Narrator - Dr. Abel 00:00 Welcome to HelixTalk, an educational podcast for healthcare students and providers, covering real life clinical pearls, professional pharmacy topics and drug therapy discussions. Narrator - ? 00:11 This podcast is provided by pharmacists and faculty members at Rosalind Franklin University, College of Pharmacy. Narrator - Dr. Abel 00:17 This podcast contains general information for educational purposes only. This is not professional advice and should not be used in lieu of obtaining advice from a qualified health care provider. Narrator - ? 00:27 And now on to the show. Dr. Sean Kane 00:31 Welcome to HelixTalk 88 I'm your co host. Dr. Kane, Speaker 1 00:34 I'm Dr. Schuman. I'm Dr. Patel, and today I'd actually like to introduce a guest speaker with us today. Dr. Eileen Mintz is our current PGY two resident at a level federal healthcare center, hailing from Northeast where she did her PGY one at Kingsbrook, and is again excited to come by with us and talk about our topic about migraines or powerful peptides, CGRP and the paradigm shift in migraine prevention. Glad to have you. Dr. Speaker 2 01:01 Mintz, thank you for having me. I'm excited to be here. Dr. Sean Kane 01:05 So Dr. Schuman, you first brought up this topic. I had actually never even heard of this drug category, and it sounds like this could be something groundbreaking in the future, that listeners, whether it be pharmacists or other healthcare professionals, are likely to be encountering this new drug class in the near future. Is that correct? Speaker 1 01:21 Yeah. So it's funny because people say, Oh, it say it's a new thing, a new target. Well, technically, it's not as new. First of all, back in episode 64 we talked about stimulation of the trigeminal nerve, and that leads to vasodilation and pain as this is pathophysiology of a migraine headache. And so we've got the role for serotonin. We already know that part, and that's why we look at triptans (5‑HT1B/1D agonists). Those medications have been used for years as a way of blocking the signaling pathways, and that's something we've known for a while. So what's new over here, then? So what's what's really new is there's more to the story. Substance P and something known as calcitonin gene related peptide. We'll call it CGRP. Moving forward, it's kind of like calcitonin, but a little bit different. These are the substances that are involved in that pathway, and it's something we really first found out about back in the early 1980s so again, as we talk about this, like this is a new target, but it's it's been around. They noted that trigeminal cell nerve cells had CGRP. In fact, we even noted in a couple of small studies that triptans, in the way they work, sumatriptan, for example, actually lowered CGRP. And it seems to be that this is something further upstream. So we've kind of got this downstream effect. We have tryptans, and they're squeezing the vessels to help with migraines, but kind of upstream, we have this neuropeptide CGRP, which is, is the major player in it. And therefore, maybe this is something, again, early on we can, we can block, and instead of kind of addressing the headaches when they occur, maybe we can prevent them by playing with the CGRP. So Dr Dr. Sean Kane 02:55 Mintz, if I'm understanding correctly, based on the pathophysiology, we're kind of preventing the thing that causes that pathway for migraines just earlier on in the pathway. And it sounds like this might be more of a preventative therapy versus a triptans. That is typically more of a you have a migraine now will give you an as needed therapy. Speaker 2 03:15 Yeah, exactly these medications are going to be used more for preventative therapy, as opposed to acutely when you do have a migraine. So it's going to be something you'd be taking once monthly in order to prevent the migraines from happening, to decrease the amount of migraines that you would get, instead of to just treat the migraine that you're having. Dr. Khyati Patel 03:35 So Dr. Schuman, you said that this is nothing new. As far as the drug target goes. Can you give us more of a pertinent history that CGRP as a target? Speaker 1 03:44 Yeah. So again, it was first noted in 1982 again, we're going to blast to the 80s. Everything old is new. So they found that this, they noted the CGRP, and then in 1985 the first paper came out about its Roman migraines. And so kind of what happened in between them, what they found is, because it's a peptide, and it was new. The first step to creating a drug for is they had to really identify what in the world the compound was. And so first research was, what is CGRP? What does it look like? And after that, they had to figure, okay, like, like, any kind of this applies, really, to any sort of bench, to bedside model is okay, we've got the we got the compound. Well, what's the receptor look like? We've got to find a way to modify the receptor then, and and they did that. They had a lot of trouble trying to identify it. And then the next step was to create a compound that also binds to the site as an antagonist. What they tried doing was, again, taking that peptide and kind of chopping in different places. And if you chopped into one place, you created something with affinity for the receptor, but didn't work as well. And so again, that's a good example of an antagonist. And then they