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What are CGRPs?

CGRP stands for calcitonin-gene-related peptide. It is a protein that acts like a neurotransmitter (a chemical messenger) throughout the brain and body. CGRP is present in large numbers in the trigeminal system, the sensory nerves that supply the head and neck. Researchers discovered CGRP is found in high levels in migraine sufferers during an attack, providing a new target for pharmaceutical drugs to focus on. To target CGRP, pharmaceutical researchers have developed monoclonal antibodies, a type of biologic therapy that targets and neutralizes either CGRP or its receptors. These new treatments are classified as CGRP antagonists or inhibitors. They work by blocking the action of CGRP by either binding with CGRP to prevent it from binding with the receptor or by attaching to the receptor itself to prevent CGRP from binding with the receptor.1,2

Three CGRP treatments – Aimovig™ (erenumab-aooe), developed by Novartis and Amgen3, Ajovy (fremanezumab-vfrm), developed by Teva, and Emgality (galcanezumab-gnlm), developed by Eli Lilly – have been approved by the U.S. Food and Drug Administration (FDA), and several others are currently in development. One has been submitted to the U.S. Food and Drug Administration (FDA) for possible approval, and one more is still in phase III clinical trials. Phase III clinical trials study a particular treatment in large numbers of patients to determine the effectiveness of a drug, as well as understand any potential side effects, and are required before filing for approval from the (FDA). The two anti-CGRP products currently in development are:

  • Eptinezumab (ALD403), developed by Alder Biopharmaceuticals1
  • Ubrogepant, developed by Allergan (still in phase III clinical trials)4

How effective are CGRP drugs?

In addition to the novelty of a new treatment option, CGRPs have shown promising results in their ability to reduce the number of migraine days per month or reduce the pain associated with migraines. Four of the CGRP drugs – erenumab, galcanezumab, fremanezumab, and eptinezumab – are preventive migraine medications, given to reduce the frequency and severity of episodic and chronic migraines. Ubrogepant is an acute migraine medication, given when a migraine attack occurs to stop the migraine and provide relief from migraine symptoms.

It is important to note that the results from each of the clinical trials cannot be compared to each other, as each trial was set up differently. There have been no head-to-head studies comparing the CGRP treatments to each other. Some of the findings from clinical trials include:

  • Erenumab demonstrated a reduction of 6.6 fewer migraine days per month5
  • Galcanezumab demonstrated at least a 50% reduction in migraine headache days compared to placebo6
  • Fremanezumab demonstrated a reduction of 3.4 to 3.7 fewer migraine days per month7
  • Eptinezumab demonstrated a reduction of 3.9 to 4.3 fewer migraine days per month8
  • Of patients taking ubrogepant for a migraine attack, 20.7% to 21.8% experienced freedom from pain two hours after their first dose3

How are CGRP treatments administered?

The different CGRP treatments are administered in various ways:

  • Erenumab and galcanezumab are given by subcutaneous (under the skin) injection monthly
  • Fremanezumab is given by subcutaneous injection monthly or once every three months
  • Eptinezumab is administered by intravenous (IV) infusion every 12 weeks
  • Ubrogepant is an oral tablet given as an acute medication to treat a migraine attack

What are common side effects of CGRP antagonist?

Each CGRP treatment will have its own unique safety profile, but early results from clinical trials have indicated that these new medications will be more tolerable than other medications currently available for migraine.

Common side effects of CGRP antagonists include:

  • Injection site pain (for those that are injected)
  • Upper respiratory tract infection
  • Runny/stuffy nose
  • Back, abdominal, or joint pain
  • Urinary tract infection
  • Fatigue
  • Nausea and vomiting7,9-11
Written by: Emily Downward | Last Reviewed: March 2019
  1. Migraine: the CGRP story. Pharmaceutical Journal. Available at http://www.pharmaceutical-journal.com/news-and-analysis/features/targeting-the-cgrp-protein-could-lead-to-a-preventative-treatment-for-migraine/20201917.article. Accessed 5/10/18.
  2. Goadsby PJ, Edvinsson L & Ekman R. Vasoactive peptide release in the extracerebral circulation of humans during migraine headache. Ann Neurol 1990;28:183–187. doi: 10.1002/ana.410280213
  3. FDA Approves Aimovig (erenumab-aooe), a Novel Treatment Developed Specifically for Migraine Prevention. Amgen press release. Available at https://www.amgen.com/media/news-releases/2018/05/fda-approves-aimovig-erenumabaooe-a-novel-treatment-developed-specifically-for-migraine-prevention/. Accessed 5/17/18.
  4. Barber J. Higher dose of Allergan’s oral CGRP receptor antagonist ubrogepant hits main goals of Phase III acute migraine trial. First Word Pharma. Available at https://www.firstwordpharma.com/node/1560352. Accessed 5/10/18.
  5. Tepper S, Ashina M, Reuter U, et al. Safety and efficacy of erenumab for preventive treatment of chronic migraine: a randomised, double-blind, placebo-controlled phase 2 trial. Lancet Neurol. 2017;16:425-434.
  6. AAN 2018: Lilly’s Galcanezumab Significantly Reduced Monthly Migraine Headache Days in Patients with Migraine Who Previously Failed to Respond to Multiple Preventive Therapies. Eli Lilly. Press Release April 24, 2018. Available at https://investor.lilly.com/news-releases/news-release-details/aan-2018-lillys-galcanezumab-significantly-reduced-monthly. Accessed 5/10/18.
  7. Teva's Fremanezumab Meets all Primary & Secondary Endpoints Across Both Monthly and Quarterly Dosing Regimens in Phase III Study in Episodic Migraine Prevention [press release]. June 7, 2017. Available at http://www.tevapharm.com/news/teva_s_fremanezumab_meets_all_primary_secondary_endpoints_across_both_monthly_and_quarterly_dosing_regimens_in_phase_iii_study_in_episodic_migraine_prevention_06_17.aspx. Accessed 5/10/18.
  8. Alder BioPharmaceuticals Announces Positive Eptinezumab Phase 3 Results for Prevention of Frequent Episodic Migraine [press release]. June 27, 2017. Available at https://globenewswire.com/news-release/2017/06/27/1029420/0/en/Alder-BioPharmaceuticals-Announces-Positive-Eptinezumab-Phase-3-Results-for-Prevention-of-Frequent-Episodic-Migraine.html. Accessed 5/10/18.
  9. Brauser D. Phase 3 STRIVE and ARISE Trials Show Efficacy, Safety for Erenumab in Migraine Prevention. Medscape. April 26, 2017. Available at http://www.medscape.com/viewarticle/879161. Accessed 5/10/18.
  10. Dodick DW, Goadsby PJ, Spierings EL, et al. Safety and efficacy of LY2951742, a monoclonal antibody to calcitonin gene-related peptide, for the prevention of migraine: a phase 2, randomised, double-blind, placebo-controlled study. Lancet Neurol. 2014;13:885-892. Abstract
  11. Dodick DW, Goadsby PJ, Silberstein SD, et al; ALD403 study investigators. Safety and efficacy of ALD403, an antibody to calcitonin gene-related peptide, for the prevention of frequent episodic migraine: a randomised, double-blind, placebo-controlled, exploratory phase 2 trial. Lancet Neurol. 2014;13:1100-1107. Abstract