Calcitonin gene-related peptide–targeted therapies for migraine

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Hello and welcome to the Australian Prescriber Podcast. I'm Jo Cheah, a hospital pharmacist in Melbourne. In this episode of the Australian Prescriber Podcast, I'll be interviewing consultant neurologist Dr Bronwyn Jenkins. The episode will cover classifying migraines and headaches, current therapies, and delve into calcitonin gene-related peptide–targeted medications used for migraine treatment and prevention. Welcome Bronwyn.

Thanks Jo.

Thanks for coming onto the programme. Bronwyn and co-authors Stephanie Barnes and Lucy Aldous have written the article ‘Calcitonin gene-related peptide–targeted therapies for migraine’. It's a bit of a mouthful, so happy to shorten that down to CGRP-targeted therapies. So Bronwyn to start off today, can you tell me who is currently affected by migraines and how does it impact their quality of life?

Yeah, really anyone can be affected. It's a polygenetic disorder in most people, but the practice that we see is mainly bookended by teenagers and perimenopausal women, because the prevalence ramps up with hormonal factors in the female population. There are obviously men also, but it's probably less than a third of my practice that are male. So, we get to usually in the working years just as people are entering the workforce or choosing what they're going to go back to after having children. So, it's a highly burdensome population that we are looking at when we are looking at the lost time from their migraine attack. So, it's predominantly female, predominantly around hormonal factors, but it's not all hormonal. And in fact, we get very little success in suppressing or managing just hormonal factors. So, the demographics doesn't really help us in how we treat the disorder.

And can you briefly describe different types of headaches and migraines and how they're classified?

Yeah, so I think migraine is the most common primary headache disorder that we'll all see, because tension-type headaches, low grade, tight aching headaches anywhere around their head, often described as a tight band, don't have any associated features. So they don't have sensitivity to light noise, nausea, and need to rest. They don't ramp up if there's increased concentration or exercise. So migraine headaches have those associated features and so there's a high sensitivity of diagnosing it if they have 2 of the 3 of sensitivity to light or noise or nausea. And my most sensitive question is asking whether they can do all their activities. If they are limited in their activities, then we are usually looking at migraine disorder even if they have a whole mix of tension-type headaches as well. So, it's a weird thing that migraine disorder will often have both subtypes of headache within it, but really the migraine trumps the tension-type headache, in that the headache will respond to migraine treatments.

It gets even more important to be able to pick the difference between a migraine day and a tension-type headache day. When we are looking at the new therapies that we're going to talk about today, the difference between a migraine and tension-type day is that migraine day has some headache attacks. Not all of them, but some that have a moderate or worse severity. The other thing about migraine disorder is that it can be classified as chronic or episodic. And chronic doesn't mean how long they've had it, how many years they've had it. It is actually the frequency of headache days. So chronic migraine is where they have 15 days of headache of which 8 are migrainous in characteristics, whereas episodic is less than this number.

And before we get to discussing CGRP-targeted therapies, could you give a brief rundown on the currently approved therapies for acute migraines and migraine prevention?

Yeah, so with acute migraine, we treat them as required for an attack. So, if they've got nausea, they need to absorb their medications. So using an antiemetic like metoclopramide or ondansetron wafer. If they have a low-grade headache, sometimes an anti-inflammatory like high-dose aspirin or other anti-inflammatories can be useful as long as they can tolerate it in their gut. Paracetamol is not often useful when they don't have a good preventive therapy like the new treatments. And the most effective class that's on the PBS [Pharmaceutical Benefits Scheme]are the triptans, which we've had for over 30 years. They're highly effective disease-specific ways of stopping a migraine attack acutely.

Preventives are different. We use them for people that have more than 4 significant migraine days a month. So it all hangs in the balance of what we mean by significant, and usually that's something that they can't control or they're missing time from their activities, or just too many onsets to know which ones to treat early enough to actually be successful or at risk of medication overuse, taking too many of their acute medications.

So preventives are probably still underused, and currently we've had a whole list of oral preventives borrowed from other classes of medications. So, we have some antihypertensives. Good if you've got high blood pressure but not so good if you've got low blood pressure. Antidepressants like amitriptyline. We've got antiepileptics with topiramate being the gold standard of effectiveness, but with a few little caveats of side effects potentially, as well as valproate, obviously. So we borrow them from other medication classes and we have to consider the likelihood of tolerability as well as effectiveness and the doses that can be used in migraine. And there's some useful tools like the Therapeutic Guidelines and things that guide us in the lower doses that we use in migraine prevention of those classes that have been available for decades.

