In 2018, we began a new era in migraine prevention. Before then, preventing migraine was only possible with treatments borrowed from other medical conditions. People with migraine disease were frequently treated with blood pressure medications, antidepressants, anti-seizure medications, and even treatments originally targeted for cosmetic purposes. We typically learned about their effectiveness in treating migraine by accident. No preventive treatment had been designed specifically for migraine.
However, on May 17, 2018, that all changed when Aimovig™ (erenumab) was approved by the United States’ Food and Drug Administration (FDA). Aimovig™ is one medication in a class of new preventive treatments called calcitonin gene-related peptide (CGRP) monoclonal antibodies (mabs). They are part of a larger category of medications called CGRP inhibitors.
Technically, CGRP monoclonal antibodies are not drugs; they are antibody proteins
Technically, CGRP monoclonal antibodies are not drugs; they are antibody proteins that have been developed in laboratories to either block a receptor site in the body (e.g., our brain) or neutralize other proteins so they can not bind to those receptors. The CGRP monoclonal antibodies, specifically, block the CGRP protein or its receptor sites.
What is CGRP & How Is It Involved in a Migraine Attack?
CGRP is a protein found in our brain and other parts of our body. It works as a neurotransmitter. Dr. David Dodick describes CGRP as a “sensory signaling protein.”¹ It has been on the radar of migraine researchers for more than thirty years. Those studying migraine discovered that CGRP is prevalent in the trigeminal system. Notably, researchers found that people experiencing migraine had higher levels of CGRP in blood and saliva samples. People with Chronic Migraine also had elevated levels of CGRP.², ³
When CGRP is released in the brain, it can trigger a migraine attack. Although the mechanism is not entirely known, it is hypothesized that when CGRP is released it may heighten the sensitivity of nerves, particularly in the trigeminal system. Migraine triggers that are normally benign can cause inflammation. This series of events gets relayed to the brain as a pain signal or migraine attack.⁴,⁵
The CGRP Monoclonal Antibodies
Currently, three CGRP monoclonal antibodies have been approved by the FDA and are available by prescription in the United States: Aimovig™ (erenumab), Ajovy™ (fremenezumab), and Emgality™ (galcanezumab). Aimovig™ is also available in Canada, Switzerland, Australia, and the European Union (EU).⁶,⁷ Ajovy™ was recently approved in the EU in early April 2019.
The table below provides some basic comparisons of the three medications.⁸
As I mentioned above, we have CGRP receptors in our brain and throughout our bodies. CGRP monoclonal antibodies work by either binding to these receptors or binding to the CGRP peptide itself. Aimovig™ works by blocking the receptors, which prevents CGRP from binding to them and, ultimately, helps prevent a migraine attack. Emgality™ and Ajovy™ work by blocking the CGRP peptide. As Dr. David Dodick describes, the latter two “mop up” excess CGRP. By doing so, they prevent CGRP from triggering events that can lead to a migraine attack.⁹
Aimovig™ comes in an auto-injector similar to those you might have used if you have a sumatriptan injector. Ajovy™ comes in a small, pre-filled syringe. Emgality™ has the option of either an auto-injector or a pre-filled syringe. U.S. costs for each of the three CGRP monoclonal antibodies are the same: $575 per month before insurance. However, assistance programs vary for each medication (more below). Although approved in the EU, Aimovig™ was deemed too expensive by the National Institute for Health and Care Excellence (NICE) and is not covered for most patients in the United Kingdom’s National Health System. For now, patients who want to access Aimovig™ in the U.K. are doing so out of pocket.¹⁰,¹¹ The exception is patients with Chronic Migraine within the NHS Scotland system where it was recently approved.
How Effective are the CGRP Monoclonal Antibodies?
At this point, the results of the clinical trials are our most rigorous source of information on effectiveness. Those trials included participants who were randomly assigned to either receive a CGRP monoclonal antibody or be part of a control group that did not receive the medication (i.e., they received a placebo). Clinical trials were carried out separately for each of Aimovig™, Ajovy™, and Emgality™.
For those with Chronic Migraine, results across these clinical trials of the CGRP monoclonal antibodies are very similar (see chart above). Each provided about two to three more migraine-free days for those who received the medication compared to those participants in the control group.¹²
Disaggregating the data a little, an impressive proportion of people in the Chronic Migraine trials reported a reduction in migraine days of 50 percent or more. Among those in the Aimovig™ and Ajovy™ trials, roughly 40 percent of patients with Chronic Migraine reported a 50 percent or greater reduction in migraine days. For those in the Emgality™ trial for Chronic Migraine, about 28 percent reported a 50 percent or greater reduction in migraine days. Note that the results from these trials were not compared against one another, so differences are unknown and may not be significant.