also, though had to find something that actually lasted long enough to have an effect. And a lot of times, what they found was a very quick thing. You could buy into the receptor block it, but then it dissociates pretty rapidly. And so they wanted to find something that looked like they wanted to know a peptide, but something else. Could be used clinically. Dr. Sean Kane 05:02 And of course, like if you think about it, one of the reasons that it takes so long for drug to go from A to Z in terms of original development all the way to the market, is it's not just about, you know, identifying the antagonist. It's about everything you just mentioned, in terms of making it stick to that receptor. The kinetics of the drug Half Life cross probably crossing the blood brain barrier is important in this circumstance. I mean, so much goes into that, and there's so many pitfalls along the way. It's not surprising that this has taken, you know, several decades to kind of come to fruition in terms of finally having drug compounds that made it to the market, Speaker 1 05:35 yeah, and they so the first time that you kind of really see anything come to fruition was in, I believe, around the year 2000 there was a non peptide antagonist. Of course, it had a very long name, proprietary name, but they eventually called it olcegepant, the first of the gepants. There were eight studies done on that one. It seemed to disappear in development after reading a little bit more. I think they had trouble marketing it. Had trouble making it as an oral formulation, so they kind of scrapped the project. After that, there was another one, telcagepant — an orally active small-molecule CGRP antagonist — but hepatotoxicity with LFT elevations was noted, and it was discontinued in 2011. But the clinical data with both of these medications said these things worked, these treatments worked. It said CGRP is a relevant target. It's a viable target. Now we just find need to find a good way, again, of antagonizing the receptors, doing it in a longer lasting way, without causing lft elevation. So that's where from 2001 to 2011 and then a little further, they start coming out some newer medications. And so, like with a lot of places we go to monoclonal antibodies that that's been a target for many different disease states. And said, can we come up with a Mab for CGRP? And they did Dr. Khyati Patel 07:05 all right. So it seems like we have what, three or four different drugs in this particular category. Can we go over them, please? Sure. Speaker 2 07:12 So there are currently four medications, but only three of them have been approved. One is still pending FDA review. They work similarly, except that erenumab (Aimovig) binds the receptor, whereas the other approved agents bind the ligand. Dr. Sean Kane 07:36 So could you just go through the pronunciation guide, if you will, for the brand and generic names, sure. Speaker 2 07:42 So we have erenumab (Aimovig), galcanezumab (Emgality), and fremanezumab (Ajovy); the first was approved in May 2018 and the other two in September 2018. Dr. Sean Kane 08:06 That's actually pretty amazing how this drug category that was decades in development within, you know, several months, we now have three new drugs to the market despite this vast decade long development process. Speaker 1 08:21 It's one of those. It's almost like a movie script means you have this race that all these these different organizations, different individuals, kind of all coalescing, that the theory came out, and then people all had their molecule candidates. And it's kind of a race to see which one was able to show the studies get through that marketing approval and get the FDA approval. And so aim of it became, again, the first one in May. But then the others were also able to kind of take their candidates and move them forward too. Dr. Khyati Patel 08:45 And as I hear their generic names, I hear the MAB in them, right? So I'm thinking their amount of color antibodies, and somehow, I don't think they're given by mouth. Is that correct? Speaker 2 08:55 Yeah, that's correct. So all the approved formulations are currently given subcutaneously, the one still in studies, called eptinezumab, is given by IV infusion and is being studied as a quarterly dose, whereas for the most part, the other three are given monthly. Although fremanezumab does have an option to be given quarterly as well, but all the currently approved ones are subcutaneous. Dr. Khyati Patel 09:22 That sounds much better, because I wouldn't be asking my patient to take a medication to prevent migraine. That is an injection on a daily basis. So it sounds good that they're either monthly or quarterly. Speaker 1 09:31 Yeah, I have a hard time with my patients, getting them to do sub q injections of sumatriptan just on an as needed basis, because again, not everyone likes that kind of invasive model. So this is nice. And again, I think to my patient population, where medication adherence, compliance is a big concern, especially when you have a horrible headache and, oh yeah, keep taking those medications. When you're having them, keep pushing through. Remembers to take your medication. No, that doesn't always happen. And so these monthly and quarterly, it's, again, it's right off the bat that's a very. Attractive option for somebody. Dr. Khyati Patel 10:02 So I can relate these