Calcitonin gene-related peptide receptor antagonist

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

Contents

Several monoclonal antibodies that bind to the CGRP receptor or peptide have been approved for prevention of migraine. [2] 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. [3] [4] [5] Drugs of this class have also been investigated for use in osteoarthritis. [6]

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. [20] 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. [21] Botox blocks the CGRP cascade of nerve cells. [22]

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. [23] 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. [24] 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. [25]

As of February 2020, eptinezumab (Vyepti) was approved by the FDA for the treatment of migraine via intravenous infusion as well. [26]

Three small-molecule antagonists have been approved for treatment of migraine: ubrogepant, rimegepant, and atogepant. [4] [3] [5] Ubrogepant and rimegepant are approved for acute treatment. [4] [3] Atogepant and rimegepant are approved for preventative treatment. [5] [3]

Related Research Articles

<span class="mw-page-title-main">Migraine</span> Disorder resulting in recurrent moderate–severe headaches

Migraine is a genetically-influenced complex neurological disorder characterized by episodes of moderate-to-severe headache, most often unilateral and generally associated with nausea and light and sound sensitivity. Other characterizing symptoms may include vomiting, cognitive dysfunction, allodynia, and dizziness. Exacerbation or worsening of headache symptoms during physical activity is another distinguishing feature.

<span class="mw-page-title-main">Sumatriptan</span> Medication used for migraines & cluster headaches

Sumatriptan, sold under the brand name Imitrex among others, is a medication used to treat migraine headaches and cluster headaches. It is taken orally, intranasally, or by subcutaneous injection. Therapeutic effects generally occur within three hours.

Neurogenic inflammation is inflammation arising from the local release by afferent neurons of inflammatory mediators such as Substance P, Calcitonin Gene-Related Peptide (CGRP), neurokinin A (NKA), and endothelin-3 (ET-3). In such neurons, release of these pro-inflammatory mediators is thought to be triggered by the activation of ion channels that are the principal detectors of noxious environmental stimuli. In particular, the heat/capsaicin receptor TRPV1 and the irritant/wasabi receptor TRPA1. TRPA1 channels stimulated by lipopolysaccharide (LPS) may also cause acute neurogenic inflammation. Once released, these neuropeptides induce the release of histamine from adjacent mast cells. In turn, histamine evokes the release of substance P and calcitonin gene-related peptide; thus, a bidirectional link between histamine and neuropeptides in neurogenic inflammation is established.

<span class="mw-page-title-main">Calcitonin gene-related peptide</span> Peptide hormone in animals

Calcitonin gene-related peptide (CGRP) is a member of the calcitonin family of peptides consisting of calcitonin, amylin, adrenomedullin, adrenomedullin 2 (intermedin) and calcitonin‑receptor‑stimulating peptide. Calcitonin is mainly produced by thyroid C cells whilst CGRP is secreted and stored in the nervous system. This peptide, in humans, exists in two forms: CGRP alpha, and CGRP beta. α-CGRP is a 37-amino acid neuropeptide and is formed by alternative splicing of the calcitonin/CGRP gene located on chromosome 11. β-CGRP is less studied. In humans, β-CGRP differs from α-CGRP by three amino acids and is encoded in a separate, nearby gene. The CGRP family includes calcitonin (CT), adrenomedullin (AM), and amylin (AMY).

<span class="mw-page-title-main">Antimigraine drug</span> Medication intended to reduce the effects or intensity of migraine headache

Antimigraine drugs are medications intended to reduce the effects or intensity of migraine headache. They include drugs for the treatment of acute migraine symptoms as well as drugs for the prevention of migraine attacks.

<span class="mw-page-title-main">Telcagepant</span> Chemical compound

Telcagepant (INN) is a calcitonin gene-related peptide receptor antagonist which was an investigational drug for the acute treatment and prevention of migraine, developed by Merck & Co.

Preventive treatment of migraine can be an important component of migraine management. The goals of preventive therapy are to reduce the frequency, painfulness, and/or duration of migraine attacks, and to increase the effectiveness of abortive therapy. Another reason to pursue prevention is to avoid medication overuse headache (MOH), otherwise known as rebound headache, which can arise from overuse of pain medications, and can result in chronic daily headache. Preventive treatments of migraine include medications, nutritional supplements, lifestyle alterations, and surgery. Prevention is recommended in those who have headaches more than two days a week, cannot tolerate the medications used to treat acute attacks, or those with severe attacks that are not easily controlled.

Zucapsaicin (Civanex) is a medication used to treat osteoarthritis of the knee and other neuropathic pain. Zucapsaicin is a member of phenols and a member of methoxybenzenes. It is a modulator of transient receptor potential cation channel subfamily V member 1 (TRPV-1), also known as the vanilloid or capsaicin receptor 1 that reduces pain, and improves articular functions. It is the cis-isomer of capsaicin. Civamide, manufactured by Winston Pharmaceuticals, is produced in formulations for oral, nasal, and topical use.

<span class="mw-page-title-main">Olcegepant</span> Chemical compound

Olcegepant is a calcitonin gene-related peptide receptor antagonist being studied as a potential treatment for migraines.

Rinat Neuroscience Corporation was a privately held biotechnology company that discovered and developed antibody-based drugs, including:

Eptinezumab, sold under the brand name Vyepti, is a medication used for the preventive treatment of migraine in adults. It is a monoclonal antibody that targets calcitonin gene-related peptides (CGRP) alpha and beta. It is administered by intravenous infusion.

