TRANSCRIPT:

Voice-over: Welcome to Spotlight on Migraine hosted by the Association of Migraine Disorders. Join us for fresh perspectives by medical experts and advocates as we explore the spectrum of migraine and dig deeper into this complex disease. This episode is brought to you, in part, by our generous sponsors, Biohaven and Impel Pharmaceuticals. 

In this episode, Dr. Timothy Smith joins us to talk about zavegepant, a new option from the gepants class of medications that blocks CGRP. It is currently being studied as a nasal spray and oral gel cap for the acute and preventive treatment of migraine.

Dr. Timothy Smith: Hello, everyone, this is Tim Smith from St. Louis. I’ll be talking with you today about zavegepant. It’s an investigational product that is undergoing research for treatment of migraine. You may have heard about some of the topline results from an acute nasal spray version of this product that has been recently published for acute therapy. But the product is also entering into studies for prevention. 

We’ll start by kind of framing things in the context of what’s been going on for the last few years, and I tell people that we’re in the middle of a 5-, maybe 6-year cycle of new treatment approvals. I think this began in 2018 or so with the CGRP monoclonals, and new products have been entering the market since that time and more to come. And you can see I’ve outlined that there is 7 new preventives, 11 new acute abortive therapies or combination therapies or new delivery system, and then some neuromodulation devices also coming to the market for migraine management. 

And also, from a very exciting standpoint, there are at least 9 future molecular targets that are creeping towards the development phase, and we’ll be doing clinical trials on some of those candidates, I think, over the coming years. So, it could be that the best is yet to come. It’s very exciting. When we take a deeper dive into looking at the preventive therapies and this new development cycle and these new products coming onto the market, most of us are familiar by now with the CGRP monoclonal antibodies. There are 4 of them that are marketed for migraine prophylaxis. They all work well and are well tolerated. 

And then, we have 3 small molecule CGRP blockers – we call them the gepants. Rimegepant or Nurtec ODT is already FDA approved for regular use as a preventive. Atogepant is pending approval at this time, probably approved by September of 2021. And then our topic of the day is zavegepant, which is currently under study, and we’ll talk a little bit more about that as we move along. 

So let’s drill down into the gepants a little bit and mostly focusing on the gepants for prophylaxis. We know that ubrogepant and rimegepant have been approved for acute therapy, but we want to talk about preventive therapy primarily. And when we look at these 3 candidates or 3 molecules that we’re looking at, rimegepant is already marketed and FDA approved as a migraine preventive. And then we have atogepant coming to the market soon, and then zavegepant is just now getting underway with the studies. 

These are all orally administered gepant drugs. Patients should take them on a regular basis, and they block CGRP receptors. And the cool thing is, at least in theory, these small molecular weight agents may get to CGRP receptors, may reach some receptors that are not reached by monoclonal antibodies. So we’re hopeful that maybe they can have some added benefit to our patients. And importantly, there are no significant liver enzyme abnormalities for any of these 3 molecules, and that’s important because the first-generation gepant molecules, telcagepant and olcegepant, had liver enzyme problems and never got to the marketplace. But these 3 products look very clean so far. 

Just a quick snapshot of atogepant. It’s an oral swallowed tablet taken 60 mg daily. We think it’ll be marketed in Q3 of 2021, probably September. It has excellent tolerability. Some adverse events have been reported, and you see them listed there – nausea, fatigue, constipation, nasopharyngitis, and urinary tract infection. These were in low numbers but did show up in the clinical trial process. The liver enzymes looked great, though, and there’s a fairly benign drug interaction profile. 

With rimegepant, we know it was first approved for abortive therapy but was just market approved in the spring of 2021 and is approved as a 75 mg every other day dosing regimen. And in the studies, we allowed patients to take an additional dose on a non-dosing day if they had a breakthrough migraine attack. And we saw that the topline results were positive with about 5 migraine days per month being reduced for those patients in the study. Tolerability, liver enzymes looked great. Longer-term safety analysis has been completed; did not identify any new problems.