drugs to some of my osteoporosis patient who received Prolia. And Prolia is labeled clearly, say it has to be given by a healthcare professional. Are these drugs, something like that, or patients can inject these at home. Speaker 2 10:15 So patients can actually inject these at home. So pretty easy administration, just your standard subcutaneous injection technique that a patient can self administer, Dr. Khyati Patel 10:25 as long as they're trained on how to do it, yeah, Speaker 1 10:27 exactly, yeah. And a number of them, you know, come in almost looking like similar to the pens we use for insulin as subcutaneous a Jovi, as that quarterly or the option to give quarterly feminism AB, does come in more of a pre filled syringe. Almost looks like a smaller version, again, of something like a woven ox or type of syringe, but very clear instructions on there how to administer it, what you need. But again, pre filled syringes, remove them and give them yourself in one of a few different sites. And it does appear to be pretty straightforward. Dr. Sean Kane 10:57 So we mentioned that this is chronically taken. It's something that you don't take when you have a migraine, but to prevent migraines, we discussed how patient adherence may be a problem given that you have to give it subcutaneously as an injection. The one like caveat here is going to be that I think many patients that have disabling migraines may be more apt to take it if it works really well. So what kind of efficacy data. Do we have to really encourage patient compliance with this medication class? Speaker 1 11:25 So one thing that is, even, you know, after a month, you start to really see some benefit with it, that's kind of compared to things like, like with us, what I've seen clinically with Botox is that it usually takes a couple of cycles to really start to see a full benefit. But with these you see a decrease in headache days one month after use, which is definitely a good thing. And the only the kind of caveat is that it's not as if the current medications are stellar for migraine prevention. That's the one. And it says, well, we've got all these medications that are FDA approved. Do we really need another one? One estimate was found that less than 50% of those on preventative medications currently actually see a 50% reduction in migraine frequency. So many individuals currently on those treatments are kind of still seeing, you know, was it less than that? They're still having just just as many headaches. And so we do have goals. You know, if we can show that these medications actually have a pretty significant decrease in headache and frequency in terms of days in a month, that's a pretty big deal. And there's still plenty of room Dr. Sean Kane 12:21 on the market for that. Just to set the stage, what are some of the other agents that are commonly used for migraine prevention in patients like this? Speaker 2 12:31 So some current agents we normally use are topiramate, beta blockers, and venlafaxine — those are the majority of what I've seen used. Speaker 1 12:42 yeah, sometimes we also see, you know, Depakote has an FDA approval for valproic acid, but for tolerability reasons. That's not usually when a lot of patients like, oh yeah, give me a give me a big dose of Depakote, and then tricyclics as well. But again, as Dr. Mintz pointed out, and we have concerns with them, with beta blockers, exercise tolerance, bradycardia, I see that with number of individuals sexual dysfunction in our younger population is a big concern with SNRIs and TCAs, and then with topiramate specifically. Again, I work in a traumatic brain injury clinic, and we already have a lot of cognitive impairment or anxiety, which also contributes so more medications that can lead to word finding difficulties or some of that cognitive dulling, that's usually a no go for a lot of my patients. So again, not just, you know, if they can work, but if they can show a better tolerability. Again, there's, there may be a good role for them. Dr. Khyati Patel 13:30 So you said Aimovig, the new mAb, came out first in the market — if you can talk a little bit about its efficacy, because, you know, it's leader, and the trial design is a little bit different, and then the next one in the market learn something from the successes and challenges of the first drug. Speaker 2 13:47 Yeah, sure. So Aimovig (erenumab) was studied in both episodic and chronic migraine. So in terms of their episodic migraine study, they saw a decrease in both 70 milligrams and 140 milligrams of minus 3.2 migraines and minus 3.7 migraines per month, compared to placebo, which was minus 1.8 migraine days per month. So as you can see, there was a decrease in migraine headache days with both of these medications in terms of a 50% reduction in the mean migraine days per month from baseline to months four to six. We did see that the 70 milligram group had a 43.3% reduction, whereas the 140 milligram group had a 50% reduction as compared with a 26.6% reduction in placebo. So there definitely were some good responses seen here. Speaker 1 14:43 Yeah, again, we're getting kind of close to that 50% reduction goal, which seems to be one of the big targets. And the other thing to look at in these numbers, again, you know, 3.2 or 3.7 might so we're getting close to four migraines a month, depending upon the individual and