Calcitonin gene-related peptide receptor antagonist

{{Short description|Class of drugs}} '''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).<ref>{{Citation |last1=Rashid |first1=Abin |title=Calcitonin Gene-Related Peptide Receptor |date=2024 |work=StatPearls |url=https://www.ncbi.nlm.nih.gov/books/NBK560648/ |access-date=2024-07-30 |place=Treasure Island (FL) |publisher=StatPearls Publishing |pmid=32809483 |last2=Manghi |first2=Ali}}</ref>

The CGRP family of small proteins are present in the sensory nerves of the head and neck and are involved in transmission of pain.<ref name=":3" /> Nerve activation can trigger the release of CGRP and other neuropeptides, leading to inflammation, pain, and swelling in the case of migraine.<ref name="Pietra">{{cite journal |last1=Pietra |first1=AD |last2=Kuburas |first2=A |last3=Russo |first3=AF |date=September 2025 |title=PACAP versus CGRP in migraine: From mouse models to clinical translation. |journal=Cephalalgia |volume=45 |issue=9 |article-number=3331024251364242 |doi=10.1177/03331024251364242 |pmid=40931761 |doi-access=free }}</ref> Several monoclonal antibodies that bind to the CGRP receptor or peptide have been approved for prevention of migraine.<ref>{{Cite web|date=2018|title=Erenumab (AIMOVIG) Prescribing Information|url=https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/761077s000lbl.pdf|website=FDA.gov|publisher=U.S. Food and Drug Administration|archive-url=https://web.archive.org/web/20181207235808/https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/761077s000lbl.pdf |archive-date=2018-12-07 }}</ref> As of March 11, 2024, the American Headache Society issued a statement that "CGRP targeting therapies are a first-line option for migraine prevention"<ref name=":3">{{Cite web |last=Gibb |first=Vera |date=2024-04-26 |title=American Headache Society Position Statement: Calcitonin Gene-Related Peptide (CGRP) Inhibitors should now be considered a first-line option for migraine prevention |url=https://www.migrainedisorders.org/ahs-statement-cgrp/ |access-date=2025-11-05 |website=Association of Migraine Disorders |language=en-US}}</ref> 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.<ref name=":3" /> Small molecule CGRPR antagonists have also been approved in the U.S. as antimigraine agents.<ref name=":0">{{Cite web |date=June 2021 |title=Nurtec ODT Prescribing Information |url=https://www.accessdata.fda.gov/drugsatfda_docs/label/2021/212728s006lbl.pdf |archive-url=https://web.archive.org/web/20210528184316/https://www.accessdata.fda.gov/drugsatfda_docs/label/2021/212728s006lbl.pdf |archive-date=2021-05-28 |website=FDA.gov |publisher=U.S. Food and Drug Administration}}</ref><ref name=":1">{{Cite web |date=2019 |title=Ubrogepant Prescribing Information |url=https://www.accessdata.fda.gov/drugsatfda_docs/label/2019/211765s000lbl.pdf |archive-url=https://web.archive.org/web/20200717082408/https://www.accessdata.fda.gov/drugsatfda_docs/label/2019/211765s000lbl.pdf |archive-date=2020-07-17 |website=FDA.gov |publisher=U.S. Food and Drug Administration}}</ref><ref name=":2" />

==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.<ref name="WebMD">{{cite web |title=Migraine: How CGRP Inhibitors Can Help |url=https://www.webmd.com/migraines-headaches/cgrp-inhibitors-for-migraine |website=WebMD |access-date=6 November 2025 |language=en}}</ref>