And I guess, the whole reason we're meeting today is to discuss the CGRP-targeted therapies. So would you provide an overview of these therapies including their mechanism of action and maybe some examples of the drugs that are available in this drug class?

Yeah, absolutely. So, I wrote an article in the [Australian] Prescriber about 10 years ago, I think, actually. And so the previous medications are well covered in that. This was very much an article to cover the new treatments which we need to know more about, particularly seeing as GPs [general practitioners] are allowed to initiate whilst under the care of a neurologist as well as continue them. So they're not scary treatments. They're really fantastic as far as effectiveness, tolerability, and the current safety 7 years into massive worldwide use. In Australia, we have them all approved on the TGA [Therapeutic Goods Administration], but I'll stick to talking mainly about the ones that are on PBS because they're the ones that are more relevant that we're going to see because they're more affordable. There'll be a sprinkling of patients who are using private pay systems because they don't have Medicare or whatnot. But the ones on PBS are all targeted against the CGRP peptide or ligand, so the protein which is a neurotransmitter.

CGRP stands for Calcitonin Gene-Related Peptide. It's obviously too much to say, so we just call them CGRP. CGRP is a really important neurotransmitter. It's considered the most important one to our current knowledge. And so, it's a disease-specific preventive. So just like the triptans overhauled acute treatment 30 years ago, these are overhauling preventive treatment in the group that are severely affected enough and not tolerating the other preventives, and so are able to be prescribed this on PBS. So we have fremanezumab, brand name is Ajovy, and galcanezumab, the brand name is Emgality, on the PBS, and they're subcutaneous injections that are given once every 4 weeks, once a month by the person themselves. And we get a trial of 3 months before they then continue them with 6-monthly authority scripts. We also have Vyepti, eptinezumab is the proper name, which is a 12-weekly infusion, which comes with a small cost for the infusion because there's no MBS [Medicare Benefits Schedule] Medicare item for that, but it's readily available in the major cities. It's just a bit more difficult regionally where there's no infusion centres to give those therapies potentially.

But those 3 are all targeted against the same part of the CGRP pathway, which is the peptide. The other CGRP monoclonal antibody therapy that we have in Australia that's not subsidised on PBS is erenumab or Aimovig, and that's against the receptor. We are trying to see whether there can be some agreement made with PBS because it's under review at the moment that we're making this recording. But yeah, currently our treatments all have the same target.

So in terms of the drug class itself, what are the most common side effects that we should be looking for, and what ongoing monitoring would be required? As you said, GPs can initiate and continue therapy, so it'd be great to know what we should be looking for in the community.

Yeah, absolutely. So the wording is initiating and continuing whilst under the care of the neurologist. And it's like interpreting a lot of guidelines. We're not really sure the frequency that a neurologist should be involved in, but it hasn't really changed my practice that most patients are coming to me for the original initiation. I wouldn't use them still in patients that have a vascular problem that's active. CGRP is involved in dilation of arteries, it's in the arterial walls as well as being in the gut. And so, we don't use them when someone's pregnant because they're involved in the placenta. We don't use them when someone's got an aneurysm, a recent stroke or angina or a heart attack, because it may block abnormal dilation that's required in those vascular disorders.

It can also worsen Raynaud phenomenon and there's a relative contraindication in inflammatory bowel disease, which is not an absolute contraindication. So there's a group that we wouldn't use them in. And so that's why I think mostly neurologists are still initiating them. As far as monitoring them though for side effects, you can get redness at the injection site, which is minimised by ice packs, antihistamine, rotating sites, so not using the same site every month. And it’s usually not a big issue because it doesn't change from that local reaction into a more generalised systemic allergy, although, that happens really rarely. I've had 2 patients out of many hundreds that have had a systemic allergy. So, the site reactions are not uncommon and it's not a reason for stopping them as long as it's tolerable to the person. And the other side effect came out in real-world use and that's constipation.

So if the person has really bad constipation to start with, I wouldn't start them on this class. But certainly if they develop it, it has been a reason that some of my patients have had to stop it. These treatments have quite a long half-life, so it takes a while to get over a side effect if it happens. That sounds really bad that there are those 2 side effects, but the most extraordinary thing in my practice is they are actually really well tolerated. So, don't be worried about this class of medication being something to watch out for because they're not immunosuppressive, they're not sedative, they're not going to drop their blood pressure. So, it's a refreshing change to have a monoclonal antibody therapy that is so well tolerated as long as, obviously, the person qualifies, doesn't have a contraindication and then responds.

That's right. And because they are quite a new drug class, any odd adverse effects that are popping up, that's where postmarketing surveillance is really important and reporting of adverse drug reactions, if anything, is noticed in the community.

