steps. Nature Reviews Neurology. 2021;17(8):501–514.
  3. Committee for Medicinal Products for Human Use (CHMP). Ajovy (fremanezumab), Summary of Product Characteristics. EPAR. Teva GmbH. 2019 https://www.ema.europa.eu/en/documents/product-information/ajovy-epar-product-information_en.pdf. Accessed 26 October 2021.
  4. 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.
  5. 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.
  6. US Food and Drug Administration. Full Prescribing Information - Galcanezumab. 2018 https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/761063s000lbl.pdf. Accessed 26 October 2021.
  7. US Food and Drug Administration. Full Prescribing Information - Erenumab. 2021 https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/761077s000lbl.pdf. Accessed 26 October 2021.
  8. US Food and Drug Adminstration. Full Prescribing Information - Fremanezumab. 2018 https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/761089s000lbl.pdf. Accessed 26 October 2021.
  9. US Food and Drug Administration. Full Prescribing Information - Eptinezumab. 2020 https://www.accessdata.fda.gov/drugsatfda_docs/label/2020/761119s000lbl.pdf. Accessed 26 October 2021.
  10. 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.
  11. Goadsby PJ, Reuter U, Hallström Y, Broessner G, Bonner JH, Zhang F, et al. A Controlled Trial of Erenumab for Episodic Migraine. New England Journal of Medicine. 2017;377(22):2123–2132.
  12. Stauffer VL, Dodick DW, Zhang Q, Carter JN, Ailani J, Conley RR. Evaluation of galcanezumab for the prevention of episodic migraine: The EVOLVE-1 randomized clinical trial. JAMA Neurology. 2018;75(9):1080–1088.
  13. Skljarevski V, Matharu M, Millen BA, Ossipov MH, Kim BK, Yang JY. Efficacy and safety of galcanezumab for the prevention of episodic migraine: Results of the EVOLVE-2 Phase 3 randomized controlled clinical trial. Cephalalgia. 2018;38(8):1442–1454.
  14. Detke HC, Goadsby PJ, Wang S, Friedman DI, Selzler KJ, Aurora SK. Galcanezumab in chronic migraine: The randomized, double-blind, placebo-controlled REGAIN study. Neurology. 2018;91(24):E2211–E2221.
  15. Silberstein SD, Dodick DW, Bigal ME, Yeung PP, Goadsby PJ, Blankenbiller T, et al. Fremanezumab for the Preventive Treatment of Chronic Migraine. New England Journal of Medicine. 2017;377(22):2113–2122.
  16. Ashina M, Saper J, Cady R, Schaeffler BA, Biondi DM, Hirman J, et al. Eptinezumab in episodic migraine: A randomized, double-blind, placebo-controlled study (PROMISE-1). Cephalalgia. 2020;40(3):241–254.
  17. Lipton RB, Goadsby PJ, Smith J, Schaeffler BA, Biondi DM, Hirman J, et al. Efficacy and safety of eptinezumab in patients with chronic migraine: PROMISE-2. Neurology. 2020;94(13):E1365–E1377.
  18. Tepper S, Ashina M, Reuter U, Brandes JL, DoleĹžil D, Silberstein S, et al. Safety and efficacy of erenumab for preventive treatment of chronic migraine: a randomised, double-blind, placebo-controlled phase 2 trial. The Lancet Neurology. 2017;16(6):425–434.
  19. Mavridis T, Deligianni CI, Karagiorgis G, Daponte A, Breza M, Mitsikostas DD. Monoclonal antibodies targeting CGRP: From clinical studies to real-world evidence—what do we know so far? Pharmaceuticals. 2021;14(7):700.
  20. Lambru G, Hill B, Murphy M, Tylova I, Andreou AP. A prospective real-world analysis of erenumab in refractory chronic migraine. Journal of Headache and Pain. 2020;21(1):61.
  21. Faust E, Pivneva I, Yang K, Betts KA, Ahmed Z, Joshi S, et al. Real-World Treatment Profiles, Clinical Outcomes, and Healthcare Resource Utilization of Patients with Migraine Prescribed Erenumab: A Multicenter Chart-Review Study of US Headache Centers. Neurology and Therapy. 2021;10(1):293–306.
  22. Ornello R, Casalena A, Frattale I, Gabriele A, Affaitati G, Giamberardino MA, et al. Real-life data on the efficacy and safety of erenumab in the Abruzzo region, central Italy. Journal of Headache and Pain. 2020;21(1). doi:10.1186/s10194-020-01102-9.
  23. Hines DM, Shah S, Multani JK, Wade RL, Buse DC, Bensink M. Erenumab patient characteristics, medication adherence, and treatment patterns in the United States. Headache. 2021;61(4):590–602.
  24. Robblee J, Devick KL, Mendez N, Potter J, Slonaker J, Starling AJ. Real-World Patient Experience With Erenumab for the Preventive Treatment of Migraine. Headache. 2020;60(9):2014–2025.
  25. Scheffler A, Messel O, Wurthmann S, Nsaka M, Kleinschnitz C, Glas M, et al. Erenumab in highly therapy-refractory migraine patients: First German real-world evidence. Journal of Headache and Pain. 2020;21(1). doi:10.1186/s10194-020-01151-0.