<span class="mw-page-title-main">Galcanezumab</span> Monoclonal antibody

Galcanezumab, sold under the brand name Emgality, is a humanized monoclonal antibody used for the prevention of migraine. It is also used for the treatment of cluster headaches.

<span class="mw-page-title-main">Erenumab</span> Chemical compound

Erenumab, sold under the brand name Aimovig, is a medication which blocks the calcitonin gene-related peptide receptor (CGRPR) for the prevention of migraine. It is administered by subcutaneous injection.

<span class="mw-page-title-main">Rimegepant</span> Medication for acute migraine in adults

Rimegepant, sold under the brand name Nurtec ODT among others, is a medication used for the acute treatment of migraine with or without aura in adults and the prophylactic/ preventive treatment of episodic migraine in adults. It is taken by mouth to dissolve on or under the tongue. It works by blocking CGRP receptors.

Fremanezumab, sold under the brand name Ajovy, is a medication used to prevent migraines in adults. It is given by injection under the skin.

<span class="mw-page-title-main">Ubrogepant</span> Medication for migraine headache acute treatment

Ubrogepant, sold under the brand name Ubrelvy, is a medication used for the acute (immediate) treatment of migraine with or without aura in adults. It is not indicated for the preventive treatment of migraine. Ubrogepant is a small-molecule calcitonin gene-related peptide receptor antagonist. It is the first drug in this class approved for the acute treatment of migraine.

Peter GoadsbyFRS FRACP FRCP is an Australian neuroscientist who is Director of the National Institute for Health Research - Wellcome Trust King’s Clinical Research Facility and Professor of Neurology at King's College London. His research has focused particularly on the mechanism and alleviation of migraine and cluster headaches.

<span class="mw-page-title-main">Atogepant</span> Chemical compound

Atogepant, sold under the brand name Qulipta among others, is a medication used to prevent migraines. It is a gepant, an orally active calcitonin gene-related peptide receptor antagonist.

The amylin receptors (AMYRs) are heterodimers of the calcitonin receptor that are bound to by amylin with high affinity and consist of AMY1, AMY2, and AMY3. Amylin mimetics that are agonists at the amylin receptors are being developed as therapies for diabetes and obesity, and one, pramlintide, has been FDA approved. The AMY1 receptor may be activated by both amylin and the calcitonin gene-related peptide (CGRP) and could play a role in the effects of CGRP receptor antagonists developed for migraine. Dual agonists of the amylin and calcitonin receptors (DACRAs) are under development for obesity. Amylin and its receptors are believed to play a role in Alzheimer's disease.

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. ↑ "Erenumab (AIMOVIG) Prescribing Information" (PDF). FDA.gov. U.S. Food and Drug Administration. 2018. Archived (PDF) from the original on 2018-12-07.
  3. 1 2 3 4 5 "Nurtec ODT Prescribing Information" (PDF). FDA.gov. U.S. Food and Drug Administration. June 2021. Archived (PDF) from the original on 2021-05-28.
  4. 1 2 3 4 "Ubrogepant Prescribing Information" (PDF). FDA.gov. U.S. Food and Drug Administration. 2019. Archived (PDF) from the original on 2020-07-17.
  5. 1 2 3 4 "Qulipta Prescribing Information" (PDF). FDA.gov. U.S. Food and Drug Administration. March 2022. Archived (PDF) from the original on 2021-11-14.
  6. ↑ 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.
  7. ↑ 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.
  8. ↑ 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.
  9. ↑ "Zavzpret (zavegepant) nasal spray" (PDF). Food and Drug Administration . 9 March 2023. Retrieved 11 December 2024.
  10. ↑ "Pfizer's ZAVZPRET™ (Zavegepant) Migraine Nasal Spray Receives FDA Approval" (Press release). 10 March 2023.
  11. ↑ "Press release: Merck Announces Second Quarter 2011 Financial Results". Merck. July 29, 2011. Archived from the original on April 12, 2013.
  12. ↑ 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.
  13. ↑ 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.
  14. ↑ 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.
  15. ↑ 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.
  16. ↑ "Eptinezumab Prescribing Information" (PDF). FDA.gov. U.S. Food and Drug Administration. 2020. Archived (PDF) from the original on 2020-02-25.
  17. ↑ H. Spreitzer (29 February 2016). "Neue Wirkstoffe – TEV-48125". Österreichische Apothekerzeitung (in German) (5/2016): 12.
  18. ↑ 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.
  19. ↑ "Drug Approval Package: Emgality (galcanezumab-gnlm)". www.accessdata.fda.gov. Retrieved 2021-07-09.
  20. ↑ 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.
  21. ↑ "How the germ behind flesh-eating disease hijacks neurons to avoid immune destruction".
  22. ↑ "Combining Botox and a CGRP antibody: should it be covered by insurance companies? - Migraine Canada™". 2020-05-10. Retrieved 2024-07-30.
  23. ↑ Rosenberg, J. (18 May 2018). "FDA Approves Erenumab, First CGRP Inhibitor for Prevention of Migraine". AJMC. Retrieved 6 April 2019.
  24. ↑ "FDA Approves Second Anti-CGRP Treatment for Migraine". American Migraine Foundation. Retrieved 6 April 2019.
  25. ↑ "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.
  26. ↑ "Eptinezumab-jjmr (Vyepti) Approved By FDA for Migraine Prevention". American Headache Society. Archived from the original on 2021-10-19. Retrieved 2021-07-09.
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