The director of the Dartmouth Headache Clinic at Dartmouth-Hitchcock Medical Center spoke about the potential of a DHE therapy for acute migraine treatment.
Stewart Tepper, MD
The migraine space has observed a huge bump in excitement this year, with the first preventive agent gaining approval.
Although the calcitonin gene-related peptide (CGRP) inhibitors have proven in trials to be highly effective, as Stewart Tepper, MD, pointed out, the majority of patients who will benefit from them will still require acute therapies.
The director of the Dartmouth Headache Clinic at Dartmouth-Hitchcock Medical Center, has been involved in the treatment of the headache condition for quite some time, including work on clinical trials of dihydroergotamine (DHE) agents, not unlike the intranasal product currently being tested by Impel Neuropharma.
Tepper spoke with NeurologyLive to provide some further insight into what’s currently known about DHE agents, and what to expect from the one being tested.
Stewart Tepper, MD: We have the migraine Migranal Valeant product which has been on the market for 20 years, so we know that a nasal delivery system for DHE does work.
The inhaled route is being avoided because of the problems in the device manufacturing that had occurred with the MAP product, so any consideration for developing a new orally inhaled DHE was probably tarred by the same brush. There was an orally inhaled ergotamine in the 1980s, now off the market. It was my understanding that the FDA wanted to inspect the manufacturing plant at that time, and it was difficult to get the ergot into the inhaler properly. It is tricky to put an ergot into an inhaler. Ergots are big molecules and have some instability. For all of those reasons I think startups decided not to proceed with another inhaled DHE.
Startups can proceed with a DHE autoinjector. I’m aware of at least 2 companies that are working on simple-to-use autoinjectors for home use.
Nasal DHE development has also proceeded. Impel has a provisional device called a POD and uses an HFA propellant. They were able to prove in their pharmacokinetic trials that using the HFA propellant pushes the DHE high up into the nose. The top of the olfactory passages is very capillary rich and is very satisfactory for drug absorption. For example, there is a dry sumatriptan nasal powder which is breath propelled in which the patient blows the sumatriptan up the nose, marketed as Onzetra. It is very well absorbed and has minimal adverse events. Liquid nasal sumatriptan can taste very bad, but Onzetra has a mild taste because it’s blown so high up the nose and absorbed so well. The Impel designers essentially said, “We can do that with DHE; all we have to do is propel it with an HFA propellant.”
They then worked with the manufacturer of the Migranal glass ampule to develop their own DHE in a vial, that consists of liquid DHE. This vial is then attached with their HFA propellant device on top of it, and had patients put it in the nose, press down on the actuator and, administer the DHE high up in the nasal passages. All of that was set up to make DHE administration easy and allow for a very rapid drug development timeline.
What the FDA has allowed, since DHE is such an old drug and since Impel is using the Migranal product, is for the developers to prove biologic equivalence. The FDA wanted a Phase I, healthy volunteer study looking at the pharmacokinetics of the Impel device compared with parenteral and liquid nasal DHE. This crossover study was presented at the American Headache Society meeting in June.
They compared the pharmacokinetics of the Impel DHE, of Migranal liquid nasal DHE, and of intravenous DHE, and were able to show that the Tmax, the time to maximal serum concentration for the Impel product was seen in thirty minutes, with clinically meaningful levels at 10-20 minutes, while the Cmax, the maximal serum concentration, was less than that of intravenous DHE, but four-times higher than that of nasal DHE. They anticipated with the quick Tmax and the intermediate Cmax, that the Impel product will be more comparable clinically to intravenous DHE on efficacy.
All subjects were treated with an anti-nauseant in the trial. There was no vomiting with the new device, but there were still 3 people who received intravenous DHE who vomited. The absence of vomiting may be due to the maximum serum concentration being than that of intravenous DHE, which is nauseating and which we always pre-treat with anti-nausea medicine.
