Gepants: A New Class of Migraine Treatments

What is a Gepant?

Gepants are a class of drugs specifically designed to treat migraine attacks when they occur by targeting the calcitonin gene-related peptide (CGRP) pathway. CGRP is a protein found in the nervous system that plays a crucial role in inflammation, the transmission of pain and the dilation of blood vessels in the brain.

Research has shown that elevated levels of CGRP are found in individuals during migraine attacks, and its inhibition can lead to relief from migraine symptoms.

How Do Gepants Work?

Our brain does not have the ability to feel pain. Instead, the nerves, including the trigeminal nerve, pass the sensation of pain on the brain’s behalf. The trigeminal nerves are the nerves around the head which are responsible for sensations in the face, head and motor functions such as chewing.
During a migraine headache, CGRP is released and binds to receptors in the trigeminal nerves which leads to pain.

Gepants work by blocking CGRP receptors. By binding to the CGRP receptor, gepants prevent the interaction between CGRP and its receptor, effectively disrupting the pain signalling pathway associated with migraine attacks. This results in reduced inflammation, blood vessel dilation, and the transmission of pain signals in the brain. Patients experience relief from migraine symptoms, including headache, nausea, and sensitivity to light and sound.

How Effective Are Gepants?

Some of the key findings from several clinical trials on gepants include (1-4):

• Reduction in pain: Gepants have demonstrated a statistically significant reduction in migraine pain compared to placebo. In these studies, a higher percentage of patients treated with gepants experienced pain relief within two hours of administration.
• Relief from other migraine symptoms: Gepants have also shown efficacy in providing relief from other migraine-associated symptoms, such as photophobia (sensitivity to light), phonophobia (sensitivity to sound), and nausea.
• Sustained pain relief: Some studies have reported sustained pain relief with gepants, where patients experienced pain relief for up to 24-48 hours after a single dose.
• Lower rates of recurrence: Gepants have demonstrated lower rates of migraine recurrence within 24-48 hours compared to placebo, indicating that they can provide lasting relief from acute migraine attacks.
• Tolerability and safety: Gepants are generally well-tolerated, with a favourable safety profile. The most common side effects include mild to moderate instances of nausea, dizziness, or fatigue. Importantly, they have shown a lower incidence of cardiovascular side effects compared to triptans, making them a suitable alternative for patients with contraindications to triptan use.

It is important to note that the efficacy of gepants may vary among individuals, and the choice of treatment should be tailored to each patient’s specific needs and medical history with their doctor.

Side Effects

Gepants have a favourable safety profile, with reported side effects generally being mild and transient. Common side effects may include nausea, dizziness, fatigue, and dry mouth.

Importantly, gepants do not exhibit the vasoconstrictive properties associated with triptans, making them a safer choice for patients with cardiovascular risk factors. You should discuss potential side effects, contraindications, and drug interactions with your prescribing doctor.

Comparison with Triptans

Triptans have long been the gold standard for acute migraine treatment. While they are effective in relieving migraine symptoms for many individuals, they are not universally successful, and some patients may experience inadequate relief or intolerable side effects. Additionally, triptans are contraindicated for patients with certain cardiovascular conditions due to their vasoconstrictive properties.

Gepants, on the other hand, offer a unique advantage over triptans due to their distinct mechanism of action. Unlike triptans, gepants do not cause vasoconstriction, making them a safer option for patients with cardiovascular concerns. Moreover, gepants have demonstrated comparable or superior efficacy in treating migraine attacks compared to triptans, leading to a promising alternative for those who do not respond well to traditional treatments. The evidence has suggested that using gepants does not lead to medication overuse headache.

Comparison to anti-CGRP monoclonal antibodies

Gepants and CGRP monoclonal antibodies are two different classes of medications that target the calcitonin gene-related peptide (CGRP) pathway, which is implicated in migraine pathophysiology. Although they both aim to manage migraine by targeting the CGRP pathway, there are some key differences between the two:

Mechanism of action:

Gepants are small molecule CGRP receptor antagonists. They work by binding to the CGRP receptor and blocking the interaction between CGRP and its receptor. This prevents the activation of the receptor and the subsequent cascade of biochemical events which promote the release of inflammatory mediators, dilate blood vessels and increase sensitivity of pain-sensing nerve fibres. These are thought to contribute to migraine pain and other migraine symptoms.

CGRP monoclonal antibodies, on the other hand, are large proteins that target either the CGRP ligand itself or its receptor. By binding to the CGRP ligand, they prevent it from interacting with the receptor, thus blocking the cascade signalling pathway. Alternatively, by binding to the receptor, they can prevent CGRP from activating it.

Administration:

Gepants are typically administered orally as pills, making them convenient for patients to use on an as-needed basis for acute migraine treatment.

CGRP monoclonal antibodies are administered via subcutaneous injection or intravenous infusion. They are prescribed for the preventive treatment of migraine and are administered on a regular basis, such as once per month or once every few months, depending on the specific medication.

Pharmacokinetics:

Gepants have a relatively short half-life, meaning they are cleared from the body more quickly. This allows for faster onset of action and makes them suitable for acute migraine treatment.

CGRP monoclonal antibodies have a longer half-life and remain in the body for an extended period, providing a sustained therapeutic effect that is suitable for migraine prevention.

Side effects and contraindications:

Gepants may have mild and transient side effects such as fatigue and nausea.

CGRP monoclonal antibodies are also generally well-tolerated with a low incidence of side effects. Some common side effects may include injection site reactions, constipation, and upper respiratory tract infections.