=== Small molecule CGRP antagonists (gepants) === * Ubrogepant is approved for acute treatment of migraines<ref name="Tfelt-Hansen">{{cite journal|last1=Tfelt-Hansen|first1=P|last2=Olesen|first2=J|date=April 2011|title=Possible Site of Action of CGRP Antagonists in Migraine|journal=Cephalalgia|volume=31|issue=6|pages=748–50|doi=10.1177/0333102411398403|pmid=21383046|doi-access=free}}</ref><ref name=":1" /><ref name=":3" /> *Rimegepant (BMS-927711) is approved for acute migraine treatment (since February 2020)<ref name="Negro">{{cite journal |last1=Negro |first1=A |last2=Martelletti |first2=P |title=Rimegepant for the treatment of migraine. |journal=Drugs of Today|date=December 2020 |volume=56 |issue=12 |pages=769–780 |doi=10.1358/dot.2020.56.12.3211624 |pmid=33332483 |issn=1699-3993}}</ref> and for preventive treatment of episodic migraines (since May 2021).<ref name="Altamura">{{cite journal |last1=Altamura |first1=C |last2=Brunelli |first2=N |last3=Marcosano |first3=M |last4=Fofi |first4=L |last5=Vernieri |first5=F |title=Gepants - a long way to cure: a narrative review. |journal=Neurological Sciences |date=September 2022 |volume=43 |issue=9 |pages=5697–5708 |doi=10.1007/s10072-022-06184-8 |pmid=35650458 |pmc=9159895 }}</ref><ref name=":0" /><ref name=":3" /> *Atogepant (AGN-241689) is approved for preventative treatment of migraines<ref name=":2">{{Cite web|date=March 2022|title=Qulipta Prescribing Information|url=https://www.accessdata.fda.gov/drugsatfda_docs/label/2021/215206Orig1s000lbl.pdf|url-status=live|website=FDA.gov|publisher=U.S. Food and Drug Administration|archive-url=https://web.archive.org/web/20211114014201/https://www.accessdata.fda.gov/drugsatfda_docs/label/2021/215206Orig1s000lbl.pdf |archive-date=2021-11-14 }}</ref><ref name=":3" /> * Zavegepant (BHV- 3500) is a nasal spray approved for acute treatment of migraines.<ref>{{Cite web |date=9 March 2023 |title=Zavzpret (zavegepant) nasal spray |url=https://www.accessdata.fda.gov/drugsatfda_docs/appletter/2023/216386Orig1s000ltr.pdf |archive-url=https://web.archive.org/web/20230310224239/https://www.accessdata.fda.gov/drugsatfda_docs/appletter/2023/216386Orig1s000ltr.pdf |archive-date=March 10, 2023 |access-date=11 December 2024 |website=Food and Drug Administration}}</ref><ref>{{cite press release | url=https://www.businesswire.com/news/home/20230309005795/en/Pfizer%E2%80%99s-ZAVZPRET%E2%84%A2-zavegepant-Migraine-Nasal-Spray-Receives-FDA-Approval | title=Pfizer's ZAVZPRET™ (Zavegepant) Migraine Nasal Spray Receives FDA Approval | date=10 March 2023 }}</ref><ref name=":3" /> *Telcagepant (MK-0974), reached phase III clinical trials; development discontinued in 2011.<ref>{{cite news|date=July 29, 2011|title=Press release: Merck Announces Second Quarter 2011 Financial Results|work=Merck|url=http://www.mercknewsroom.com/press-release/financial-news/merck-announces-second-quarter-2011-financial-results|archive-url=https://web.archive.org/web/20130412063354/http://www.mercknewsroom.com/press-release/financial-news/merck-announces-second-quarter-2011-financial-results|archive-date=April 12, 2013}}</ref> *Olcegepant (BIBN-4096BS) is a drug candidate<ref name="Recober">{{cite journal|last1=Recober|first1=A|last2=Russo|first2=AF|date=August 2007|title=Olcegepant, a Non-Peptide CGRP1 Antagonist for Migraine Treatment|journal=IDrugs: The Investigational Drugs Journal|volume=10|issue=8|pages=566–74|pmid=17665333}}</ref> *BI 44370 TA (BI 44370)<ref name="Diener">{{cite journal | last1 = Diener | first1 = HC | last2 = Barbanti | first2 = P | last3 = Dahlöf | first3 = C | last4 = Reuter | first4 = U | last5 = Habeck | first5 = J | last6 = Podhorna | first6 = J | title = BI 44370 TA, an Oral CGRP Antagonist for the Treatment of Acute Migraine Attacks: Results From a Phase II Study | journal = Cephalalgia| date = April 2011 | volume = 31 | issue = 5 | pages = 573–84 | doi = 10.1177/0333102410388435 | pmid = 21172952 | doi-access = free }}</ref> * MK-3207<ref name = "Li">{{cite journal | last1 = Li | first1 = CC | last2 = Vermeersch | first2 = S | last3 = Denney | first3 = WS | last4 = Kennedy | first4 = WP | last5 = Palcza | first5 = J | last6 = Gipson | first6 = A | last7 = Han | first7 = TH | last8 = Blanchard | first8 = R | last9 = De Lepeleire | first9 = I | last10 = Depré | first10 = M | last11 = Murphy | first11 = MG | last12 = Van Dyck | first12 = K | last13 = de Hoon | first13 = JN | title = Characterizing the PK/PD Relationship for Inhibition of Capsaicin-Induced Dermal Vasodilatation by MK-3207, an Oral Calcitonin Gene Related Peptide Receptor Antagonist | journal = British Journal of Clinical Pharmacology | date = May 2015 | volume = 79 | issue = 5 | pages = 831–7 | doi = 10.1111/bcp.12547 | pmid = 25377933 | pmc = 4415719}}</ref> * SB-268262

