The Holy Grail of Migraine Medications? – CGRP Blockers

With the six newest migraine drugs specifically designed for migraine prevention and acute treatment, is this new class – CGRP blockers the holy grail of migraine medications?

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Calcitonin-gene-related peptide (CGRP) is a small molecule that is synthesized in our nervous system throughout the brain and other parts of the body to act as a chemical messenger between different cells. Since its discovery in 1982, CGRP has been demonstrated to play an integral role in migraine pathophysiology. The current theory explaining the cause of migraines is the dysfunction of the brain stem, which regulates pain sensations and blood vessel tone.

The activation of the CGRP pathways during a migraine attack causes the amplification of pain sensations and the dilation of blood vessels. The link between CGRP release and migraines has been demonstrated in early studies where researchers saw an increase in plasma concentration of CGRP levels during an acute migraine attack and a decrease in plasma concentration of CGRP levels during migraine abortive treatments. Additionally, when patients who were prone to migraine attacks were given an infusion of CGRP, it triggered migraine-like headaches. If you wish to understand the action of anti-CGRP medications, watch our webinar about them: CGRPs made easy.

Two kinds of anti-CGRP medications (oral vs mAbs):

Oral anti-CGRP medications called “-gepants” were initially developed and tested in the early 2000s but the discovery of liver toxicity with its use caused many drug companies to stop pursuing this class of drugs.

In clinical studies, gepants demonstrated comparable efficacy to triptans and was found to have minimal adverse cardiovascular symptoms unlike triptans, making gepants a good alternative for those who cannot use triptans for cardiovascular problems. Gepants are still being developed for acute migraine treatment. There are currently one gepants in development, atogepant, and two available in the US market under the brand name Ubrelvy™ (ubrogepant) and Nurtec® ODT (rimegepant).

With many drug companies halting the development of gepants, the use of monoclonal antibodies (mAbs) to target CGRP molecules and its receptors were developed. Monoclonal antibodies are proteins that uses the immune system to target specific molecules inside your body. Currently, there are four anti-CGRP mAbs that have been developed, galcanezumab, eptinezumab, erenumab, and fremanezumab used for migraine prevention.

Out of these four, three are now available in the US market under the brand name Aimovig™, Ajovy™, and Emgality™ .

Differences between the anti-CGRP drugs

The first calcitonin-gene receptor peptide (CGRP) drug for treating migraines has been approved by the FDA with the introduction of Aimovig™ by Amgen and Novartis and more recently, two additional CGRP drugs  Ajovy™ by Teva and Emgality™ by Eli Lilly have been approved. There are currently two other CGRP drugs undergoing the drug approval process. The CGRP drug class offers a new way to treat migraines by using immunotherapy to specifically target the CGRP receptors. Many doctors and experts are excited with the CGRP drug’s potential to become a significant advancement in the migraine armamentarium with its high efficacy and low side effect profiles observed in the clinical trials. Although this new class of drug is promising, there are still many unanswered questions and unknowns regarding CGRP drugs.

Unknown Long Term Data

The biggest unknown is the long-term safety and efficacy of the drug, as no long-term data currently exists. CGRP is involved and affects many different physiologic systems including the cardiovascular system, gastrointestinal system, pituitary system, and the immune system. The short-term safety data has shown predominantly mild and low adverse effects but there is limited data on how long term effects of interfering with CGRP will affect the many different physiologic systems CGRP is involved in. Some potential long-term adverse effects could be increased risk of heart attacks and stroke from the loss of the protective cardiovascular role CGRP has on the cardiovascular system, decreased wound-healing abilities, and increased risk for ulcers and inflammatory bowel disease from the thinning of the mucosal lining of the gut.

Developing Antibodies To The Drug

The new CGRP drugs on the market are monoclonal antibodies, which uses the body’s immune system to target specific receptors in the body. The disadvantage of using antibodies is the risk of the body developing antibodies to neutralize the drug. When the body develops anti-drug antibodies, the efficacy and bioavailability of the drug can become greatly reduced and eventually render the drug ineffective. The body can also develop hypersensitivity reactions to the drug as body can think the antibody is a foreign agent and mount an immune attack on the drug.

Unknowns Within Drug Site Of Action

Although scientists have a general idea of how the CGRP drug works, there is still incomplete information on exact site of action of the CGRP drugs and other sites of action the CGRP can potentially affect. Other potential questions that remain to be answered are determining which migraine patients will respond the best with this drug and who will have minimal response to the drug, what the duration of the treatment should be, and what drug combinations can used with the new drug.

As with any newly approved medications that comes onto the market, there are many unknowns and unanswered questions that can only be answered with once a greater number of people use the drug and for a longer time.

With the two newest migraine drugs specifically designed for migraine prevention released this year, is this new class of CGRP drugs the new holy grail of migraine medications? We have divided learning about the CGRP drug class into a three-part newsfeed series. Today we will look into deeper the differences between the two new FDA-approved CGRP drugs.

Monoclonal antibodies (mAbs) blocking CGRP activity have been introduced to the US market for the prevention of migraines. Aimovig™ (erenumab) was the first anti-CGRP mAb FDA approved treatment specifically developed to prevent migraines in May, 2018. Ajovy™ (fremanezumab) is the second anti-CGRP agent to gain FDA approval for migraine prophylaxis in September, 2018. The introduction of anti-CGRP medications mark a new era in the history of migraine preventive treatment. Despite similarities in the advantages and disadvantages in mAb therapy, there are some differences between erenumab and fremanezumab in the mechanism of action, the type of mAb, and the dosage.