Acute vs. Preventive Treatment

Gepants were designed for acute treatment of a migraine attack when it starts. They are intended to be taken as soon as the patient experiences the onset of migraine symptoms, providing rapid relief from the debilitating effects of the condition. By blocking the CGRP receptor, gepants can help to stop the perpetuation of the migraine attack.

However, the potential of gepants extends beyond acute treatment, and some variants have been investigated for their effectiveness in preventive migraine therapy. Research shows that certain gepants may also be effective in reducing the frequency of migraine attacks when taken regularly. This could be a game-changer for individuals who experience chronic migraine whose acute medication may also be used to help prevent future attacks. Gepants may be a very versatile treatment choice for many if it is approved for both acute and preventive use in Australia.

Can gepants cause Medication Overuse Headache?

Medication overuse headache (MOH) may occur when acute headache medication, such as pain relief and triptan are taken frequently or in excessive amounts, resulting in a worsening of headache symptoms and frequency. This can create a vicious cycle of increased medication use and worsening headaches, ultimately leading to chronic daily headaches.

Gepants have not shown any evidence of contributing to MOH. Therefore they may be useful for those with frequent migraine attacks.

Variants of Gepants

Several gepants have been developed, each with varying characteristics and indications. USA brand names have been used which may be different to those in Australia once the treatment is approved for use.

• Rimegepant (Nurtec): has been shown to treat and prevent migraine attacks in adults. For prevention it is used every other day. It is an oral disintegrating tablet.
• Ubrogepant (Ubrelvy): Also approved for the acute treatment of migraine in adults, ubrogepant is an oral tablet that has demonstrated efficacy in reducing migraine symptoms within two hours of administration.
• Atogepant (Qulipta): has been shown to reduce migraine attack frequency when taken daily.
• Zavegepant (Zavzpret): has been developed for acute treatment. It has been formulated as a nasal spray.

Gepant Availability in Australia

Two gepants, atogepant (Qulipta) and rimegepant (Nurtec), were submitted to the Therapeutic Goods Administration (TGA) which is responsible for the approval of new medicines in Australia. These submissions were made, respectively, in August and September 2022. As of August 2023, rimegepant (Nurtec) is listed on the Australian Register of Therapeutic Goods (ARTG), but atogepant (Qulipta) is still unapproved.

They were both also submitted for PBS listing and were discussed in the July 2023 Pharmaceutical Benefits Access Committee (PBAC) agenda for review. Atogepant (Qulipta) was submitted for migraine prevention in people with highly episodic or chronic migraine, while rimegepant (Nurtec) was submitted for acute treatment in people who have not responded adequately to at least 2 triptans.

Unfortunately both medications were not recommended by the PBAC. Migraine & Headache Australia encourages a resubmission by the manufacturers, so they can work with PBAC to find a common ground that considers all stakeholders including patients. It is common for applicants to not be successful in their first submission. We hope that a future submission for PBS listing will be successful.

Conclusion

Gepants represent a significant breakthrough in migraine treatment, offering a promising option for those who are yet to find an effective acute migraine medication. With their unique mechanism of action, favourable safety profile, and potential use in both acute and preventive treatment, gepants have the potential to significantly improve the quality of life for people who experience migraine in Australia.

As availability increases and more gepant variants become accessible, it is essential for patients to consult with their healthcare providers to determine the most appropriate treatment plan for their individual needs. By staying informed about the latest advancements in migraine treatments like gepants, patients can take an active role in managing their condition and improving their quality of life. If you haven’t already, please subscribe to our monthly newsletter for alerts about the latest new treatments, research, news and events in migraine and headache.

Further information & resources

If you would like to learn more about migraine treatment options or any other topics discussed in this article, you can check out the following articles:

• Migraine – a comprehensive article about migraine symptoms, causes, treatments, and more.
• Treatment Options – migraine treatment options including treatment directory.
• New treatments update – this page will have the latest information about PBS listings for new migraine medications.
• Calcitonin Gene-Related Peptide Antibodies (CGRP) for Migraine – an explanation of what CGRPs are and how they work.

References:

1. Lipton, R. B., Dodick, D. W., Ailani, J., Lu, K., Finnegan, M., Szegedi, A., & Trugman, J. M. (2019). Effect of ubrogepant vs placebo on pain and the most bothersome associated symptom in the acute treatment of migraine: The ACHIEVE II randomized clinical trial. JAMA, 322(19), 1887-1898.
2. Croop, R., Goadsby, P. J., Stock, D. A., Conway, C. M., Forshaw, M., Stock, E. G., … & Lipton, R. B. (2019). Efficacy, safety, and tolerability of rimegepant orally disintegrating tablet for the acute treatment of migraine: a randomised, phase 3, double-blind, placebo-controlled trial. The Lancet, 394(10200), 737-745.
3. Dodick, D. W., Lipton, R. B., Ailani, J., Lu, K., Finnegan, M., Trugman, J. M., & Szegedi, A. (2019). Ubrogepant for the treatment of migraine. New England Journal of Medicine, 381(23), 2230-2241.
4. Ailani, J., Lipton, R.B.,  Goadsby, P.J., Guo, H.  Miceli, R., Severt, L.,  Finnegan, M., Trugman, J.M.  (2021)  Atogepant for the Preventive Treatment of Migraine. N Engl J Med.  Aug 19;385(8):695-706. https://www.nejm.org/doi/10.1056/NEJMoa2035908