the severity of their migraines. You know that could. Certainly have a clinical relevance for number of individuals, again, if somebody is having them, you know, every, every day, or, you know, most of the days. That may not be as much, but for number of individuals, that's, that's a pretty big deal. Dr. Sean Kane 15:12 And I love how studies like this give you kind of two different endpoints, right? So you have this, like continuous endpoint of mean or average number of days that you didn't have a migraine, or reduction in migraines, but then you also have this dichotomous yes, no, did you have clinically relevant reduction in your number of migraines? And this is cool, because sometimes in these studies, you just have a portion of patients that are just non responders, and they really mess up your average or your mean. But when you dichotomize that endpoint and say, You know what? Percent of patients had at least a 50% reduction, it gives you a better idea of, like, your typical response rate overall, when you compare a lot of different individuals. And again, numerically, you basically doubled your response rate versus placebo, going from roughly 25% to about 50% of patients having a good response to the medication. Yeah. Speaker 1 16:00 One other thing to note with this and the other ones moving forward, as far as inclusion, exclusion criteria, you know, individuals who didn't have a therapeutic response to two migraine preventative treatments with this medication, that was exclusion. Some of the other ones, it'll be two medications or three failures. But you know, to kind of tow it a little bit towards those that, or I should say, away from those who were non responders on a whole lot of medication classes. And that's, you know, that sometimes takes away a little bit of the clinical applicability, but it's fairly par for the course for a lot of a lot of conditions. So what about for chronic migraine? What was the data? Did it look the same as episodic migraine? Speaker 2 16:35 Yeah, so for chronic migraines, it actually saw a bigger decrease in days — in both the erenumab 70 mg and 140 mg groups we saw a 6.6‑day decrease versus 4.2 days with placebo. So it is kind of the same difference as compared to placebo. But as we are starting with more headache days for patients who do have chronic migraines as compared to episodic the decrease was bigger overall. Dr. Sean Kane 17:05 So we were saying, in chronic migraine, we measure like, how many days do you have a chronic migraine, and then how many fewer days did you have when we gave you the study drug, both Speaker 2 17:15 of the studies were looking at migraine headache days as their primary objective to see a decrease from baseline to either three months or six months in chronic migraine headache days, whereas their secondary endpoints were the percentage decrease from baseline. But again, Speaker 1 17:33 if you've got these chronic daily headaches, again, there's gonna be more room for adjustment in there, because you're starting off with a much higher number. Dr. Sean Kane 17:39 So I'm less familiar with the kind of terminology of migraines. I assumed migraines were migraines, but it sounds like we're we have a different study for episodic migraine versus chronic migraine. Can you just help me understand why do we need two different studies in these two apparently different types of migraines? Sure. Speaker 2 17:56 So chronic migraines are considered chronic when you're having 15 plus migraine headache days per month, whereas in an episodic migraine, you have anywhere from four to less than 15 migraine headache days per month. So there is a little bit of a discrepancy in how many days you're experiencing this migraine. Dr. Sean Kane 18:15 It sounds like in this chronic migraine trial, the baseline number of days was about 18 out of 30 days where these patients were having migraines in Speaker 2 18:24 Yeah, the baseline in the chronic migraine study here was 18 Dr. Sean Kane 18:28 days, which is pretty substantial. If you just think 18 out of 30 days, you're having headaches that are disabling enough that you want to enroll yourself in a trial to try to fix that problem. Speaker 2 18:38 Yeah, definitely. And that's why that decrease of 6.6 days can be pretty significant for someone who's struggling with migraines for more than half of the month. Dr. Khyati Patel 18:47 So the absolute difference we talked about between placebo and the drug was, what 2.5 days of reduction. If you're looking at a baseline of 18 days somebody is coming with that average what is, what is the clinical significance of reducing those days by 2.5 or three? Speaker 1 19:05 I think a couple of things. One is, you know, as a higher placebo response. Or, I think what it shows too is it's some of the, you know, we think placebo response in psychiatric studies. You think that sometimes just coming in, talking about things, kind of processing through itself is therapeutic. And so it kind of shows you there. I think some of the almost kind of, you can take and talk about, some of the non some of the non pharmacologic things that they may have been or just the being in the study that kind of helped, and so that's one piece of maybe explaining some of the placebo response. But I think from an individual standpoint, that that 2.5 days a month, again, I think it depends, but I think