Calcitonin gene-related peptide receptor antagonist

Calcitonin gene-related peptide (CGRP) receptor antagonists, commonly known as gepants, are a class of drugs that act as antagonists of the calcitonin gene-related peptide receptor (CGRPR).[1]

The CGRP family of small proteins are present in the sensory nerves of the head and neck and are involved in transmission of pain.[2] Nerve activation can trigger the release of CGRP and other neuropeptides, leading to inflammation, pain, and swelling in the case of migraine.[3] Several monoclonal antibodies that bind to the CGRP receptor or peptide have been approved for prevention of migraine.[4] As of March 11, 2024, the American Headache Society issued a statement that "CGRP targeting therapies are a first-line option for migraine prevention"[2] in the United States. The prior use of non-specific migraine preventive medication approaches is therefore no longer required before CGRP treatments can be prescribed.[2] Small molecule CGRPR antagonists have also been approved in the U.S. as antimigraine agents.[5][6][7]

Drugs of this class have also been investigated for use in osteoarthritis.[8]

Examples of CGRP inhibitors

Small molecule CGRP antagonists are generally administered by mouth as pills. One type is a nasal spray. In contrast, CGRP monoclonal antibodies involve large molecules which must be given intravenously or as injections. Injections can be self-administered with an automatic pen monthly or quarterly, depending on the drug.[9]

Small molecule CGRP antagonists (gepants)

  • Ubrogepant is approved for acute treatment of migraines[10][6][2]
  • Rimegepant (BMS-927711) is approved for acute migraine treatment (since February 2020)[11] and for preventive treatment of episodic migraines (since May 2021).[12][5][2]
  • Atogepant (AGN-241689) is approved for preventative treatment of migraines[7][2]
  • Zavegepant (BHV- 3500) is a nasal spray approved for acute treatment of migraines.[13][14][2]
  • Telcagepant (MK-0974), reached phase III clinical trials; development discontinued in 2011.[15]
  • Olcegepant (BIBN-4096BS) is a drug candidate[16]
  • BI 44370 TA (BI 44370)[17]
  • MK-3207[18]
  • SB-268262

Monoclonal antibodies targeting the CGRP receptor

Monoclonal antibodies targeting the CGRP molecule

Medical applications

Migraine

As of 2024, eight blockers of CGRP or its receptor have been approved by the US Food and Drug Administration for the treatment or prevention of migraine.[24] These include erenumab, brand name Aimovig, approved in the U.S. for use for migraines in 2018. It interacts by blocking the CGRP receptor.[25] 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.[26] Galcanezumab, brand name Emgality, was the third treatment to be approved in the U.S. in 2018 for use in migraines. It also interacts with the CGRP protein.[27]

As of February 2020, eptinezumab (Vyepti) was approved by the FDA for the treatment of migraine via intravenous infusion as well.[28]

Three small-molecule antagonists have been approved for treatment of migraine: ubrogepant, rimegepant, and atogepant.[6][5][7] Ubrogepant and rimegepant are approved for acute treatment.[6][5] Atogepant and rimegepant are approved for preventative treatment.[7][5]

Necrotizing fasciitis

A study has found botox effective against necrotizing fasciitis caused by S. pyogenes in mice.[29] 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.[30] Botox blocks the CGRP cascade of nerve cells.[31]