  26. Bogdanov A, Chia V, Bensink M, Urman R, Fischer L, Rasmussen S, et al. Early use of erenumab in US real-world practice. Cephalalgia Reports. 2021;4. doi:10.1177/25158163211020419.
  27. Raffaelli B, Kalantzis R, Mecklenburg J, Overeem LH, Neeb L, Gendolla A, et al. Erenumab in Chronic Migraine Patients Who Previously Failed Five First-Line Oral Prophylactics and OnabotulinumtoxinA: A Dual-Center Retrospective Observational Study. Frontiers in Neurology. 2020;11. doi:10.3389/fneur.2020.00417.
  28. Barbanti P, Aurilia C, Cevoli S, Egeo G, Fofi L, Messina R, et al. Long-term (48 weeks) effectiveness, safety, and tolerability of erenumab in the prevention of high-frequency episodic and chronic migraine in a real world: Results of the EARLY 2 study. Headache. 2021;61(9):1–13.
  29. Barbanti P, Aurilia C, Egeo G, Fofi L, Cevoli S, Colombo B, et al. Erenumab in the prevention of high-frequency episodic and chronic migraine: Erenumab in Real Life in Italy (EARLY), the first Italian multicenter, prospective real-life study. Headache. 2021;61(2):1–10.
  30. Straube A, Stude P, Gaul C, Schuh K, Koch M. Real-world evidence data on the monoclonal antibody erenumab in migraine prevention: perspectives of treating physicians in Germany. The Journal of Headache and Pain. 2021;22(1):133.
  31. Dodick D, Ailani J, Tepper S, Pannacciulli N, Navetta M, Xue F, et al. Risk of hypertension in erenumab-treated patients with migraine in clinical trials and in the postmarketing setting. Presented at the 63rd Annual Scientific Meeting American Headache Society 2021 3–6 June 2021 Virtual IOR-08. 2021. https://headachejournal.onlinelibrary.wiley.com/doi/10.1111/head.14130. Accessed 27 October 2021.
  32. Saely S, Croteau D, Jawidzik L, Brinker A, Kortepeter C. Hypertension: A new safety risk for patients treated with erenumab. Headache. 2021;61(1):202–208.
  33. Breen ID, Mangold AR, VanderPluym JH. The evolving understanding of risk with calcitonin gene-related peptide monoclonal antibodies based on real-world data: A focus on hypertension and Raynaud phenomenon. Headache. 2021;61(8):1274–1276.
  34. Haanes KA, Edvinsson L, Sams A. Understanding side-effects of anti-CGRP and anti-CGRP receptor antibodies. Journal of Headache and Pain. 2020;21(1). doi:10.1186/s10194-020-01097-3.
  35. Vernieri F, Altamura C, Brunelli N, Costa CM, Aurilia C, Egeo G, et al. Galcanezumab for the prevention of high frequency episodic and chronic migraine in real life in Italy: a multicenter prospective cohort study (the GARLIT study). Journal of Headache and Pain. 2021;22(1):35.
  36. Cohen J, Thompson S, Patterson-Lomba O, Driessen M, Seminerio M, Carr K, et al. Real-world data on reductions in migraine and headache days with fremanezumab treatment for US patients with chronic and episodic migraine: Results from a physician chart review study. Presented at the 63rd Annual Scientific Meeting American Headache Society 2021 3–6 June 2021 Virtual P-96. 2021. https://headachejournal.onlinelibrary.wiley.com/doi/10.1111/head.14130. Accessed 27 October 2021.
  37. Cohen J, Thompson S, Ayyagari R, Driessen M, Seminerio M, Carr K, et al. Real-world data on quarterly and monthly fremanezumab for reducing migraine days and headache days in US adult patients with migraine: Results from a physician chart review study. Presented at the 63rd Annual Scientific Meeting American Headache Society 2021 3–6 June 2021 Virtual P-97. 2021. https://headachejournal.onlinelibrary.wiley.com/doi/10.1111/head.14130. Accessed 27 October 2021.
  38. Tangirala K, Pedarla V, Driessen M, Krasenbaum L, Thompson S, Maughn K, et al. Real-world impact of AJOVY use on clinical outcomes among migraine patients with comorbid depression, anxiety or hypertension. Presented at the 63rd Annual Scientific Meeting American Headache Society 2021 3–6 June 2021 Virtual P-100. 2021. https://headachejournal.onlinelibrary.wiley.com/doi/10.1111/head.14130. Accessed 27 October 2021.
  39. Fofi L, Egeo G, Aurilia C, Costa C, Altamura C, Vernieri F. Fremanezumab in the prevention of high-frequency episodic and chronic migraine: Friend (fremanezumab in real world study), the first Italian multicenter, prospective real-life study. Presented at the World Congress of Neurology (WCN 2021) 3-7 October 2021 Virtual 119272. 2021.