for some individuals that patients I talked to, that in and of itself, is a pretty big deal. But again, not for everyone. What do you think Dr. What do you think? Speaker 2 19:43 Dr. Mintz, yeah, I think that for people who are struggling with so many headaches per month and not going to work and missing days and not being very productive, I think just getting back two to three days per month can be pretty significant, especially for their quality of life. And the Speaker 1 19:59 other thing i. Sometimes look at too, is that's potentially 2.5 less days of an abortive medication, you know. So again, if we're trying to and out of that, they'll depend later on as we talk through what are the adverse effects of this medication. But in general, you know, if you are concerned about recurrent use of abortives, then if we can spare some of that use, then that can generally be a good thing. Dr. Sean Kane 20:20 I think part of this, too, is setting expectations for the patient. This is not going to get rid of all of your migraines, right? This is going to reduce it by a couple days per month of chronic migraine, so as long as the patient doesn't expect that, they just will be headache free indefinitely. I think that, you know, realistic expectations are really important here. All right, so we're ready to talk about Speaker 1 20:39 the next medication in the class. Let's move on. Yes, all right — so I think that the next one here is galcanezumab. This was studied in episodic migraine over six months. They really had two studies here, 800 to 900 patients. Typical patient had nine migraines a month. So again, still fitting within that episodic, not quite to that 15 are chronic, and excluded patients with history of failure to three or more classes. So again, it's been two to three with most of these medications that nothing surprising. Dr. Sean Kane 21:09 And just to highlight that, you know that means that in this type of study, they're getting rid of the patients that may be more refractory to therapy or patients that are harder to treat, which is kind of in their interest to prove that their drug is really effective. But then in clinical practice, when you see that patient that has failed a multitude of different therapies, they may not respond as well because they weren't the typical patient included in the trial totally. Speaker 1 21:30 And that's that's something we run into in our clinic, is those those failures and those that do. And so that has to eventually, hopefully be something that we do try to look at in these medications. But again, most companies aren't going to do it off the bat for an approval. They're going to do that once you get on the market, then we're going to start trying to push for the next steps. So what they found is, with 120 milligram dose, again, this is subcutaneous every month, found a 1.9 days decrease, about two days with 120 milligram about the same with a 240 milligram dose, 1.8 day reduction in number of migraines, both of them significant versus placebo and again, benefit seen after one month. So compared to something like Botox, that is, that is a little bit of a wrap, a more rapid reduction there and then, as with the other, they also looked at the data in terms of a dichotomy. So 50% reduction at six months. Did they have that? Yes or no, 120 milligram, 20.5% 240 milligram, those really not better at all, 19.2% placebo though, 8.9% so we're getting about double the the efficacy there compared to the placebo group, which pretty big deal. And then we're also looking and they did a second study, and in this one, though, the results were pretty much similar in terms of the relative numbers, but overall higher for every group. So placebo in the second study, 36% reduction. So I take that, and I think most individuals would take that, however, getting us, or 60% of them, on the medication, whether the 120 or the 240 milligram about 60% of individuals saw a 50% reduction in migraines. So you're more likely than not to see a 50% reduction according to that study. Again, that's the kind of number that I think gets a lot of attention for people that have frequent migraines. Dr. Sean Kane 23:15 Just to clarify in terms of number of migraines per month, those it was roughly two days fewer versus placebo. So again, we see a couple day decrease in terms of number of migraines per month, which you know, for this patient group, they're having slightly fewer migraines per month. So that's a pretty big deal for them and Speaker 1 23:33 Dr. Mintz, so what's the — what do we got for the third medication? Speaker 2 23:36 So our third medication, fremanezumab, was also studied in both episodic and chronic migraine. In episodic migraine study, it was given either monthly, quarterly or as compared to placebo. So this is our medication that can be used every three months as well. So here we had a mean number of headache days, starting with about nine. And this study actually included patients who were on preventative medications as well. So around 21% of them were receiving other preventative medications. Speaker 1 24:08 And that's, I think, something we were talking Dr. Kane before, is it's a little bit surprising. Though. You would think the number would be much higher for individuals that do have severe migraines. You would maybe think that the number of them would be coming in already