The Evolving Role of CGRP-targeting Therapies in Migraine Prevention

Richard Lipton, MD, Albert Einstein College of Medicine, provides insights on the American Headache Society’s position statement update on calcitonin gene-related peptide (CGRP)-targeting therapies as a first-line option for the prevention of migraine. He also discusses recent advancements in CGRP targeting therapies.

Could you please introduce yourself by stating your name, title, organization, and relevant professional experience?

My name is Richard Lipton, MD, and I am a neurologist epidemiologist. I work at the Albert Einstein College of Medicine in the Bronx, New York, where I direct the Montefiore Headache Center. I've been involved in patient care and headache medicine as well as research for over 40 years.

How have CGRP-targeting therapies changed the landscape of migraine prevention, and what clinical outcomes have you observed in patients compared to traditional treatments.

There has been a real sea change in migraine therapeutics over the past 5 or 6 years related to the development of CGRP targeted therapies. CGRP is a peptide neural transmitter involved in the pain pathways for migraine, but it is also involved in other physiologic functions. It is found in all areas that are involved in migraine, including the sensory nerves to the head and the central projections of those sensory nerves. CGRP has been involved in migraine for a long time, but as of right now, in the US there are a total of eight treatments that have received US Food and Drug Administration (FDA) approval for migraine that target CGRP. Four of them are small molecules (three administered orally and one administered by nasal spray), and four of them are injectable monoclonal antibodies approved for prevention.

CGRP targeted therapies have taught us that the molecular mechanism useful in the acute treatment of migraine can also be useful in the preventive treatment of migraine. So, until the advent of CGRPs, we drew a line in the sand and said there are acute treatments like triptans and nonsteroidal anti-inflammatories such as dihydroergotamine. And then there are preventive treatments like beta blockers, anti-epilepsy drugs, and antidepressants. We thought that the fundamental pharmacology of the molecule determined whether it would work as an acute or a preventive treatment. But the CGRP targeted therapies work both as acute and preventive treatments. This development has created a set of new therapeutic opportunities that have really shifted the landscape.

How do you think insights from the study by Charles et al fit into the current landscape of migraine treatment options?

There are six CGRP targeted therapies that can be used to prevent migraine attacks. And when I say prevent, what I mean is reduce the frequency or severity of attacks. Although these drugs are more likely to be 100% effective than previous preventive therapies, it would be unusual for someone to go on a migraine medication and have their attacks completely eliminated. Of the preventive therapies, four are injectable monoclonal antibodies, three are given subcutaneously, and one is given intravenously. Most of them are given on a monthly basis, but there is an intravenous monoclonal antibody called bapineuzumab that can be given every 3 months instead. The alternative are a class of drugs called gepants, which are CGRP receptor targeted small molecules, and the two FDA-approved small molecules are rimegepant, which is dosed every other day, and atogepant, which is dosed on a daily basis.

In comparison with the preventive treatments that we had before the CGRP target therapies, these are drugs that were designed and developed specifically for the treatment of migraine. Most of the preventive therapeutic armamentarium prior to the CGRRP-targeted therapies were developed to treat hypertension, angina, depression, or epilepsy and were adopted for migraine. But these were drugs that were specifically designed to treat migraine and specifically block the CGRP pathway, which plays a central role in migraine pain. One of their biggest advantages—and this is true across all six available preventive CGRP targeted treatment options—is that they all kick in more quickly than the oral generic medications. And broadly speaking, all of them deliver statistically significant benefits within 1 week of initiating therapy. Also, all of them can be initiated at an optimal dose.

Many of the older therapies had more side effects. It was important to begin at a low dose and gradually escalate the dose and a trial to determine whether a drug like topiramate worked could take 6 to 8 weeks or sometimes longer as we tried to get the dose optimized. So, these CGRP-targeted therapies have favorable side effect profiles. They kick in much earlier, and broadly speaking, less dose adjustment is required than in their predecessor drugs. Although there is not a lot of head-to-head data, the trials suggest—and certainly my clinical practice experience suggests—that these drugs are more effective than their predecessors as well.