  40. Baig A, Suneja A, Ahmed Z. Real-world outcomes of eptinezumab. Presented at the 63rd Annual Scientific Meeting American Headache Society 2021 3–6 June 2021 Virtual P-111. 2021. https://headachejournal.onlinelibrary.wiley.com/doi/10.1111/head.14130. Accessed 27 October 2021.
  41. Breen ID, Brumfiel CM, Patel MH, Butterfield RJ, Vanderpluym JH, Griffing L, et al. Evaluation of the Safety of Calcitonin Gene-Related Peptide Antagonists for Migraine Treatment among Adults with Raynaud Phenomenon. JAMA Network Open. 2021;4(4):e217934.
  42. Aurilia C, Cevoli S, Egeo G, Fofi L, Messina R, Samerno A. Long-term (>48 weeks) safety and tolerability of erenumab in real-life. 2021. Presented at International Headache Congress IHS and EHF Joint Congress 2021, September 8–12 2021. Virtual. P0347.
  43. Peikert A, Stuhler E, Tozzi V, Kochling M, Israel-Willner H, Dikow H, et al. Two years of guideline-oriented migraine therapy with Erenumab under the regulatory conditions of the healthcare system in Germany. 2021. Presented at International Headache Congress IHS and EHF Joint Congress 2021, September 8–12 2021. Virtual. P-0346.
  44. Fofi L, Egeo G, Aurilia C, Costa C, Altamura C, Vernieri F, et al. Fremanezumab in the prevention of highfrequency episodic and chronic migraine: FRIEND (FRemanezumab In rEal world stuDy), the first Italian multicenter, prospective real-life study. 2021. Presented at International Headache Congress IHS and EHF Joint Congress 2021, September 8–12 2021. Virtual. P0318.
  45. Aurilia C, Cevoli S, Egeo G, Fofi L, Messina R, Salemo A, et al. Long term (48-weeks) effectiveness, safety and tolerability of erenumab in the prevention of highfrequency episodic and chronic migraine in realworld: the EARLY 2 study. 2021. Presented at International Headache Congress IHS and EHF Joint Congress 2021, September 8–12 2021. Virtual. AL045.
  46. Vernieri F, Altamura C, Brunelli N, Costa C, Aurilia C, Egeo G, et al. GalcanezumAb for prevention of high frequency episodic and chronic migraine in the Real Life in ITaly: a multicenter prospective cohort study (the GARLIT study). 2021. Presented at International Headache Congress IHS and EHF Joint Congress 2021, September 8–12 2021. Virtual. AL057.
  47. Altamura C, Brunelli N, Costa C, Aurilia C, Egeo G, Fofi L, et al. The real-life early and continuative response to Galcanezumab in chronic migraine: 3-month analysis of the multicenter prospective cohort GARLIT study. 2021. Presented at International Headache Congress IHS and EHF Joint Congress 2021, September 8–12 2021. Virtual. P0343.
  48. Straube A, Broessner G, Gaul C, Hamann X, Kraya T, Schauerte I, et al. FINESSE: Fremanezumab for Preventive Treatment in Migraine. 2021. Presented at International Headache Congress IHS and EHF Joint Congress 2021, September 8–12 2021. Virtual. P0325.
  49. Gal C, Koch M, Baufeld C. Characterisation of patient and treatment profiles of migraine patients treated with erenumab in routine clinicl practice: Interim results from the SPECTRE study. 2021. Presented at International Headache Congress IHS and EHF Joint Congress 2021, September 8–12 2021. Virtual. P0308.
  50. Schiano di Cola F, Caratozzolo S, Bolchini M, di Cesare M, Liberini P, Rao R. Galcanezumab in real life: safety and efficacy over 12 months of treatment. 2021. Presented at 7th Congress of European Academy of Neurology (EAN) 2021, June 19–22 2021. Virtual. EP0-417.
  51. Eli Lilly. Lilly Announces the Launch of TRIUMPH, the First, Long-Term, Real-World Evidence Study of Emgality® (galcanezumab-gnlm). 2019. http://www.prnewswire.com/news-releases/lilly-announces-the-launch-of-triumph-the-first-long-term-.
  52. European Network of Centres for Pharmacoepidemiology and Pharmacovigilance (ENCEPP). The European Union Electronic Register of Post-Authorisation Studies (EU PAS Register): EUPAS33068. 2020. http://www.encepp.eu/encepp/viewResource.htm;jsessionid=ZwOBRSYbXKxNzgibWUni0IYuxv8Ww0LAVIzlxyc040Sa0z0mDLoS!301285667?id=34651#. Accessed 27 October 2021.
  53. Ashina M, Amin FM, Kokturk P, Cohen JM, Konings M, Tassorelli C, et al. PEARL study protocol: A real-world study of fremanezumab effectiveness in patients with chronic or episodic migraine. Pain Management. 2021;11(6):647–654.
Welcome:

This content has been developed independently by Medthority who previously received educational funding in order to help provide its healthcare professional members with access to the highest quality medical and scientific information, education and associated relevant content.

Learning Zones

The Learning Zones are an educational resource for healthcare professionals that provide medical information on the epidemiology, pathophysiology and burden of disease, as well as diagnostic techniques and treatment regimens.