on preventative medication. So that's a little bit surprising. Dr. Sean Kane 24:23 So it sounds like in the study, they probably had some more study designs in terms of the endpoints that they were looking at Correct. Speaker 2 24:29 Yeah, exactly. They looked at the same endpoint of migraine headache days per month as compared to placebo, and this one saw kind of similar results as well. With the monthly dosing, they saw a decrease of minus 1.5 days. And with the every three month dosing, they saw a decrease of minus 1.3 days as compared to placebo. In terms of the 50% reduction rate in monthly migraine days, the monthly saw 47.7% reduction rate, whereas the every three. Months saw 44.4% reduction rate, so pretty similar as compared to a 27.9% reduction in placebo. Dr. Sean Kane 25:08 So, you know, it's really difficult to compare apples to apples, where you can't take this study compare it to any of the other studies that we've talked about. But I think it's reasonable to say that a a roughly maybe doubling of your response rate is what you might expect, and roughly speaking, about one and a half to two days fewer migraines per month seems to be kind of the trend with most of this data here. Yeah. Speaker 2 25:31 For the most part, most of these medications seem to be as effective as each other. While they there are some differences in the study designs. For the most part, the responses seem pretty similar, right? Speaker 1 25:42 And again, unfortunately, since they're all against placebo, we don't have those comparisons to see what is it compared to, you know, on top of topiramate; although we do have some patients who are on preventative medications already, but we don't really have the data to say, you know, what's the incremental response on top of Topiramate or on top of propranolol? And again, the other interesting thing is, we talk about these, the average decrease in migraine days versus number more than 50% so a lot. So there's kind of the idea that a number of people, even though, on average, some of these numbers are a little bit lower, and on and a number of people are seeing a pretty significant Dr. Sean Kane 26:15 reduction, just to nerd out a little bit, so using that as an end point, right? So number of days with a migraine, it doesn't really capture like the severity of the migraine, right? So maybe some of these migraines are less severe when you're given this chronic medication, or maybe it is identical, and you would have to kind of dig into the data a little bit deeper if they do report that kind of an endpoint. So this is a good starting point, but there's other questions that I think that you could easily ask to delve deeper into the data. Dr. Khyati Patel 26:42 Yeah, and then kind of get more quality of life improvement, like those humanistic outcome times data as well. Yeah. Speaker 1 26:48 So for anyone doing study design something commonly the Sheehan disability scale is one that's commonly used in a lot of studies that I see for pain and also for psychiatric disorders. So that's for anyone designing studies things like that. Quality of Life metrics are pretty important. And so in the interest of time, I don't want to get in too much into some of the the scoring, but some of these studies, particularly the arise, study phase three for a runumab, did look at some of these humanistic outcomes, Dr. Patel, you were mentioning looking at, you know, physical function impact and diary scores and things like that. So again, if anyone was just want to look at that data. We're going to post that on our on our site as well, and so you can kind of take a look at some of those other outcomes. Dr. Khyati Patel 27:27 So I'm imagining that for this drug, the data for chronic migraine prevention were kind of in the same pattern as the other two that we discussed, correct, right? Speaker 1 27:37 So again, here we're talking about, you know, monthly, quarterly injections up from an azumab or placebo. Mean number of headache days here, interestingly enough, is 13. So kind of a little surprising, because Dr. Mintz, you were just saying 15 is kind of the bottom cut off for a chronic and so these individuals actually didn't quite meet that, which is interesting. Dr. Sean Kane 27:57 And this isn't that uncommon, that sometimes they will change some criteria to make it easier to enroll patients, or because they feel like their drug will look better if they slightly change your rules a little bit. And as providers, we just have to be aware that this may not meet the exact criteria that everyone follows. Speaker 1 28:14 All right. So with this one again, what do they find? Number of headache days per month. Quarterly injections decrease by 4.3 days. Monthly injection, 4.6 days. Placebo, 2.5 days. So again, depending upon the group we're looking at, somewhere between, you know, 1.8 day reduction to a 2.1 day reduction compared to placebo, and that was statistically significant. And with all the other studies, you're also looking at that 50% reduction in number of headache days per month here, we saw 38% reduction, around 40% with quarterly, about the same monthly, 41% and placebo, 18% so again, Dr. Kane, kind of looking at your you're doubling the response rate, as you mentioned, compared to placebo here. Speaker 2 28:55 And this trial also did allow for patients who were on medications prior