Mechanism of action

Both erenumab and fremanezumab prevent migraines by blocking the CGRP pathway. However, there is a major difference in how they block the CGRP pathway. Erenumab binds to the CGRP receptor and blocks the CGRP receptor function. Fremanezumab binds directly to the CGRP molecule instead of its receptor and prevents CGRP from binding to the receptor. Despite their differences in how they block the CGRP system, both mechanisms of action ultimately lead to inhibiting the functions of CGRP in migraine headache.

The type of mAb

Both erenumab and fremanezumab are produced using recombinant DNA technology in Chinese hamster ovary cells. Erenumab is a fully human immunoglobulin mAb, while fremanezumab is a humanized immunoglobulin mAb. The distinction between a fully human mAb and a humanized mAb is humanized mAb is a combination of human and mouse antibody. The potential for the mAb to provoke an immune response by the body or “immunogenicity” is theoretically lower in fully human mAb than humanized mAb. Immunogenicity has many definitions but what makes it unique is that it occurs when our bodies treat a protein as if it is a foreign substance and try to attack the protein with antibodies.  Immunomic therapies have been around for years and have been used for developing vaccines.  As such, this type of drug is in essence a vaccine to prevent migraines.

Dosage regimen

The administration method for both drugs is monthly subcutaneous injections. The recommended dose of erenumab is 70 mg once monthly. Some patients may benefit from a higher dose of 140 mg once monthly, which is administered as two consecutive subcutaneous injections of 70 mg each. The recommended dosage for fremanezumab is 225 mg once monthly. Unlike erenumab, fremanezumab has the option for longer dosing intervals of 675 mg every 3 months (quarterly). This is administered as three consecutive subcutaneous injections of 225 mg each. Aimovig™ is available in a prefilled autoinjector or prefilled syringe while Ajovy™ is only available in prefilled syringe. Both Aimovig™ and Ajovy™ are intended for patient self-administration at home.

Adverse events

The most common adverse events for both drugs was injection site reactions. Fremanezumab seems to have a higher rate of injection site reactions than erenumab, with 43-45% vs. 38% (placebo) reporting injection site reactions for fremanezumab and 5-6% vs. 3% (placebo) for erenumab. For pharmacokinetics, the time to reach peak concentrations were similar for both drugs, approximately 6 days. However, the time to reach steady state was faster for erenumab (3 months) than fremanezumab (6 months).

Reference List

1. Mitsikostas DD and Reuter U. Calcitonin gene-related peptide monoclonal antibodies for migraine prevention: comparisons across randomized controlled studies. Curr Opin Neurol. 2017;30:000-000. doi: 10.1097/WCO.0000000000000438

2. Edvinsson L, Hannes KA, Warfvinge K, Krause DN. CGRP as the target of new migraine therapies – successful translation from bench to clinic. Nat Rev Neurol. 2018;14(6):338-350.

3. Holland PR and Goadsby PJ. Targeted CGRP small molecule antagonists for acute migraine therapy. Neurotherapeutics. 2018;15:304. doi:10.1007/s13311-018-0617-4.

4. Aimovig™ [package insert]. Thousand Oaks, CA; Amgen; Published May, 2018. https://pi.amgen.com/~/media/amgen/repositorysites/pi-amgen-com/aimovig/aimovig_pi_hcp_english.ashx

5. Ajovy™ [package insert]. North Wales, PA; Teva Pharmaceutical USA, Inc; Published September, 2018. https://www.ajovyhcp.com/globalassets/ajovy/ajovy-pi.pdf

6. Villalón CM, Olesen J. The role of CGRP in the pathophysiology of migraine and efficacy of CGRP receptor antagonists as acute antimigraine drugs. Pharmacol Ther. 2009;124(3):309-323. doi:10.1016/j.pharmthera.2009.09.003

7. Rosenfeld MG, Mermod JJ, Amara SG, et al. Production of a novel neuropeptide encoded by the calcitonin gene via tissue-specific RNA processing. Nature. 1983;304:129-135. doi:10.1038/304129a0

8. Emgality™ [package insert]. Indianapolis, IN; Eli Lilly and Company; Published September, 2018. http://pi.lilly.com/us/emgality-uspi.pdf

9. Deen M, Correnti E, Kamm K, et al. Blocking CGRP in migraine patients – a review of pros and cons. J Headache Pain. 2017;18:96. doi: 10.1186/s10194-017-0807-1.

10. Dodick DW, Ashina M, Brandes JL, et al. ARISE: A phase 3 randomized trial of erenumab for episodic migraine. Cephalagia. 2018;38(6):1026-1037.

11. Rosenfeld MG, Mermod JJ, Amara SG, et al. Production of a novel neuropeptide encoded by the calcitonin gene via tissue-specific RNA processing. Nature. 1983;304:129-135. doi:10.1038/304129a0

12. Sarchielli P, Alberti A, Codini M, Floridi A, Gallai V. Nitric oxide metabolites, prostaglandins and trigeminal vasoactive peptides in internal jugular vein blood during spontaneous migraine attacks. Cephalalgia. 2000;20(10):907-908. doi:10.1046/j.1468-2982.2000.00146.x

13. Juhasz G, Zsombok T, Modos EA, et al. NO-induced migraine attack: Strong increase in plasma calcitonin gene-related peptide (CGRP) concentration and negative correlation with platelet serotonin release. Pain. 2003;106:461-470. doi:10.1016/j.pain.2003.09.008

14. Juhasz G, Zsombok T, Jakab B, Nemeth J, Szolcsanyi J, Bagdy G. Sumatriptan causes parallel decrease in plasma calcitonin gene-related peptide (CGRP) concentration and migraine headache during nitroglycerin induced migraine attack. Cephalalgia. 2005;25:179-183. doi:10.1111/j.1468-2982.2005.00836.x

Jenny from Migraine Buddy
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