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Migraines are not simply a bad headache; they are a neurological disorder that can significantly impact daily life. Often characterized by throbbing pain on one side of the head, they can be moderate to severe and are often accompanied by nausea, vomiting, and sensitivity to light and sound. Migraine treatment generally focuses on managing acute attacks and, in some cases, preventing future ones. The market for migraine drugs, both as treatments and prophylactic options, has surged over the past few years, with a host of medications from numerous big names like Pfizer, AbbVie, Eli Lilly, Amgen, Teva, and others, fighting for ground.
First-line treatment for migraines currently includes medications like painkillers, triptans (a class of drugs that act on serotonin receptors in the brain), anti-nausea medications, antidepressants, anti-seizure drugs, and even Botox injections to the face and neck to numb the nerves. However, individual responses to these treatments can vary, and they may not work for some people.
Fortunately, in the last few years, the biotech industry has come up with novel migraine treatments that target a neuropeptide called calcitonin gene-related peptide (CGRP), which has long been thought to play a role in the onset of migraines.
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The advent of “gepants” for migraines
The role of CGRP in migraines, specifically its involvement in pain and inflammation during migraine attacks, was first hypothesized around 1983 and later supported by studies demonstrating elevated CGRP levels during migraine attacks. In the late 1990s, this evidence prompted a few big pharma companies to begin developing small molecule CGRP receptor antagonists, now known as “gepants,” which work by blocking CGRP from attaching to its receptor, in turn preventing it from initiating pain signals.
The first generation of gepants, developed between 2004 and 2011, established the validity of CGRP as a therapeutic target. However, further development was halted, either due to a lack of oral availability or concerns of hepatotoxicity. Now, though, a second generation of gepants, such as AbbVie’s ubrogepant and Pfizer/Biohaven’s rimegepant, have been approved for the acute or preventative treatment of migraines with or without aura.
In fact, just last month, new data from a phase 3 trial showed that ubrogepant can effectively reduce the non-headache-related symptoms of migraines, such as sensitivity to light and sound, nausea, neck pain, brain fog, and dizziness, when taken one to six hours prior to a headache beginning. This discovery is extremely encouraging, as, despite the commonality of these indicators, very little research has looked into how to manage them, and no other treatment has genuinely been shown to alleviate them.
There is now also a third generation of gepants that are starting to become available, like zavegepant, which is the first approved medication of this class to be administered as a nasal spray. This offers an alternative treatment option for migraine sufferers who cannot take oral medications or would simply prefer an alternative to oral administration.
Monoclonal antibodies targeting CGRP: A game changer in migraine treatment
Hailed as being even more revolutionary than gepants, however, is the development of monoclonal antibodies that target CGRP.
Monoclonal antibodies have emerged as a major class of therapeutics in recent years, with the U.S. Food and Drug Administration (FDA) having now approved well over 100 drugs of this kind for a wide range of diseases like cancer and autoimmune conditions.
Given their ability to target specific molecules, companies also saw an opportunity to develop monoclonal antibodies as a preventative treatment for migraines by making them target CGRP, with Amgen and Novartis’ Aimovig (erenumab) becoming the first approved biologic drug of this kind to target the receptor after being given the green light by the FDA in 2018. This was then quickly followed by the approvals of Teva’s Ajovy (fremanezumab), Lilly’s Emgality (galcanezumab), and Lundbeck’s Vyepti (eptinezumab).
These antibodies have proven extremely effective at reducing the number of migraine days for many individuals. In fact, in clinical trials, they were shown to reduce migraines by at least 50% in a significant portion of patients. This was also the case when looking at long-term data, with patients on Aimovig, for instance, experiencing at least a 50% reduction in the number of monthly migraine days requiring acute medication at week 52.
The introduction of monoclonal antibodies in the treatment of neurological conditions first came in 2004, with the FDA approval of Tysabri (natalizumab) for multiple sclerosis. Since then, several other monoclonal antibodies have been approved for neurological diseases. When treating conditions like multiple sclerosis, these drugs generally work by acting on the immune system. But this comes with both risk and reward: while they have the ability to decrease disease progression, many carry boxed warnings due to the potential for serious side effects.
Fortunately, when it comes to treating migraines, which is now largely accepted as a neurological condition, monoclonal antibodies do not affect or alter the immune system, do not seem to have off-target toxicity, and appear to have fewer side effects than other preventive medicines for migraine, making them not just extremely effective, but also a safe treatment option for patients.
Other new migraine treatments on the horizon
Axsome Therapeutics launches new migraine drug Symbravo
Another recently approved migraine treatment is Axsome’s Symbravo, which was finally given the green light by the FDA for the acute treatment of migraine with or without aura in January 2025 after the regulatory agency previously rejected it for manufacturing issues in 2022.
Formerly known as AXS-07, Symbravo has been shown to provide patients with relief within two hours and to sustain its efficacy for up to 48 hours, with some patients able to achieve these benchmarks with just a single dose of treatment. The rapid-acting oral therapy is a combination treatment of meloxicam and rizatriptan – meloxicam is a nonsteroidal anti-inflammatory drug (NSAID) developed with Axsome’s Molecular Solubility Enhanced Inclusion Complex (MoSEIC) rapid-absorption technology, and rizatriptan is an approved 5-HT1B/1D agonist (a triptan) that was previously sold by Merck as Maxalt before it went generic.
