Calcitonin Gene‐Related Protein (CGRP)‐Targeted Treatments for Migraine Prevention

An entirely new class of migraine preventive medications became available in 2018. These preventive medications were the first modern medications designed for migraine, unlike other currently available preventive treatments THAT were made for other conditions and only later found to have some degree of migraine preventive benefit. There are now 3 of these monoclonal antibody drugs (MABs) approved by the FDA for the prevention of both episodic migraine (fewer than 15 days per month) and chronic migraine (15 or more migraine days per month). They all are similar in how they work. There are small differences in minor side effects and how they are taken. There are larger differences in their availability through insurance and patient assistance programs. All 3 anti-CGRP medications target a protein fragment (peptide) or its docking station that is linked specifically to migraine pain. Giving CGRP intravenously to someone with migraine causes migraine headache, and CGRP blood levels rise during a migraine attack. Studies show that migraines can be triggered by administering this peptide and can be stopped by removing the CGRP. Even long-standing medicines used to stop migraine attacks acutely, triptans such as sumatriptan, naratriptan, zolmitriptan, and rizatriptan, decrease CGRP levels, likely contributing to their effectiveness. All 3 CGRP preventive medications are MABs. These are big molecules which, for the most part, do not cross into the brain. They are injected superficially or subcutaneously just under the skin of the abdomen or thigh, but their action goes to the nerves, tissues, and blood vessels surrounding, but probably not inside, the brain. Erenumab (Aimovig), approved by the FDA May 17, 2018, targets the CGRP docking stations or receptors outside the brain, blocking CGRP attachment. Fremanezumab (Ajovy), approved September 14, 2018, and galcanezumab (Emgality), approved September 26, 2018, are antibodies against the CGRP protein itself. A fourth anti-CGRP MAB, eptinezumab, is in development and is administered intravenously (IV). A major convenience is that all 3 currently FDA-approved medications can be given by the patient to themselves in their own homes, monthly, with easy-to-use injecting devices (Table 1). Eptinezumab, in development, will be administered IV every 3 months and requires going to an infusion center. Erenumab and galcanezumab are administered monthly. Erenumab is given using one or two 70-mg autoinjectors, once per month. Fremanezumab currently comes only in a prefilled syringe. It can be administered monthly with a single injection of 225 mg or with 3 injections at once every 3 months. Galcanezumab can be injected monthly with an autoinjector but also has the option of a prefilled syringe, depending on preference. The first month of galcanezumab requires 2 injections of 120 mg each, one on each side of the body as a loading dose. Thereafter, just one injection dose of 120 mg is given monthly. Training on self-injecting techniques can be given at the prescribing office, the pharmacy, and also via online videos on the medication websites. Generally, these new medications are easy to administer. There will always be some pain at the injection site, but most people describe it as minor. Needle-phobic individuals may prefer the autoinjectors, but the injection pain from an autoinjector vs a syringe is very similar. Those with a latex allergy should not use erenumab, as the injecting applicator has a small amount of latex that can come in contact with the skin. All 3 have the potential for injection site reactions and a possible minor increase in upper respiratory symptoms. Overall, side effects of the CGRP targeted migraine preventives are minor, if present at all. For all formulations, injection site pain can occur, and other injection site reactions such as rash or itching can arise. Mild respiratory symptoms may happen with any of these medications. Erenumab can also be associated with constipation. So far there have been no signs these medications are risky in those with heart disease, liver or kidney disease, autoimmune disease, or other serious medical problems. While they only became available to the public in 2018, they had been tested in many patients for years prior to approval. There have been theoretical concerns that blocking CGRP could prove risky for those with known heart and blood vessel disease, but even when tested in those known to have significant coronary artery disease, no problems were linked to the new drugs. Because this class of drugs is comparatively new, adverse reactions will be followed closely. Although all of the available MABs probably have similar effectiveness and safety, one area where they do separate out is availability, with and without insurance. This is a rapidly changing arena, so information given today should be cross-checked closely with up-to-date formulary and patient assistance information. The MABs in general cost about $6900 per year without insurance coverage or patient assistance. Although this winds up being less than the total cost associated with onabotulinumtoxinA (Botox®) injections, it still is a lot of money. Fortunately, most patients will be able to obtain the medications at a very affordable cost through conventional commercial insurance, prior authorization with Medicaid and Medicare, or using the patient assistance programs for each company. In order to be approved for a MAB, most patients will need to have tried 2-3 oral migraine-preventive medications, generally one from each of the antidepressant, anti-seizure, and anti-hypertensive classes, and sometimes there is requirement of a trial of one triptan such as sumatriptan. The classes of oral preventive medications were invented to treat other disorders, and have been found to have benefit for some people in preventing migraine. Insurance providers require those with migraine to have tried them before moving to pricier options. If for some reason, one or more of these classes of medication cannot be used or is not tolerated, the reasons for this needs to be documented in the chart and in the prior authorization process. Those who have commercial insurance (usually through an employer) will be able to obtain a MAB if they have tried 2-3 of the other oral migraine preventive categories. The brand of MAB available may vary according to a patient’s particular insurance. If an individual has an allergy or does not respond to one brand, they probably will be able to switch to another. All 3 MAB companies have copay assistance to limit the amount of out of pocket expense with commercial insurance. Obtaining a MAB with government subsidized insurance such as Medicaid and Medicare is currently trickier, but most of the time, prior authorization or non-profit foundations associated with each company will cover that MAB if certain criteria are met. In order to use some of these programs, if a patient is eligible for Medicaid or Medicare Extra Help, a patient first must apply for the appropriate government insurance in order to be eligible for the assistance program. All 3 companies have set income thresholds for patient assistance based on the Federal Poverty line. Please see Table 2 for details on how this is calculated. Those eligible per individual criteria for each company may get the medication for free or at low cost. For example, erenumab and fremanezumab both have thresholds of less than 500% of the poverty line ($60,700 for single and a bit higher for couple or family annual income in 2018). Galcanezumab has a lower threshold of 400% of the poverty line, about $48,560 for single and $65,840 for couple in 2018 annual income. All of the assistance plans require some income verification such as with social security statement, tax return, or W-2 statement. Obtaining galcanezumab also requires pharmacy records or receipts showing $1100 out of pocket paid in the previous year. Also, with galcanezumab’s patient assistance program, Lilly Cares Foundation, the patient must consent to a credit check. As of 2019, those who must get their medications through the CVS/Caremark Pharmacy Benefit Manager plans will not have coverage for erenumab, but will still have the other 2 MABs available. All of this information on coverage, income, insurance coverage, copays, and financial assistance is variable, and has been changed and fine-tuned many times since the drugs first came to market. Table 2 captures one point in time (February 2019) that is likely to continue to evolve as pharmaceutical and insurance companies try to keep up with the rapidly increased demand for these migraine preventives. In summary, this is an exciting time for those with migraines not responding to usual treatments. CGRP-targeted medications provide precise preventive options for those with episodic or chronic migraine. The MABs have next to no side effects for most patients, often with very quick onset of effect and high levels of effectiveness. While the effectiveness of these drugs can be impressive, they do not work for everyone. In those who have had no response over the course of 4-6 months, one drug may be discontinued with a trial switch to a different MAB. While some people have a dramatic and rapid decrease in migraine days per month, others find a more gradual subtle improvement in frequency, severity, and length of migraine attacks. We now have precisely targeted medications designed exclusively for the prevention of migraine. These drugs have already started to change our approach to effectively treating migraine, and are being tested for use in prevention of other headache disorders. This is a wonderful new set of options for migraine patients.