So onto zavegepant, this we refer to as a third-generation CGRP receptor antagonist. And basically, Biohaven, the company that owns the rights to an is conducting studies on zavegepant, have modified the basic CGRP antagonist molecule to make it amendable to some different modes of delivery, including nasal spray, injection, orally disintegrating tablet, and an oral soft gel capsule, which we think gives us our best potential for preventive therapies, and that’s the one we’re going to talk about a little more in depth as we go on. 

You may have heard of zavegepant under other names. The BHV-3500 was the original call sign that was given to the drug. And then zavegepant was the original plan, but through some international rules, that was changed around and zavegepant has been approved by both the US and world authorities as the official chemical name. And you can see I put the chemical structure of rimegepant on the left and then zavegepant on the right. You can see they don’t look very similar. There’s one strand through each side that looks similar and then the side chains that branch off from the main molecule makes a little bit of difference in how the drug is handled in the body, but it still affects the CGRP receptor in a highly effective way. 

So, just a word about the nasal spray because we do have data on this. This would not be used as a preventive therapy. It’s being investigated as an abortive therapy. We know that this drug gets absorbed well across the nasal membranes, and this gives you the chance to avoid gastrointestinal absorptions and metabolism by the liver on the first pass effect. So that should help improve speed of onset, and we think that this could be beneficial for our patients that have really rapidly progressing migraines, patients that have a lot of nausea or gastric stasis with their migraine attacks, and patients that just don’t respond very well to oral treatments. 

And we think that crossing those mucosal membranes gets this product into the bloodstream more quickly. Some scientists think that nasally administered drugs could be carried along the olfactory nerves straight to the brain, and I refer to it as sort of the superhighway to the brain. But that leaves a lot to be desired in terms of data or proof regarding that. I will mention, just as a passing note, that zavegepant nasal spray is currently being studied for management of the severe acute respiratory distress syndrome with COVID-19. It’s been shown that CGRP may be part of the inflammation cascade that causes pulmonary inflammation and causes these people to have severe respiratory distress. And so, that study is still ongoing, and we’re waiting for data on it. 

So in the clinical trials for the nasal spray – not to belabor the point – we studied 5, 10, and 20 mg for acute migraine in a study of over 2,000 volunteers with the coprimary endpoints of 2 hour pain freedom and freedom from the most bothersome non-pain symptom to include nausea with or without vomiting, light, and noise sensitivity. And the study showed that 10 mg and 20 mg were both superior to placebo. There was relief – that means going from a moderate to severe headache attack to mild or none – we saw relief at 15 minutes in this study and returned to normal function as quickly as 30 minutes. 

And the 10-mg dose was selected for subsequent pivotal trials which have recently been completed. And you can see the topline results here: pain freedom at 2 hours, those P values – I won’t bore you with the science statistics – that clearly shows that the 10 and 20 mg dose is very much separate from placebo, and that’s the topline results from the acute therapy. 

Let’s talk about the oral gel caps. So this is the newest thing for zavegepant. We’re looking at oral gel capsules taken daily as a preventive. A Phase 1 study identified 100 mg and 200 mg as the best oral doses to study. And a pivotal trial just go underway this year; it’s called BHV-3500 302 trial. It’s a Phase 2/3 randomized, placebo-controlled clinical trial. Almost 3,000 subjects will be studied at multiple centers across the country. There’ll be 3 treat arms: placebo versus 100 mg versus 200 mg. and the patients that volunteer will be treated in a double-blind phase that lasts 12 weeks and then an open-label extension to follow. 

The primary endpoint will be reduction migraine days comparing the baseline, the month before they start on drug, versus the third month of being on drug – so weeks 9 through 12 – and this has been a standard prophylaxis effectiveness measurement model. And then I’ll just throw in the extra comment there, at the bottom, that the company is planning an asthma study in Canada, and that will be kicking off soon, and this is because they are looking at CGRP as a proinflammatory substance or marker in asthma attacks. 

