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

• Erenumab (AMG-334) is approved for prevention of migraine.^[19][2]

Monoclonal antibodies targeting the CGRP molecule

• Eptinezumab (ALD403) is approved for prevention of migraine.^[20][2]
• Fremanezumab (TEV-48125) is approved for prevention of migraine.^[21][22][2]
• Galcanezumab (LY2951742) is approved for prevention of migraine and cluster headaches.^[23][2]

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]