they allowed up to a 30% of patients using a stable dose of one migraine preventative medication. And that can also possibly be the reason that their original number of headache days was lower. Dr. Sean Kane 29:15 And again, going back to like, who's included, it's just goofy to me that they would only allow about a third of their patients to be on a medication that treats the problem that they're trying to treat. I would assume that some patients may need kind of a multimodal therapy for chronic migraine prevention, and they're only allowing for a fraction of their study population to be eligible to have some of these other therapies. So again, it does lack some of this, like real world validity that we'd love to see, and maybe we'll see that down the road, now that the drugs are on the market with future studies, or even as phase four data. So it's great that these drugs appear to be effective. We'll call it a couple day reduction per month in migraines. We'll say roughly doubling your response rate in terms of a 50% reduction. And migraines, that's wonderful, but we already have drugs on the market that are effective for migraine prevention with the chink in their armor, that they typically have some side effects that patients are not excited about. And Dr. Schuman mentioned a number of those with beta blockers. With TCAS SNRIs, we have problems with those. So hopefully these new drugs that if we're going to give subcutaneous injections to a patient, it better be tolerable enough that they're excited about that efficacy profile. Speaker 2 30:27 Yeah, definitely. So in terms of safety, these seem to be pretty safe, but to put that in reference, they have only been studied for up to six months, so we don't have any long term safety data. We don't have any real world data at this point yet, but in terms of the trials, for the most part, we just saw injection-site reactions; fremanezumab showed some transient LFT elevations. So they do appear to be very tolerable and safe. Speaker 1 30:56 Yeah, I think those transient LFT elevations — you may just want to be careful again, only because that's been part of the history of this class of medication. CGRP is not exclusive to the brain, and since you know these previous ones in the gepen class, some of them are knocked out for that reason, I would probably want to be a little bit cautious, and I definitely want to see more data on that Dr. Sean Kane 31:16 so we don't observe any cognitive impairment with these drugs or anything that would be CNS oriented. Speaker 1 31:23 Then no. And that's been again, that's, you know, so far. You know, I always want to kind of wait for the other shoe to fall. But thus far, it has been really good. And one kind of cool thing we can do to look at this is something called the likelihood to help or harm, or the Lhh. It's really just a ratio of the number needed to harm over the number needed to treat. But it kind of lets you know where these drugs fall as far as for some of their side effects versus the number needed to treat in these and so an example of it, something like two to three would be a number four or two to four with like to pyramid propranolol or Botox. So they're you know, if you look at the side effect, the most common side effect, versus the likelihood of people responding, they're two to three times more likely to help you than they are to cause that side effect in question. Dr. Khyati Patel 32:06 I really like this scale, because we always talk about choosing, you know, benefits versus risk, and applying that principle when we're picking a therapy for a patient. So I really like the concept of Lhh, that you Speaker 1 32:17 Yes — definitely a shout out to Dr. Citrome. Dr. Citrome has been a big advocate for this in the realm of psychiatric/psychotropic meds. But this is really the first time I'd seen it in migraines. For example, comparison with erenumab showed the LHH was generally above 140 in some analyses. One of the studies, it was in the 40s. The others, it was 140s 140s even 160s so just to further show you the, you know, the the relatively low number needed to treat and number needed to harm with these showed a fair amount of tolerability, Dr. Sean Kane 32:45 so indicating that this has a more favorable ratio than some of these other therapies that are on the market. Yeah, it's Unknown Speaker 32:51 which I think is, again, a very great thing. Dr. Khyati Patel 32:53 So earlier we talked about that CGRP, in itself, is a vasodilator. Here are we talking about drugs that were antagonize the effect of CGRP. So what would be its effect when it comes to some of the ischemic diseases such as stroke or heart attack? Dr. Sean Kane 33:09 And this comes up all the time with trip tans, right? We have patients with hypertension or history of MI that aren't eligible for trip tans because of its vasoconstrictive effect, yeah. Speaker 2 33:18 So definitely, based on its mechanism, that can be a perceived risk, while we haven't seen any data showing that risk, per se, by blocking the protective role of vasodilation in preventing stroden and heart attack. Down the line, we might see more problems arise, but at this time, there's no documented data to show that these have that these have these risks. Dr. Khyati Patel 33:44 So basically, by antagonizing CGRP, we're not talking about causing vasoconstriction, and that