References

  1. ^ Rashid, Abin; Manghi, Ali (2024), "Calcitonin Gene-Related Peptide Receptor", StatPearls, Treasure Island (FL): StatPearls Publishing, PMID 32809483, retrieved 2024-07-30
  2. ^ a b c d e f g h i j k Gibb, Vera (2024-04-26). "American Headache Society Position Statement: Calcitonin Gene-Related Peptide (CGRP) Inhibitors should now be considered a first-line option for migraine prevention". Association of Migraine Disorders. Retrieved 2025-11-05.
  3. ^ Pietra, AD; Kuburas, A; Russo, AF (September 2025). "PACAP versus CGRP in migraine: From mouse models to clinical translation". Cephalalgia. 45 (9) 3331024251364242. doi:10.1177/03331024251364242. PMID 40931761.
  4. ^ "Erenumab (AIMOVIG) Prescribing Information" (PDF). FDA.gov. U.S. Food and Drug Administration. 2018. Archived from the original (PDF) on 2018-12-07.
  5. ^ a b c d e "Nurtec ODT Prescribing Information" (PDF). FDA.gov. U.S. Food and Drug Administration. June 2021. Archived from the original (PDF) on 2021-05-28.
  6. ^ a b c d "Ubrogepant Prescribing Information" (PDF). FDA.gov. U.S. Food and Drug Administration. 2019. Archived from the original (PDF) on 2020-07-17.
  7. ^ a b c d "Qulipta Prescribing Information" (PDF). FDA.gov. U.S. Food and Drug Administration. March 2022. Archived (PDF) from the original on 2021-11-14.
  8. ^ Nakasa, T; Ishikawa, M; Takada, T; Miyaki, S; Ochi, M (2015). "Attenuation of cartilage degeneration by calcitonin gene-related paptide receptor antagonist via inhibition of subchondral bone sclerosis in osteoarthritis mice". Journal of Orthopaedic Research. 34 (7): 1177–84. doi:10.1002/jor.23132. PMID 26686833.
  9. ^ "Migraine: How CGRP Inhibitors Can Help". WebMD. Retrieved 6 November 2025.
  10. ^ Tfelt-Hansen, P; Olesen, J (April 2011). "Possible Site of Action of CGRP Antagonists in Migraine". Cephalalgia. 31 (6): 748–50. doi:10.1177/0333102411398403. PMID 21383046.
  11. ^ Negro, A; Martelletti, P (December 2020). "Rimegepant for the treatment of migraine". Drugs of Today. 56 (12): 769–780. doi:10.1358/dot.2020.56.12.3211624. ISSN 1699-3993. PMID 33332483.
  12. ^ Altamura, C; Brunelli, N; Marcosano, M; Fofi, L; Vernieri, F (September 2022). "Gepants - a long way to cure: a narrative review". Neurological Sciences. 43 (9): 5697–5708. doi:10.1007/s10072-022-06184-8. PMC 9159895. PMID 35650458.
  13. ^ "Zavzpret (zavegepant) nasal spray" (PDF). Food and Drug Administration. 9 March 2023. Archived from the original (PDF) on March 10, 2023. Retrieved 11 December 2024.
  14. ^ "Pfizer's ZAVZPRET™ (Zavegepant) Migraine Nasal Spray Receives FDA Approval" (Press release). 10 March 2023.
  15. ^ "Press release: Merck Announces Second Quarter 2011 Financial Results". Merck. July 29, 2011. Archived from the original on April 12, 2013.
  16. ^ Recober, A; Russo, AF (August 2007). "Olcegepant, a Non-Peptide CGRP1 Antagonist for Migraine Treatment". IDrugs: The Investigational Drugs Journal. 10 (8): 566–74. PMID 17665333.
  17. ^ Diener, HC; Barbanti, P; Dahlöf, C; Reuter, U; Habeck, J; Podhorna, J (April 2011). "BI 44370 TA, an Oral CGRP Antagonist for the Treatment of Acute Migraine Attacks: Results From a Phase II Study". Cephalalgia. 31 (5): 573–84. doi:10.1177/0333102410388435. PMID 21172952.
  18. ^ 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 (May 2015). "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. 79 (5): 831–7. doi:10.1111/bcp.12547. PMC 4415719. PMID 25377933.
  19. ^ Mitsikostas, DD; Reuter, U (2017). "Calcitonin gene-related peptide monoclonal antibodies for migraine prevention: comparisons across randomized controlled studies". Curr Opin Neurol. 30 (3): 272–280. doi:10.1097/WCO.0000000000000438. PMID 28240610. S2CID 46105364.
  20. ^ "Eptinezumab Prescribing Information" (PDF). FDA.gov. U.S. Food and Drug Administration. 2020. Archived from the original (PDF) on 2020-02-25.
  21. ^ H. Spreitzer (29 February 2016). "Neue Wirkstoffe – TEV-48125". Österreichische Apothekerzeitung (in German) (5/2016): 12.
  22. ^ Walter, S; Bigal, ME (March 2015). "TEV-48125: a Review of a Monoclonal CGRP Antibody in Development for the Preventive Treatment of Migraine". Current Pain and Headache Reports. 19 (3): 6. doi:10.1007/s11916-015-0476-1. PMID 25754596. S2CID 8550606.
  23. ^ "Drug Approval Package: Emgality (galcanezumab-gnlm)". www.accessdata.fda.gov. Retrieved 2021-07-09.
  24. ^ Dance, Amber (15 October 2024). "Studies of migraine's many triggers offer paths to new therapies". Knowable Magazine. Annual Reviews. doi:10.1146/knowable-101424-1. Retrieved 5 November 2025.
  25. ^ Rosenberg, J. (18 May 2018). "FDA Approves Erenumab, First CGRP Inhibitor for Prevention of Migraine". AJMC. Retrieved 6 April 2019.
  26. ^ "FDA Approves Second Anti-CGRP Treatment for Migraine". American Migraine Foundation. Retrieved 6 April 2019.
  27. ^ "Lilly's Emgality (galcanezumab-gnlm) Receives U.S. FDA Approval for the Preventive Treatment of Migraine in Adults". Eli Lilly and Company. Retrieved 6 April 2019.
  28. ^ "Eptinezumab-jjmr (Vyepti) Approved By FDA for Migraine Prevention". American Headache Society. Archived from the original on 2021-10-19. Retrieved 2021-07-09.
  29. ^ 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. doi:10.1016/j.cell.2018.04.006. ISSN 0092-8674. PMC 5959783. PMID 29754819.
  30. ^ "How the germ behind flesh-eating disease hijacks neurons to avoid immune destruction".
  31. ^ "Combining Botox and a CGRP antibody: should it be covered by insurance companies? - Migraine Canada™". 2020-05-10. Retrieved 2024-07-30.
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