Also impressive is that unlike previous migraine preventives, the CGRP monoclonal antibodies can take as little as one week to start working for some people.¹³ In others, they may still take several months. Research has also shown that, in those who see improvement, the effectiveness over time can improve and be sustained.¹⁴
Data for those with episodic Migraine was also collected during clinical trials and is available here:
If you have started a CGRP monoclonal antibody and are unhappy with your progress, there is no rule for when to switch. Some doctors are advising patients to trial a medication for three to four months. Dr. Dodick is also cautiously optimistic that patients might find one CGRP monoclonal antibody works better for them than another, much like the triptans or antidepressants.¹⁵
What are the Side Effects & Who Should Avoid the CGRP Monoclonal Antibodies?
In clinical trials, few side effects were reported in greater frequency by those who received the CGRP monoclonal antibodies than those participants in the control group. This is welcome news to patients who have endured side effects of previous migraine preventives. Each of the three CGRP monoclonal antibodies have a slight risk of injection sight reaction or hypersensitivity reaction (i.e., an immune or allergic reaction). Aimovig™ has also been shown to cause constipation in some users.
In clinical practice and in patient-focused social media, however, patients have been sharing other possible side effects not seen in the clinical trials. In these settings, it is difficult to know if the CGRP monoclonal antibodies are the cause. Still, having these peer-to-peer resources are valuable. If you are considering starting a CGRP treatment, be informed as you join social media support groups. Shoshana Lipson is the founder of a growing Facebook community that provides rigorous resources for people using CGRP inhibitors. She has offered some insightful tips for navigating social media and CGRP inhibitors.
The effects of CGRP monoclonal antibodies were not studied on women who are pregnant or breastfeeding. For this reason, certified headache specialists are suggesting that women who plan to become pregnant not use these medications. If they are on one and decide to become pregnant, it is also suggested they allow the medications to wash out of their system for five to six months.¹⁶
That said, the emergence of the CGRPs is good news for some patients. Since CGRP monoclonal antibodies are not metabolized in the liver or excreted by the kidneys, they should be safe for people with liver or kidney conditions. This also means there are unlikely to be drug interactions between the CGRP monoclonal antibodies and other medications.¹⁷
How Do I Access Them?
Your insurance situation may be a factor in which CGRP monoclonal antibody you can ultimately access. However, to get patients started, each of the three drug manufacturers have programs that allow most patients with commercial insurance to try these new medications, as well as some who are on government-funded insurance and in need of financial assistance.
One of the best resources we have come across to navigate the various programs are these CGRP Treatment – Interactive Financial Assistance Guides that were created by the Coalition For Headache And Migraine Patients. They help explain the programs, rules, and eligibility criteria. Click here to see the guides for Aimovig™, AJOVY™, and Emgality™ and learn about the various support programs for patients with commercial and government insurance, and those who are uninsured.
We suggest being actively involved in advocating for insurance access before any free trial or copay assistance programs end.
However, these assistance programs have end dates and those on public insurance like Medicaid or Medicare might not be eligible for them. In these situations, it becomes a question of what your insurance plan covers. At this point, some insurers may still be deciding whether to include Aimovig™, Ajovy™, and Emgality™ on their plans.
We suggest being actively involved in advocating for insurance access before any free trial or copay assistance programs end. For example, work with your doctor and insurer to make sure you have a prior authorization in place for a CGRP monoclonal antibody well before any copay or other assistance program ends. This includes giving yourself and your doctor plenty of time to work through a possible insurance appeal process.
Forthcoming CGRP Medications
There are many unanswered questions about long-term side effects, access for patients with non-commercial insurance, head-to-head effectiveness, and for those of us who try a CGRP treatment with no success, the big question: what is next?
A fourth CGRP monoclonal antibody was just submitted to the FDA for approval in February 2019. Eptinezumab will be a quarterly intravenous infusion. The results in phase three trials were encouraging. Chronic Migraine patients receiving eptinezumab experienced:
• a 52 percent reduction in migraine risk beginning day one, compared to 27 percent for the control group,
• about 2.6 fewer migraine days per month compared to their control group counterparts, and
• 61 percent of those in the treatment group achieved a 50 percent or greater reduction in migraine days.¹⁸
We also look forward to the approval of a new class of small-molecule CGRP antagonists called the gepants – rimegepant, ubrogepant and atogepant – and the serotonin receptor agonist, lasmiditan. Ai was submitted to the FDA for approval in November 2018 and ubrogepant was submitted to the FDA for approval in March 2019 with the other two expected to follow before the end of 2019.
Unlike the currently available CGRP monoclonal antibodies and eptinezumab, the ditans will be used primarily as oral, acute treatments; to treat migraine attacks when they occur. These treatments appear safe for people with cardiovascular issues who cannot tolerate triptans and offer similar effectiveness.¹⁹
The gepants vary in how they are expected to be used with ubrogepant being for acute treatment, atogepant for preventive treatment, and rimegepant for both preventive and acute treatment.
