Category: Preventive

Calcitonin gene-related peptide (CGRP) inhibitors represent a new class of drugs uniquely designed to treat migraine. There are two types of CGRP inhibitors: monoclonal antibodies which are designed for migraine prevention, and gepants which can be used as both preventive and acute migraine therapies. Several options are available within both categories. While these treatments are not a cure for migraine disease, they have proven to be safe and effective.

What is CGRP?

CGRP is the acronym for calcitonin gene-related peptide. CGRP is a small molecule made up of 37 amino acids that is produced naturally by the body.¹ CGRP is involved in body functions in the gut, the reproductive tract, and blood vessels.²

CGRP may be helpful in protecting against cardiovascular issues, such as high blood pressure and heart disease. For example, in the midst of a heart attack or a stroke, CGRP may be released to help prevent such an event.¹

While CGRP is found in everyone and is helpful to some of our body functions, the effects of CGRP can also contribute to migraine attacks.

What is the role of CGRP in migraine?

CGRP is released into the body during the migraine process.¹⁸ CGRP affects the trigeminal nerve, which communicates pain and sensitivity to touch and temperature. It is released throughout the peripheral and central nervous systems during a migraine attack. When CGRP attaches to its receptors in the brain, it perpetuates the migraine process, leading to inflammation and headache pain.^{3 4} In patients who have chronic migraine disease, CGRP levels remain elevated during a migraine attack, as well as between attacks.¹⁹

Clinical studies have shown that when CGRP is injected into the body it causes moderate to severe headaches in people who have not been diagnosed with migraine disease, and migraine-like headaches in people who have migraine disease.^{1 18} This information suggests that people with migraine disease may be particularly sensitive to CGRP.¹⁸

The initial development and studies of drugs that target and reduce the amount of CGRP in the body began in the late 1990s.¹⁸ The first CGRP inhibitors to prevent, reduce, and or treat migraine attacks were approved by the FDA in 2018.³

What are CGRP Inhibitors?

CGRP inhibitors generally fall into two classes of drugs: Monoclonal antibodies and receptor antagonists.³

Monoclonal antibodies

Monoclonal antibodies work by blocking the CGRP pathway. They are a preventive treatment due to the longer duration  they remain in the bloodstream.¹ Monoclonal antibodies are FDA approved for migraine with and without aura.⁶

The following monoclonal antibodies work by binding to the CGRP molecule itself, “mopping up” the CGRP in the body.⁷ They are FDA approved for the preventive treatment of migraine in adults.

• Fremanezumab (Ajovy) is self-administered as a subcutaneous injection every month or every 3 months, depending on dosage.⁸
• Galcanezumab (Emgality) is self-administered as a subcutaneous injection every month for the preventive treatment of migraine. A different dosage is approved for the treatment of episodic cluster headache.⁹
• Eptinezumab (Vyepti) is administered in the doctor’s office as a 30 minute intravenous infusion every 3 months. It is approved for the preventive treatment of migraine in adults.¹⁰

A fourth FDA approved option, erenumab (Aimovig), works by binding to the CGRP receptor, so that the CGRP cannot be activated and result in a migraine attack.⁷ Aimovig is self-administered as an injection every month, and is approved for the preventive treatment of migraine in adults.¹¹

Gepants

Gepants are small molecule CGRP receptor antagonists that bind to and block CGRP receptors. Gepants are generally marketed for acute migraine treatment due to the shorter length of time they stay in the bloodstream, but some gepants may be used daily as a preventive treatment.^{1 4 5 12 13}

The following gepants are FDA approved for the acute treatment of migraine in adults:

• Rimegepant (Nurtec ODT) is a disintegrating 75 mg single dose oral tablet. It is also approved for the preventive treatment of episodic migraine.¹⁴
• Ubrogepant (Ubrelvy) is prescribed as a 50 or 100 mg oral tablet. A second tablet can be taken in 2 hours if the migraine pain returns. The maximum dose is 200 mg per day.¹³ It is approved for the acute treatment of migraine attacks with or without aura; it is not approved for the prevention of migraine headaches.¹⁵

A third option, atogepant (Qulipta) is FDA approved for the preventive treatment of episodic migraine in adults. It is prescribed as a daily 10 mg, 30 mg, or 60 mg oral tablet.¹⁶ At this time it is not FDA approved for acute migraine treatment.

Risks

What are the side effects?

Side effects of the CGRP monoclonal antibodies include:

• constipation¹¹
• high blood pressure¹¹
• injection site reactions, such as pain, redness, or swelling^{8 9 10 11}

Side effects of gepants include:

• constipation¹⁶
• fatigue^{15 16}
• nausea^{14 15 16}

Who is contraindicated?

CGRP inhibitors are generally well tolerated and can be used safely by patients who do not have an allergic reaction to the drug or its ingredients. 

Before taking the drug, patients should tell their healthcare provider about all medical conditions and medications, as some interactions may exist.

CGRP inhibitors have not been adequately studied for safety in pregnant women, unborn infants, or their presence and effect in human milk, milk production, or breastfeeding infants.^{13 19} Patients should tell their healthcare provider if they are pregnant, breastfeeding, plan to become pregnant, or plan to breastfeed.

Safety and effectiveness in children has also not been established.¹⁹ None of the CGRP inhibitors discussed in this article have been approved for the treatment of migraine in children.

How much relief can be expected?

In clinical trials, more than half of people found that their migraine days and/or severity of their migraine attacks dropped by 50% when using a CGRP inhibitor.⁴ Fortunately, about 70% of people see some level of improvement.¹⁷

Some people may need to take the medication for three to six months to achieve an optimal response.^{4 6} There is currently no method to predict who will have good results, and which drug within the treatment class will be the most effective.² If a patient does not find relief on one CGRP inhibitor, or has not tolerated it due to side effects, it is advisable to try another drug.¹²

CGRP inhibitors can be an equally effective option regardless of whether you have:

• Failed to see migraine improvement on one or dozens of other preventive therapies.
• Been using or overusing acute medications.
• Been newly diagnosed with migraine disease or have had migraine for a lifetime.

Costs

With a new class of medication such as CGRP inhibitors, there may be challenges for patients to access these treatments. Commercial insurance companies in the U.S. generally require failure of at least two, if not three, preventive medications from three different classes before providing prior authorization to cover these new medications. This is usually due to the high cost of the CGRP inhibitors.⁶ Without insurance coverage, a year of treatment with a CGRP inhibitor can cost a patient several thousand dollars.¹³

To assist patients in obtaining these medications, some drug companies offer programs that offer free trial doses, temporary coverage of medication, or copay assistance. These programs may not be available to patients who have government insurance.⁴

Summary

CGRP inhibitors are the first medications specifically designed for the prevention and treatment of migraine attacks. They have few side effects, and a high degree of efficacy in reducing migraine frequency and/or severity. While cost and insurance coverage of these new medications may pose a challenge for some patients, there are payment assistance programs available. CGRP inhibitors bring new hope to many patients who have struggled to find an effective migraine treatment.

Additional Resources

Links to outside organizations and articles are provided for informational purposes only and imply no endorsement on behalf of Migraine World Summit.

• What happens to your brain during a migraine – Marianne Schwarz (YouTube):  https://youtu.be/qwZypa0iKq8

• Financial assistance guides from the Coalition for Headache and Migraine Patients (CHAMP): https://headachemigraine.org/migraine-financial-assistance-guides/