Symbravo’s approval was based on results from three phase 3 trials. In one of these trials, which tested the therapy in patients with moderate to severe migraine, 77% of patients did not need rescue medication within 24 hours of dosing. Similarly, in another trial, which tested the drug in patients when the initial pain was mild, 85% did not need rescue medication within 24 hours.
Axsome officially launched Symbravo earlier this week and announced that the drug is now available by prescription in the U.S. It is worth noting that it comes with a boxed warning for cardiovascular side effects, including the risk of heart attack and stroke, with the FDA also warning of the potential of developing gastrointestinal side effects, such as ulcers.
Lundbeck’s Lu AG09222 and Biohaven’s BHV-2100 : two novel migraine drugs advancing through the clinic
As well as approved products, there are also some promising investigational migraine treatments currently in clinical development, namely Lundbeck’s Lu AG09222 and Biohaven’s BHV-2100.
Lundbeck’s candidate is a monoclonal antibody with an innovative mode of action; it is designed to bind to and inhibit pituitary adenylate cyclase-activating polypeptide (PACAP), another neuropeptide that has recently emerged as being implicated in the pathophysiology of migraine, representing a novel target for migraine treatment. This means that, if approved, Lu AG09222 could be another potential new therapeutic option for patients.
The drug is currently being tested in a phase 2b trial designed to explore different doses and routes of administration in patients with migraine for whom one to four previous preventive treatments had failed to provide a benefit. A pre-specified interim analysis from this trial recently convinced Lundbeck to switch its focus from a subcutaneous formulation of Lu AG09222 to intravenous delivery, as subcutaneous administration “was not demonstrating the desired treatment effect.” Furthermore, an intravenous version of the therapy had already shown success in a phase 2 trial.
This will delay the completion of the phase 2b trial, which is now expected to finish in the first half of 2026. If everything goes well, Lundbeck will then initiate a phase 3 trial for the migraine candidate in the second half of 2026.
Biohaven, meanwhile, initiated a pivotal phase 2 trial in September last year evaluating its own candidate in the acute treatment of migraine. BHV-2100 is a potent, orally administered transient receptor potential melastatin-3 (TRPM3) antagonist— a novel, highly selective, and non-opioid investigational treatment being developed for migraine and other pain disorders.
The drug had previously demonstrated excellent safety and tolerability across all doses in a phase 1 study in healthy adults, without the thermoregulatory adverse events observed with other TRP antagonists or the sedation associated with other pain medications. Additionally, the pharmacokinetic profile was found to be very well-suited for use in the treatment of acute migraine.
The phase 2 trial is designed to support registration with the FDA-accepted co-primary endpoints of pain freedom and freedom from the most bothersome symptom at two hours. Topline results are expected at some point this year.
Migraine treatment market set for significant growth, but challenges remain
While many experimental pain drugs have failed to make it out of the clinic over the past few years, treatments specifically intended for migraine headaches have been bucking this trend in the pain market, where the advancement of CGRP-targeted medicines has led to significant success.
This can also be seen in the fact the migraine market in the 7MM (the seven major markets in the world, encompassing the U.S., France, Germany, Italy, Spain, the U.K., and Japan) is poised to grow at a compound annual growth rate (CAGR) of 6% from $9.2 billion in 2023 to $16.4 billion in 2033.
Although this growth will primarily be driven by the increased prescription of CGRP drugs like gepants and monoclonal antibodies, cheaper drugs like triptans still dominate the current standard of care, meaning that the growth in CGRP-targeted drugs will likely be limited by reimbursement restrictions, as well as the patent expiries of all these branded drugs towards the end of the forecast period.
This, in turn, raises a question about an unmet need in patient access to novel migraine drugs once they actually hit the market. Despite it being widely recognised that monoclonal antibodies are significantly more effective than many of the older therapies, they remain second-line or third-line options for many patients due to reimbursement restrictions that require patients to try and fail with old oral preventives before these newer drugs can be prescribed.
Many countries, particularly in Europe, have stricter reimbursement rules than the guidelines recommend, meaning that access will likely be an ongoing challenge. Even gepants, which it was hoped would be cheaper and easier to prescribe than monoclonal antibody therapies due to their oral administration, have been somewhat inaccessible; they were launched at prices similar to that of the annual cost of monoclonal antibodies in most countries, resulting in similar restrictions to their reimbursement.
Last year, the American Headache Society (AHS) – the leading medical and scientific organization for healthcare professionals in migraine and other headache disorders – published a recommendation saying that new migraine therapies targeting CGRP should be considered first-line preventive treatments without requiring patients to first try older, less effective medications. This may well open the door for migraine patients to access these treatments – in the U.S., at least – but it all depends on whether insurance companies in the country will implement this recommendation.
Certainly, the accessibility challenge here will need to be addressed to ensure patients can receive the treatment they deserve as quickly as possible for a condition that can significantly interfere with their ability to function in day-to-day life.
Nevertheless, the sheer number of new drugs that have become available in the last few years, as well as the ones in clinical trials that might be approved in the near future, is undoubtedly a positive step forward in the migraine treatment field.
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