Speaker 1 33:50 does not seem to be thus far. So what they did is, there's been a little bit of data when in vitro story where they isolate, I'm pretty sure they just plucked out human coronary arteries and they injected the drug to see what that would do, and they did not see the as a constriction there. There was then another study that came out pretty recently looking at exercise treadmill tests, which is a surrogate now. Dr. Kane, thank you. Favorite Words, yep, yep. Marker for tolerance to myocardial infarction. They noted two cases of angina in the erenumab group, but overall no differences in exercise treadmill time or related outcomes compared with placebo. Dr. Sean Kane 34:25 And even if you look at like the warnings section on the package insert for these products, they don't carry any warnings about any perceived risk of cardiovascular disease or anything like that. So if the effect is there, it's either really, really small, or we just haven't seen it yet because of, you know, six month duration trials. Speaker 1 34:43 And that's going to be my only hesitation again, is one is just again, with the trip 10s, and knowing some of that history there, I think that is going to be something to watch for. But again, the other attractive thing, serotonin syndrome. We don't have a signal for serotonin syndrome here, which shouldn't be an issue in the first place, but that's. Has a lot of providers under treating patients because of that fear of an interaction, and we can certainly wipe that out, hopefully here by being, you know, it's not the same thing, even though it has that similar pathway. Again, we're not talking serotonin receptors, so Dr. Sean Kane 35:12 it sounds like there's only one side effect left then, and that's the side effect of cost, right, right? Dr. Khyati Patel 35:17 As I'm rubbing my hands over here, you know, that's what I'm trying to signify, anytime we're talking about MAbs and injectable medication, we're looking at big bugs, Speaker 1 35:26 and so unfortunately, when you when you look at it initially, the list price for amovig that was released by the company when it first came out is $600 for a once monthly injection, or about $6,900 annually. Now I do know the company is early on working with insurance providers giving essentially a year of coverage of the medication until individuals can work with their insurance and do prior offs and all that. But yeah, that is certainly not a small, small thing. Dr. Sean Kane 35:54 And you know, it is reasonable that prices will come down with competition. We already have three drugs on the market now, so those prices may drop over time. Manufacturers typically offer coupons and patient‑assistance programs, and a trial sample can make sense to see whether a patient responds. Speaker 2 36:21 Yeah, exactly. And I think for the most part, all three of the approved ones are providing some sort of patient assistance programs. Dr. Sean Kane 36:29 So to summarize, again, with without having a good feel for this drug class or the drugs in the market, I would love kind of a pronunciation guide and kind of a summary of what we have on the market currently, as of recording this episode in mid October 2018, Speaker 2 36:43 so currently we have those three medications that we've spoken about: erenumab (Aimovig), galcanezumab (Emgality), and fremanezumab (Ajovy). Dr. Sean Kane 36:56 And then, just to reiterate, all of these are subcutaneous injections. Most of them are given monthly, with feminismab, having the option of giving it every three months or quarterly. And it's really important for providers to understand that this is not a PRN medication. These are taken chronically to prevent migraines from occurring in the future, a prophylactic regimen, as opposed to a treatment regimen to treat a currently ongoing migraine correct? Dr. Khyati Patel 37:21 And most of these studies were looking at efficacy outcomes of total number of migraine day reduction as well as, are we preventing these migraines by at least 50% and total number of migraine prevention were on average. You know, we can't compare these study head to head, but anywhere between 1.5 to 2.5 days. And then as far as the 50% reduction and migraine all over we saw that these drugs were almost double the rate of placebo. Dr. Sean Kane 37:52 I think that wraps things up very nicely again. Currently, our website is kind of on lockdown because of an accreditation visit, but as of mid November, we'll be able to update with show notes that will have some links to the phase three trials of these drugs. We're also on Twitter at HelixTalk, where we release new episode notifications as well as kind of tips from older episodes that have come out some of the key points. So with that, I'm Dr. Kane. Unknown Speaker 38:16 I'm Dr. Mintz. Dr. Khyati Patel 38:18 We had Dr. Schuman, who had to run for a lecture, and I'm Dr. Patel, and as always, study hard. Narrator - Dr. Abel 38:24 If you enjoyed the show, please help us climb the iTunes rankings for medical podcasts by giving us a five star review in the iTunes Store. Search for HelixTalk and place your review there Narrator - ? 38:35 to suggest an episode or contact us. We're online at HelixTalk.com thank you for listening to this episode of HelixTalk. This is an educational production copyright Rosalind Franklin University of Medicine and Science.