Calcitonin gene-related peptide receptor antagonist explained

Calcitonin gene-related peptide (CGRP) receptor antagonists are a class of drugs that act as antagonists of the calcitonin gene-related peptide receptor (CGRPR).

Several monoclonal antibodies that bind to the CGRP receptor or peptide have been approved for prevention of migraine.[1] Nerve activation triggers the release of CGRP and other neuropeptides, leading to inflammation, pain, and swelling. Three small molecule CGRPR antagonists are approved in the U.S. as antimigraine agents.[2] [3] Drugs of this class have also been investigated for use in osteoarthritis.[4]

Examples

Non-peptide small molecules

Monoclonal antibodies targeting the CGRP receptor

Monoclonal antibodies targeting the CGRP molecule

Necrotizing fasciitis

A study has found botox effective against necrotizing fasciitis caused by S. pyogenes in mice.[19] Its mechanism of action is by blocking CGRP receptor of nerve cells, which trigger intense pain and activate CGRP cascade, which prevents the immune system attacks to control the pathogen.[20] Botox blocks the CGRP cascade of nerve cells.[21]

Migraine

As of 2018, erenumab, brand name Aimovig, was approved in the U.S. for use for migraines. It interacts by blocking the CGRP receptor.[22] As of 2018, fremanezumab, brand name Ajovy, was approved in the U.S. for use for migraines. It interacts with the CGRP protein expressed during an attack.[23] The third approved treatment, as of 2018, galcanezumab, brand name Emgality, was approved in the U.S. for use in migraines. It also interacts with the protein.[24]

As of February 2020, eptinezumab (Vyepti) was approved by the FDA for the treatment of migraine via intravenous infusion as well.[25]

Three small-molecule antagonists have been approved for treatment of migraine: ubrogepant, rimegepant, and atogepant. Ubrogepant and rimegepant are approved for acute treatment. Atogepant and rimegepant are approved for preventative treatment.