Absolutely. So, we've had 7 years of heavy use in the real world and we are very linked in Australia to the international community. And erenumab had an FDA [US Food and Drug Administration] edition of hypertension being noted. And in my practice this has been in patients with pre-existing hypertension. So if the person had uncontrolled hypertension, that might be someone to pause and consider other things such as onabotulinum toxin injections all the way around the head that's more side effect neutral. But really, this medication in the working age group that we're talking about usually can be used in most people as long as we exclude those ones with active vascular disease.

And how long should patients be on CGRP medications for migraine?

To go on it, they're meant to have chronic migraines, so the frequency of 15 days of headache a month for more than 6 months. And that group usually stay bad. So obviously, if someone has a bad month of migraine because they had COVID infection. They don't need an ongoing preventive. In my practice, my patients unfortunately usually need their preventive long term. A preventive suggests that it's preventing something going forward, and it is for that month that they're on it, but it's not disease-modifying, which is a big difference. It doesn't change them a year later. In my experience, it quickly wears off and we've got European real-world data where they have to stop it as part of qualifying for continuation, and almost all patients went back to baseline fairly quickly and definitely by the end of several months off it.

For my patients that have forgotten when they went on holidays or those sorts of things or had an inactive dose because it wasn't kept in the cold chain storage sort of manner, they really do miss it fairly quickly after that 4 weeks, and are very motivated to make sure they can be on it.

We had an issue with some stock early last year and the end of 2023, and that group did very poorly and took a while to get back to steady state. So, I'm encouraging my patients to think ahead and make sure they've got their next dose so that they can stay on their medication that's needed in the probably longer term, unless something has majorly changed, like they've got through late menopause or they've fixed their neck input or other things that were having a factor. With that medication shortage of the CGRP monoclonal antibody therapies, we actually got some not-so-good experience that switching the antibody therapies also took some time to get to steady state. So in general, we're trying to get people to stay on their treatment. In the trials though, they're showing in the real world that some people that don't respond to one, may actually respond to another.

And with that short duration of trial of 3 months, there are some patients where you've had a whisper that they've improved but not enough for ongoing qualification where you might try the other CGRP mAb [monoclonal antibody] therapy that they can self-inject to give them another 3 months. Because there is some suggestion that you get up to one-third of responders by continuing them for the first 6 months. But obviously, we stay within the recommendations of the PBS to only be prescribing them to the people that qualify so that we can protect the subsidy system that we have that helps us access our medications here.

As you said, it's not a disease-modifying drug class and you've found that patients who have come off at either by accident or due to drug shortages, they've come back to baseline quite quickly. So, it sounds like it's an indefinite treatment at the moment?

Yeah, it really is. In my group of patients, I thought I had one lady in late menopause who didn't need it anymore, and then a year later she came back with her tail between her legs telling me how many acute analgesics she'd been using and that she'd be much better off going back on her excellent preventive that had stopped her needing as many medications.

Can you confirm whether a duration is set by the PBS criteria at the moment?

No. There's no duration of how long they should be on it. I think life usually sorts it out that people have looked under that rock to see whether they still need it, because no one likes giving themselves an injection every month. It's just been my experience that people have stayed on the longer term and obviously, I see the worst patients. So hopefully in GP practice, we are not seeing them as severely affected. But chronic migraine by that stage, they're really having more headaches than not, and the nerves are firing off frequently.

And other than what's already been discussed in terms of the PBS criteria and patient eligibility, was there anything else you wanted to mention in terms of what other criteria patients need to meet in order to be able to get this drug prescribed for them?

Yeah, that's a good point. So, they need to have had chronic migraine for more than 6 months, and they need to have failed or have a contraindication or be unable to tolerate 3 of the current oral preventives. So the antihypertensives, antiepileptic, antidepressant classes and medications we talked before. So if they got low blood pressure, if they had unacceptable mood swings on topiramate, for instance, they were too sedated on their amitriptyline, then they would hopefully move to taking a CGRP monoclonal antibody therapy or with the same PBS guidelines, botulinum toxin injections under the care of a neurologist every 3 months. Because they're both really highly effective treatments for the group of patients that don't do well on the oral preventives we've been using for so long.

Your article also mentions small-molecule CGRP receptor antagonists. Did you want to talk about them and how they fit into all of this?

I'm so pleased you mentioned that because I had limited myself to the PBS-listed things, but these are really useful too. So we only have one of the gepants, the small-molecule oral medications. There's a few medication interactions through the cytochrome pathway that would limit us, so we don't give it with verapamil, for instance. Other than that, they're really useful for patients that can afford them because they're not PBS listed. So rimegepant can be used as acute or preventive treatment, which sort of blows our minds as neurologists because if we have too many days of triptans, we get into medication overuse. But gepants actually, if you have too many days, as in you take it regularly every second day in the case of rimegepant, you get less migraines overall.