===Monoclonal antibodies targeting the CGRP receptor=== * Erenumab (AMG-334) is approved for prevention of migraine.<ref>{{cite journal | pmid = 28240610 | doi=10.1097/WCO.0000000000000438 | volume=30 | issue=3 | title=Calcitonin gene-related peptide monoclonal antibodies for migraine prevention: comparisons across randomized controlled studies | journal=Curr Opin Neurol | pages=272–280 | last1 = Mitsikostas | first1 = DD | last2 = Reuter | first2 = U| year=2017 | s2cid=46105364 }}</ref><ref name=":3" />

===Monoclonal antibodies targeting the CGRP molecule=== * Eptinezumab (ALD403) is approved for prevention of migraine.<ref>{{Cite web|date=2020|title=Eptinezumab Prescribing Information|url=https://www.accessdata.fda.gov/drugsatfda_docs/label/2020/761119s000lbl.pdf|website=FDA.gov|publisher=U.S. Food and Drug Administration|archive-url=https://web.archive.org/web/20200225004647/https://www.accessdata.fda.gov/drugsatfda_docs/label/2020/761119s000lbl.pdf |archive-date=2020-02-25 }}</ref><ref name=":3" /> * Fremanezumab (TEV-48125) is approved for prevention of migraine.<ref name="Spreitzer">{{cite journal| author = H. Spreitzer| date = 29 February 2016| title = Neue Wirkstoffe – TEV-48125| journal = Österreichische Apothekerzeitung| issue = 5/2016| page = 12| language = German}}</ref><ref name = "Walter">{{cite journal | last1 = Walter | first1 = S | last2 = Bigal | first2 = ME | title = TEV-48125: a Review of a Monoclonal CGRP Antibody in Development for the Preventive Treatment of Migraine | journal = Current Pain and Headache Reports | date = March 2015 | volume = 19 | issue = 3 | page = 6 | doi = 10.1007/s11916-015-0476-1 | pmid = 25754596 | s2cid = 8550606 }}</ref><ref name=":3" /> * Galcanezumab (LY2951742) is approved for prevention of migraine and cluster headaches.<ref>{{Cite web|title=Drug Approval Package: Emgality (galcanezumab-gnlm)|url=https://www.accessdata.fda.gov/drugsatfda_docs/nda/2018/761063Orig1s000TOC.cfm|access-date=2021-07-09|website=www.accessdata.fda.gov}}</ref><ref name=":3" />