Notes and References

  1. Web site: 2018. Erenumab (AIMOVIG) Prescribing Information. live. FDA.gov. U.S. Food and Drug Administration. https://web.archive.org/web/20181207235808/https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/761077s000lbl.pdf . 2018-12-07 .
  2. Web site: June 2021. Nurtec ODT Prescribing Information. live. FDA.gov. U.S. Food and Drug Administration. https://web.archive.org/web/20210528184316/https://www.accessdata.fda.gov/drugsatfda_docs/label/2021/212728s006lbl.pdf . 2021-05-28 .
  3. Web site: 2019. Ubrogepant Prescribing Information. live. FDA.gov. U.S. Food and Drug Administration. https://web.archive.org/web/20200717082408/https://www.accessdata.fda.gov/drugsatfda_docs/label/2019/211765s000lbl.pdf . 2020-07-17 .
  4. 26686833. 2015. Nakasa. T. Attenuation of cartilage degeneration by calcitonin gene-related paptide receptor antagonist via inhibition of subchondral bone sclerosis in osteoarthritis mice. Journal of Orthopaedic Research. 1177–84. Ishikawa. M. Takada. T. Miyaki. S. Ochi. M. 10.1002/jor.23132. 34. 7. free.
  5. Tfelt-Hansen. P. Olesen. J. April 2011. Possible Site of Action of CGRP Antagonists in Migraine. Cephalalgia: An International Journal of Headache. 31. 6. 748–50. 10.1177/0333102411398403. 21383046. free.
  6. Marcus. R. Goadsby. PJ. Dodick. D. Stock. D. Manos. G. Fischer. TZ. February 2014. BMS-927711 for the Acute Treatment of Migraine: a Double-Blind, Randomized, Placebo Controlled, Dose-Ranging Trial. Cephalalgia: An International Journal of Headache. 34. 2. 114–25. 10.1177/0333102413500727. 23965396. free.
  7. Web site: March 2022. Qulipta Prescribing Information. live. FDA.gov. U.S. Food and Drug Administration. https://web.archive.org/web/20211114014201/https://www.accessdata.fda.gov/drugsatfda_docs/label/2021/215206Orig1s000lbl.pdf . 2021-11-14 .
  8. https://www.accessdata.fda.gov/drugsatfda_docs/appletter/2023/216386Orig1s000ltr.pdf
  9. Pfizer's ZAVZPRET™ (Zavegepant) Migraine Nasal Spray Receives FDA Approval . 10 March 2023 .
  10. News: July 29, 2011. Press release: Merck Announces Second Quarter 2011 Financial Results. Merck. https://web.archive.org/web/20130412063354/http://www.mercknewsroom.com/press-release/financial-news/merck-announces-second-quarter-2011-financial-results. April 12, 2013.
  11. Recober. A. Russo. AF. August 2007. Olcegepant, a Non-Peptide CGRP1 Antagonist for Migraine Treatment. IDrugs: The Investigational Drugs Journal. 10. 8. 566–74. 17665333.
  12. Diener . HC . Barbanti . P . Dahlöf . C . Reuter . U . Habeck . J . Podhorna . J . BI 44370 TA, an Oral CGRP Antagonist for the Treatment of Acute Migraine Attacks: Results From a Phase II Study . Cephalalgia: An International Journal of Headache . April 2011 . 31 . 5 . 573–84 . 10.1177/0333102410388435 . 21172952 . free .
  13. Li . CC . Vermeersch . S . Denney . WS . Kennedy . WP . Palcza . J . Gipson . A . Han . TH . Blanchard . R . De Lepeleire . I . Depré . M . Murphy . MG . Van Dyck . K . de Hoon . JN . Characterizing the PK/PD Relationship for Inhibition of Capsaicin-Induced Dermal Vasodilatation by MK-3207, an Oral Calcitonin Gene Related Peptide Receptor Antagonist . British Journal of Clinical Pharmacology . May 2015 . 79 . 5 . 831–7 . 10.1111/bcp.12547 . 25377933 . 4415719.
  14. 28240610 . 10.1097/WCO.0000000000000438 . 30 . 3 . Calcitonin gene-related peptide monoclonal antibodies for migraine prevention: comparisons across randomized controlled studies . Curr Opin Neurol . 272–280 . Mitsikostas . DD . Reuter . U. 2017 . 46105364 .
  15. Web site: 2020. Eptinezumab Prescribing Information. live. FDA.gov. U.S. Food and Drug Administration. https://web.archive.org/web/20200225004647/https://www.accessdata.fda.gov/drugsatfda_docs/label/2020/761119s000lbl.pdf . 2020-02-25 .
  16. H. Spreitzer. 29 February 2016. Neue Wirkstoffe – TEV-48125. Österreichische Apothekerzeitung. 5/2016. 12. German.
  17. Walter . S . Bigal . ME . TEV-48125: a Review of a Monoclonal CGRP Antibody in Development for the Preventive Treatment of Migraine . Current Pain and Headache Reports . March 2015 . 19 . 3 . 6 . 10.1007/s11916-015-0476-1 . 25754596 . 8550606 .
  18. Web site: Drug Approval Package: Emgality (galcanezumab-gnlm). 2021-07-09. www.accessdata.fda.gov.
  19. Pinho-Ribeiro . Felipe A. . Baddal . Buket . Haarsma . Rianne . O’Seaghdha . Maghnus . Yang . Nicole J. . Blake . Kimbria J. . Portley . Makayla . Verri . Waldiceu A. . Dale . James B. . Wessels . Michael R. . Chiu . Isaac M. . 2018-05-17 . Blocking neuronal signaling to immune cells treats streptococcal invasive infection . Cell . 173 . 5 . 1083–1097.e22 . 10.1016/j.cell.2018.04.006 . 0092-8674 . 5959783 . 29754819.
  20. Web site: How the germ behind flesh-eating disease hijacks neurons to avoid immune destruction.
  21. Web site: 2020-05-10 . Combining Botox and a CGRP antibody: should it be covered by insurance companies? - Migraine Canada™ . 2024-07-30 . en-US.
  22. Web site: Rosenberg . J. . FDA Approves Erenumab, First CGRP Inhibitor for Prevention of Migraine . AJMC . 18 May 2018 . 6 April 2019.
  23. Web site: FDA Approves Second Anti-CGRP Treatment for Migraine . American Migraine Foundation . 6 April 2019.
  24. Web site: Lilly's Emgality (galcanezumab-gnlm) Receives U.S. FDA Approval for the Preventive Treatment of Migraine in Adults . Eli Lilly and Company . 6 April 2019.
  25. Web site: Eptinezumab-jjmr (Vyepti) Approved By FDA for Migraine Prevention. 2021-07-09. American Headache Society. en-US.

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