But back to our interest in headache. This is just some information about zavegepant, just sort of a profile of the medication. We have adverse event data that comes from the nasal spray study. We’re still waiting for adverse event data from the oral study as it goes on. But you can see that the ones that separated from placebo here were abnormal taste and nasal discomfort, and this has more to do with the nasal administration method for the medication. 

We know that zavegepant is 10,000 times more selective for CGRP receptors compared to other calcitonin family receptors, and this would include amylin and calcitonin and adrenomedullin. Just kind of some scientific jargon there for you, but basically what we’re saying is that this molecule is highly selective just for CGRP receptors, and that should help it focus only on those receptors and cause and we can have confidence that we won’t have any unintended effects. As you compare, rimegepant is said to be about 65 times more selective for CGRP receptors, which it has a very clean side effect profile as well. So, whether this will make a big difference for zavegepant we don’t know yet, but it is a compelling statistic or point of information there about the 10,000 times more selective for CGRP receptors. 

Pharmacokinetically it’s excreted primarily unchanged, mostly in the urine. This means there will be less potential for drug interactions, for some liver enzyme interference, etc. It has no significant impact on efflux transporters, and this is just another mechanism of how medications are handled in the body. Some drugs that will impair or inhibit these molecules that transport drugs or medicines from one compartment to another, if there is an inhibition of that, then it can cause drug interactions or toxicities. And since zavegepant has not been shown to have a significant effect on those transporters, then perhaps that’ll lead to drug interactions as well. 

Interestingly, if we look at bioavailability of this compound, the internasal bioavailability is about 10 times greater than the oral bioavailability. That’s why the 100 to 200 mg dose orally is being selected for the future studies. Half-life there’s a wide range in the reported numbers on that, and it depends greatly on the route of administration and the animal model in which it was looked at but anywhere from 2.5 up to 19 hours. Comparatively, we know that rimegepant has a half-life of about 11 hours. So, perhaps this will be a positive profile for zavegepant to be taken regularly as a preventive. And I just reiterate the Phase 1 pharmacokinetic study that showed that at 100- or 200-mg dose, our best guess is going to be what works for patients in the study. 

So, we’re really waiting for the clinical data to come through the current clinical trials. We don’t have a whole lot else to offer, but we can look at the molecule, understand how it works, and what some of the potential advantages of a third-generation gepant might bring to the market. What we don’t know is can the acute gepants be used along with zavegepant as a preventive? We also don’t know how it will compare to atogepant or rimegepant, the other gepants that either are approved or will likely soon be approved for use. 

And will the dosing on this be daily? And that’s what we’re thinking at this time, but we need to wait for the data to show if that’s going to be the most efficacious way to use it. We also have interest in learning about the drug’s side effect profile. Will it be different from the other gepants? Will it work better than the monoclonal antibodies, for example, for prevention. We also are interested in the drug interaction issues with zavegepant. But as I just reviewed, there may be some advantages to the way this product is processed through the body that may have fewer drug interactions as it plays out. But we’ll have to let that data come to us. 

And then ultimately, if we have zavegepant FDA approved as a nasal spray for an acute abortive therapy, and it’s approved as an oral gel cap for prevention, would you use those together? Could you use the other gepants with it? And these are questions that we really don’t know how to answer at this moment, and the current clinical trials may not answer. 

Well that’s what we know about zavegepant for oral prophylaxis for migraine. And I appreciate your attention today and look forward to interacting with you soon. 

Voice-over: Thank you for tuning into Spotlight on Migraine. For more information on migraine disease, please visit MigraineDisorders.org. 

*The contents of this podcast are intended for general informational purposes only and do not constitute professional medical advice, diagnosis, or treatment. Always seek the advice of a physician or other qualified health provider with any questions you may have regarding a medical condition. The speaker does not recommend or endorse any specific course of treatment, products, procedures, opinions, or other information that may be mentioned. Reliance on any information provided by this content is solely at your own risk.