That's usually really well tolerated in fact. That once a day tablet can be really adjunctive to the triptans and the people that can take them, or it can be used in the group that can't tolerate a triptan. We come across these patients that have terrible muscular tightness or even chest pain when they take a triptan or they have a contraindication to a triptan but could take a gepant. In those cases, the gepants can be really useful. So for my working age group, if they have an almost untreatable migraine, they can't take an anti-inflammatory for whatever reason, it's not effective, their best combination of oral acute medications is not working. Having rimegepant available to take with those other medications has been able to get them back to work on that day and has got a really low rate of the headache coming back the next day or the medication needing to be repeated.

So, it's nice and long-acting as well as stabilising rather than bouncing and causing medication overuse potentially. So, it would've been great to have it on PBS, but it's really great that we've got it here on private pay as well, as an adjunctive treatment. Because of cost, it’s mainly limited to acute use, but it can be used for preventive use in small groups like the group getting pregnant that need a shorter acting treatment than the long-acting monoclonal antibody therapies [as there is a reduced washout period with the gepants compared with the monoclonal antibodies], or my couple of patients who have a systemic allergic reaction to the monoclonal antibodies that could take an oral antagonist instead. So they're really worth knowing about, but sadly we only have rimegepant in Australia at the moment.

And are there any clinical trials of interest that you'd like to mention that's being conducted in this disease group or in relation to the drug class, or any disease-modifying agents that might be in production?

I'm actually involved at the moment in a trial of a stimulator. So stimulator has been fraught with being big wire things connected to a box under the skin that's channelled through muscles. And so the risks do outweigh the benefits. But we've got this little ribbon-like device from Europe that Australia's been included in. So that trial is being run through different neurologists and, I think Headache and Migraine Australia would have that listed on their website for any patients interested. But really in the clinical practice, so in our real-world study of the CGRP use of erenumab, which was our first available in Australia, 80% of our chronic migraine patients tried on it in the first year of use were responders. So, we're pretty happy with the current treatment options available.

And just to round us out for today, could you remind our listeners of some nonpharmacological management that can be used for migraine prevention or treatment?

Absolutely. In my practice, I have a nurse who helps me with the history and information provision. We use the little handouts of the Australian New Zealand Headache Society website that is available to patients and clinicians alike. It's just 2 pages, and it talks through caffeine and safe use because it's dose dependent whether they get withdrawal headaches, sleep issues like sleep apnoea or insomnia. Anxiety and depression are probably the most important bidirectional relationship with migraine disorder. There's a couple of foods that can trigger some people, but they're not often as relevant. And patients often ask us about supplements and we can really get caught up in our practice about taking time explaining those, whereas really got some level B recommendations only. So, a little handout like that of 2 pages can be quite helpful to use in clinical practice to help with the nonpharmacological recommendations. Because I think in the clinical trials you see these new treatments, they get 50% of people having 50% response.

But in our real-world practice, like I said, there's 80% of our patients that do really well on them. And I have a huge proportion of my CGRP monoclonal antibody patients that are more than 75% better, which is so much better than they've ever been on their other preventives over time with my 20 years of being interested in headache. So, it's really exciting to see that in the real world we can get much better outcomes because we treat the person as a whole. And we don't shut them down when they talk about their anxiety disorder or their insomnia, because those things are really relevant to their care and it only takes a brief intervention to make a big impact in their health.

That's excellent. Thank you so much, Bronwyn. That takes us to the end of our episode.

No worries. Thanks for having me.

Bronwyn's full article is available on the Australian Prescriber website. The views of the hosts and the guests on the podcast are their own and may not represent Australian Prescriber or Therapeutic Guidelines. Bronwyn Jenkins received fees for being on advisory boards for Novartis, Teva, Lilly, AbbVie and Pfizer. Bronwyn previously received honoraria from Care Pharmacy, Health Ed and General Practice Conference and Exhibition for invited lectures. Bronwyn is on development and leadership, ethics, and education subcommittees of the International Headache Society (HIS), and is leading the development of educational materials for general practitioners. Bronwyn is an associate editor for Cephalalgia. She's the immediate-past president of the Australian and New Zealand Headache Society, previous board member of the IHS and an author of the 2024 IHS Global Practice Recommendations for the Acute and Preventive Pharmacological Treatment of Migraine. I'm Jo Cheah and thanks again for joining us on the Australian Prescriber Podcast.