==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.<ref name="Dance">{{cite news |last1=Dance |first1=Amber |title=Studies of migraine's many triggers offer paths to new therapies |url=https://knowablemagazine.org/content/article/health-disease/2024/progress-in-scientists-search-for-new-migraine-therapies |access-date=5 November 2025 |journal=Knowable Magazine |date=15 October 2024 |publisher=Annual Reviews |language=en |doi=10.1146/knowable-101424-1}}</ref> These include erenumab, brand name Aimovig, approved in the U.S. for use for migraines in 2018. It interacts by blocking the CGRP receptor.<ref name="1A">{{cite web |last1=Rosenberg |first1=J. |title=FDA Approves Erenumab, First CGRP Inhibitor for Prevention of Migraine |url=https://www.ajmc.com/newsroom/fda-approves-erenumab-first-cgrp-inhibitor-for-prevention-of-migraine |website=AJMC |date=18 May 2018 |access-date=6 April 2019}}</ref> 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.<ref>{{cite web |title=FDA Approves Second Anti-CGRP Treatment for Migraine |url=https://americanmigrainefoundation.org/resource-library/fda-approves-second-anti-cgrp-treatment-for-migraine/ |website=American Migraine Foundation |access-date=6 April 2019}}</ref> 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.<ref>{{cite web |title=Lilly's Emgality (galcanezumab-gnlm) Receives U.S. FDA Approval for the Preventive Treatment of Migraine in Adults |url=https://investor.lilly.com/news-releases/news-release-details/lillys-emgalitytm-galcanezumab-gnlm-receives-us-fda-approval |website=Eli Lilly and Company |access-date=6 April 2019}}</ref>

As of February 2020, eptinezumab (Vyepti) was approved by the FDA for the treatment of migraine via intravenous infusion as well.<ref>{{Cite web|title=Eptinezumab-jjmr (Vyepti) Approved By FDA for Migraine Prevention|url=https://americanheadachesociety.org/news/eptinezumab-vyepti-approved-by-fda/|access-date=2021-07-09|website=American Headache Society|language=en-US|archive-date=2021-10-19|archive-url=https://web.archive.org/web/20211019045818/https://americanheadachesociety.org/news/eptinezumab-vyepti-approved-by-fda/}}</ref>

Three small-molecule antagonists have been approved for treatment of migraine: ubrogepant, rimegepant, and atogepant.<ref name=":1" /><ref name=":0" /><ref name=":2" /> Ubrogepant and rimegepant are approved for acute treatment.<ref name=":1" /><ref name=":0" /> Atogepant and rimegepant are approved for preventative treatment.<ref name=":2" /><ref name=":0" />

== Research == Drugs of this class have been investigated for use in osteoarthritis in mice.<ref>{{Cite journal |last1=Nakasa |first1=T |last2=Ishikawa |first2=M |last3=Takada |first3=T |last4=Miyaki |first4=S |last5=Ochi |first5=M |year=2015 |title=Attenuation of cartilage degeneration by calcitonin gene-related paptide receptor antagonist via inhibition of subchondral bone sclerosis in osteoarthritis mice |journal=Journal of Orthopaedic Research |volume=34 |issue=7 |pages=1177–84 |doi=10.1002/jor.23132 |pmid=26686833 |doi-access=free}}</ref>

===Necrotizing fasciitis=== A study has found botox effective against necrotizing fasciitis caused by ''S. pyogenes'' in mice.<ref>{{Cite journal |last1=Pinho-Ribeiro |first1=Felipe A. |last2=Baddal |first2=Buket |last3=Haarsma |first3=Rianne |last4=O'Seaghdha |first4=Maghnus |last5=Yang |first5=Nicole J. |last6=Blake |first6=Kimbria J. |last7=Portley |first7=Makayla |last8=Verri |first8=Waldiceu A. |last9=Dale |first9=James B. |last10=Wessels |first10=Michael R. |last11=Chiu |first11=Isaac M. |date=2018-05-17 |title=Blocking neuronal signaling to immune cells treats streptococcal invasive infection |journal=Cell |volume=173 |issue=5 |pages=1083–1097.e22 |doi=10.1016/j.cell.2018.04.006 |issn=0092-8674 |pmc=5959783 |pmid=29754819}}</ref> 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.<ref>{{cite web | url=https://medicalxpress.com/news/2018-05-germ-flesh-eating-disease-hijacks-neurons.html | title=How the germ behind flesh-eating disease hijacks neurons to avoid immune destruction}}</ref> Botox blocks the CGRP cascade of nerve cells.<ref>{{Cite web |date=2020-05-10 |title=Combining Botox and a CGRP antibody: should it be covered by insurance companies? - Migraine Canada™ |url=https://migrainecanada.org/posts/advocacy/combining-botox-and-a-cgrp-antibody-should-it-be-covered-by-insurance-companies/ |access-date=2024-07-30 |language=en-US}}</ref>

==References== {{Reflist}}

Category:Calcitonin gene-related peptide receptor antagonists