While researchers and headache specialists tackle unanswered questions, there are a wealth of resources available for patients on these treatments. In this issue of My Chronic Brain, Shoshana Lipson shares advice for navigating social media resources on CGRP inhibitors. Other helpful resources include:
- Migraine.com: Questions to Ask your Doctor about Anti-CGRP Treatments
- American Migraine Foundation: Guide to Understanding the Anti-CGRP Treatments
- Migraine and the New Anti-CGRP Treatments: Facebook Live with Dr. David Dodick
- What to Know About the New Anti CGRP Migraine Treatment Options: Facebook Live Recap with Dr. Stewart Tepper
- Dr. Amaal Starling Facebook Live Video on CGRP medications
- Dr. Bill Young & Shoshana Lipson Facebook Live Video on the CGRP Medications: Updates & Q&A
With more preventive and abortive treatments on the horizon, we urge you not to lose hope that an effective treatment is near. At the 2019 Migraine World Summit, Dr. Andrew Charles echoed this sentiment, explaining that we are in an exciting time for migraine treatment. Understanding that migraine has a chemical component means new targets and new treatments, including migraine-specific treatments. Advances in precision medicine mean treatments might eventually be tailored to individual patient genetics.²⁰ We promise to keep you updated as more information becomes available on these and other treatments.
REFERENCES & NOTES
¹ Dodick, D. (2018) “Migraine and the New Anti-CGRP Treatments: Live with Dr. David Dodick” www.youtube.com/watch?v=B6y-yTqTDPw. Retrieved April 8, 2019
² Goadsby, P.J. et al. (1990) “Vasoactive peptide release in the extracerebral circulation of humans during migraine headache” Annals of Neurology, Vol. 28, Issue 2 www.ncbi.nlm.nih.gov/pubmed/1699472. Retrieved April 8, 2019
³ American Migraine Foundation info.americanmigrainefoundation.com/understanding-the-new-anti-cgrp-treatments. Retrieved April 8, 2019
⁴ Geppetti, P. (2019) “CGRP and Butterbur: Comparing the Evidence” Migraine World Summit
⁵ Underwood, E. (2018) “FDA just approved the first drug to prevent migraines. Here’s the story of its discovery and its limitations.” Science. Retrieved April 8, 2019
⁶ Novartis (2018) “CGRP inhibitor Aimovig® (erenumab) now available in Canada for the prevention of migraine” www.pharmaceutical-technology.com/news/novartis-migraine-aimovig-ec-approval. Retrieved April 8, 2019
⁷ “Novartis’ migraine drug Aimovig gets EC approvals” (2018) Pharmaceutical Technology https://www.pharmaceutical-technology.com/news/novartis-migraine-aimovig-ec-approval
⁸ See the Coalition for Headache and Migraine Patients (CHAMP) CGRP Treatment – Interactive Financial Assistance Guides for more information: headachemigraine.org/cgrp-treatment-financial-assistance-guides
⁹ Underwood, E. (n 5)
¹⁰ Liu, Angus (2019) “Novartis’ Aimovig fails to win NICE backing amid tight migraine fight with Lilly, Teva” Fierce Pharma. https://www.fiercepharma.com/pharma/novartis-aimovig-fails-to-win-nice-backing-amid-tight-migraine-competition-lilly-teva. Retreived April 8, 2019
¹¹ Personal correspondence with Amy from themigrainelife.com
¹² In studies, the CGRP monoclonal antibodies provided four to six migraine-free days, but the control-group also saw a reduction of about two days, on average (the “placebo effect”).
¹³ Geppetti P.J. (n 4)
¹⁵ Dodick, D. (n 1)
¹⁶ American Migraine Foundation (n 3)
¹⁷ Dodick, D. (n1)
¹⁹ Alder (2018) “Alder Announces Eptinezumab Significantly Reduces Migraine Risk Meets Primary and All Key Secondary Endpoints in Pivotal PROMISE 2 Phase 3 Trials for Chronic Migraine Prevention” investor.alderbio.com/news-releases/news-release-details/alder-announces-eptinezumab-significantly-reduces-migraine-risk Retrieved April 8, 2019
²⁰ Migraine World Summit “Evening With Celebrities & Expert Panel [Live Stream]” www.facebook.com/MigraineWorldSummit/videos/258153375137163/ Retrieved April 8, 2019
Beth has Chronic Migraine and lives in Vermont with her furry cat, Sophie. She has a background in education program evaluation and spends her days advocating for migraine research and awareness, baking, and listening to audio books.
Connect with Beth: Twitter @Beth_Morton, Instagram @counterfactual.brain & TheCounterfactualBrain.wordpress.com