In your experience, how might the results from the Charles et al report influence clinical practices or treatment protocols for patients suffering from migraines?

One disadvantage of the CGRP-targeted therapies is that they are more expensive than their oral generic predecessors, which is not surprising. These are newer branded medications. And so, in an environment where a new class of medications is better tolerated and more effective than its predecessors, the question that arises is where do they fit in the therapeutic landscape?

When both the monoclonal antibodies and the oral gepants became available, there was initially a requirement that people try and fail oral generic medications before they gained access to the CGRP-targeted therapies. The Charles et al paper explicitly recommends that CGRP preventive therapies should be considered first-line treatments. Now, that does not necessarily mean that there are no other first-line treatments. Previously FDA-approved drugs such as two beta blockers, two anti-epilepsy drugs, and a botulinum toxin A for people with chronic migraine are in most respects also first line treatments.

The Charles paper suggests that there should not be so much trial and failure required of the patients for whom the clinician believes that CGRRP-targeted therapies are the optimal first choice. Interestingly, since the Charles paper was published, many health plans have moved CGRP-targeted therapies into first-line position. And there has been a substantial reduction in the requirements for prior authorization and step edits before CGRP targeted therapies could be given. From my perspective, that is all good.

These are relatively easy drugs to use. They had previously been primarily used by specialists, generally neurologists or headache specialists as providers. But in fact, the CGRP-targeted therapies are easier to use well as migraine preventives over a drug like tira or divalproex sodium. They are also much better tolerated. So, I consider the Charles paper an important step toward letting physicians, other kinds of clinicians, and patients decide what initial preventive treatment would be best for a person with migraine, beginning with the most effective treatment without the necessity for multiple step edits.

Given the recent advancements in CGRP targeting therapies, what do you foresee as the next steps in research and development, and how might these innovations shape the future of migraine prevention strategies?

The emergence of CGRP-targeted therapies took a long time. Since the early eighties, CGRP has played an essential role in migraine, and it took a long time to develop effective ways of blocking CGRP and getting those agents incorporated into practice. Migraine is an incredibly common condition. There are 40 million Americans who have migraine, and there are over a billion people on a global basis who have migraine. It is anything but a one size fits all condition.

So, there are other therapeutic options in development that have other molecular targets. There are people who do wonderfully well on CGRP- targeted therapies, but there are other people whose treatment needs are not met by these classes of medication. So, there are new medicines being developed, which I hope will improve outcomes both for people who are CGR- partially responsive and those who are not responsive at all to CGRP. There is a lot of work being done on combination therapies.

There is also a lot of work being done with CGRP-targeted therapies on the acute treatment side. For preventive treatments, we treat patients at regular intervals to keep attacks from coming on or reduce their severity. For acute treatment, we wait until there is a high probability of an attack and then treat only when treatment is explicitly needed.

There are new paradigms emerging for acute treatment. One of them is treating patients during the prodrome, and that has been shown to be a strategy that is useful for a drug called ubrogepant, which is a CGRP blocker. There are other strategies, one of which is called situational prevention, which involves treating patients on a short-term basis only when there's a high probability of headache. There are also multiple external neuromodulatory devices that are now available, including transcranial magnetic stimulation, vagus nerve stimulation, transcutaneous supraorbital nerve stimulation. There is emerging work with implantable devices that are implanted under the skin but outside the skull. I consider all of those developments incredibly exciting and approaches that offer hope for the nearly billion people in the world to suffer from migraine.

Reference

Charles AC, Digre KB, Goadsby PJ, Robbins MS, Hershey A. Calcitonin gene-related peptide-targeting therapies are a first-line option for the prevention of migraine: An American Headache Society position statement update. Headache. 2024;64(4):333-341. doi: 10.1111/head.14692