Calcitonin gene-related peptide receptor antagonist

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 which binds to the CGRP receptor or peptide have been approved for prevention of migraine.[1] Three small molecule CGRPR antagonists are approved in the U.S. as antimigraine agents.[2][3][4] Drugs of this class have also been investigated for use in osteoarthritis.[5]

Examples

Non-peptide small molecules
  • Ubrogepant is approved for acute treatment of migraines[6][3]
  • Rimegepant (BMS-927711) is approved for acute and preventative treatment of migraines[7][2]
  • Atogepant (AGN-241689) is approved for preventative treatment of migraines[4]
  • Telcagepant (MK-0974), reached phase III clinical trials; development discontinued in 2011.[8]
  • Olcegepant (BIBN-4096BS) is a drug candidate[9]
  • BI 44370 TA (BI 44370)[10]
  • MK-3207[11]
  • SB-268262

Monoclonal antibodies targeting the CGRP receptor
  • Erenumab (AMG-334) is approved for prevention of migraine.[12]

Monoclonal antibodies targeting the CGRP molecule

Necrotizing fasciitis

A study has found botox effective against necrotizing fasciitis caused by S. pyogenes in mice. 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.[17] Botox blocks the CGRP cascade of nerve cells.

Migraine

As of 2018, erenumab, trade name Aimovig, was approved in the U.S. for use for migraines. It interacts by blocking the CGRP receptor.[18] As of 2018, fremanezumab, trade name Ajovy, was approved in the U.S. for use for migraines. It interacts with the CGRP protein expressed during an attack.[19] The third approved treatment, as of 2018, galcanezumab, trade name Emgality, was approved in the U.S. for use in migraines. It also interacts with the protein.[20]

As of February 2020, Vyepti (eptinezumab) was FDA approved for the treatment of migraine via intravenous infusion as well.[21]

Three small-molecule antagonists have been approved for treatment of migraine: ubrogepant, rimegepant, and atogepant.[3][2][4] Ubrogepant and rimegepant are approved for acute treatment.[3][2] Atogepant and rimegepant are approved for preventative treatment.[4][2]

Metabolic health

Mice given a CGRP receptor antagonist improved insulin secretion and reduced chronic inflammation, improving the metabolic health of the animals.[22]

References
  1. "Erenumab (AIMOVIG) Prescribing Information" (PDF). FDA.gov. U.S. Food and Drug Administration. 2018. Archived (PDF) from the original on 2018-12-07.
  2. "Nurtec ODT Prescribing Information" (PDF). FDA.gov. U.S. Food and Drug Administration. June 2021. Archived (PDF) from the original on 2021-05-28.
  3. "Ubrogepant Prescribing Information" (PDF). FDA.gov. U.S. Food and Drug Administration. 2019. Archived (PDF) from the original on 2020-07-17.
  4. "Qulipta Prescribing Information" (PDF). FDA.gov. U.S. Food and Drug Administration. March 2022. Archived (PDF) from the original on 2021-11-14.
  5. 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.
  6. 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. doi:10.1177/0333102411398403. PMID 21383046.
  7. 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. doi:10.1177/0333102413500727. PMID 23965396.
  8. "Press release: Merck Announces Second Quarter 2011 Financial Results". Merck. July 29, 2011. Archived from the original on April 12, 2013.
  9. 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.
  10. 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: An International Journal of Headache. 31 (5): 573–84. doi:10.1177/0333102410388435. PMID 21172952.
  11. 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.
  12. 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.
  13. "Eptinezumab Prescribing Information" (PDF). FDA.gov. U.S. Food and Drug Administration. 2020. Archived (PDF) from the original on 2020-02-25.
  14. H. Spreitzer (29 February 2016). "Neue Wirkstoffe – TEV-48125". Österreichische Apothekerzeitung (in German) (5/2016): 12.
  15. 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.
  16. "Drug Approval Package: Emgality (galcanezumab-gnlm)". www.accessdata.fda.gov. Retrieved 2021-07-09.
  17. "How the germ behind flesh-eating disease hijacks neurons to avoid immune destruction".
  18. Rosenberg, J. "FDA Approves Erenumab, First CGRP Inhibitor for Prevention of Migraine". AJMC. Retrieved 6 April 2019.
  19. "FDA Approves Second Anti-CGRP Treatment for Migraine". American Migraine Foundation. Retrieved 6 April 2019.
  20. "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.
  21. "Eptinezumab-jjmr (VYEPTI™) Approved By FDA for Migraine Prevention". American Headache Society. Retrieved 2021-07-09.
  22. Riera CE, Huising MO, Follett P, Leblanc M, Halloran J, Van Andel R, de Magalhaes Filho CD, Merkwirth C, Dillin A (2014). "TRPV1 pain receptors regulate longevity and metabolism by neuropeptide signaling". Cell. 157 (5): 1023–1036. doi:10.1016/j.cell.2014.03.051. PMID 24855942.


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