That was the first study on the new nasal DHE device and given the comparable pharmacokinetics and the modest adverse events, the next step is a safety study. The current study is an open-label study which will go 6 months or 12 months, in which patients with episodic migraine (2 to 14 days of migraine per month) can use the new POD DHE as their acute medication through the Impel device. Patients will use it to terminate their attacks instead of taking a triptan or using other products that are currently available. There will be periodic evaluations by ear, nose, and throat doctors (ENTs) in the nasal cavities of these patients for adverse events associated with DHE use. Patients will also be evaluated for olfaction.
The FDA may approve the Impel nasal DHE based on safety and pharmacokinetics. As noted, DHE is an old drug, and Impel is using an existing FDA-approved nasal formulation. Submission to the FDA is likely to occur in 2019.
One of the questions with the Impel device is, will this startup ever even bother doing an efficacy study? I suspect they probably will. They don’t need to from a regulatory standpoint, those of us who use DHE a lot in headache medicine, would like to teach our general neurology colleagues about the utility of having a user-friendly DHE at home. The MAP inhaled DHE was a completely new delivery system to a new organ system—the lungs—so the FDA required a full, phase III, randomized, controlled trial for safety and efficacy and a safety extension trial of a year’s duration, different than what is being required for the Impel device.
Let’s assume that the Impel nasal DHE with the HFA propellant is close to as effective as IV DHE, and that the adverse events are generally tolerable, that patients sometimes may need anti-nausea treatment, but many times don’t, and that safety is demonstrated. Then, the question becomes, when do patients use DHE?
There are many clinical situations for using DHE:
Another issue in migraine treatment is acute medication formulation. The Impel device is a formulation that bypasses the gut, so people who don’t do well with oral drugs because they have a quick time to vomiting or because they are nauseated could find a nasal formulation is a reasonable alternative.
The easy answer for the general neurologist is that acute medicines and preventive medicines have been different. The monoclonal antibodies are delivered once a month for prevention, and they can naturally convert patients from chronic migraine to episodic migraine. This has been documented, for example, with erenumab. Patients will start off with more than 15 headache days a month and after 12 weeks, or 1 year, or 3 years with erenumab, significant percentages of them drop below 15 headache days per month and have much more standard episodic migraine patterns. But, the monoclonal antibodies don’t treat the attacks acutely. Patients on these monoclonal antibodies, almost all, are going to require acute medicines. A few of them, a very few of them, get a 100% response and stop having attacks completely. But even patients who get a 100% response from a monoclonal antibody 1 month may not get a 100% response the next month and have a breakthrough migraine or 2.
Every single migraine patient treated with the monoclonal antibodies is going to need acute medication to treat their attacks. Then, you’re in the same old ballpark. If the attack is a morning migraine, if the attack is a menstrual migraine, the patient is going to need something which optimally gives them what is a sustained pain-free response. You want them to be able to take the acute medicine, be pain free within 2 hours without significant adverse events, and most of the time not get a recurrence. If they end up chasing a prolonged attack with the triptans, then DHE becomes a reasonable alternative for them.
Muddying the waters is that, in addition to the monoclonal antibodies, gepants, small CGRP molecule receptor antagonists, have been developed. Here is where the acute and preventive definitions and categories blur, because gepants can be used acutely to treat migraine, and they work. In fact, 7 of them have been tested, and all of them worked acutely. But gepants can also be used daily for prevention of migraine. Allergan released data at the AHS meeting that atogepant worked pretty comparably to galcanezumab in episodic migraine reduction without significant adverse events. Biohaven presented two positive Phase 3 trials for acute treatment of episodic migraine attacks with rimegepant. They announced that they are going to study rimegepant daily for prevention of migraine. In that situation, you can imagine that someone would take 75 mg of rimegepant daily, and then if they got a breakthrough, take extra rimegepant, which is a very different way to approach prevention and acute treatment.
There are 2 new categories of acute medications, the gepants and also a serotonin-1F agonist called lasmiditan, which is an Eli Lilly drug. Neither the gepants nor lasmiditan cause vasoconstriction, and they both work for acute treatment of migraine. Ergots and triptans cause vasoconstriction, and patients with vascular disease or multiple risk factors for vascular disease will not be able to use DHE or triptans. They’ll go to these new categories of gepants or lasmiditan.
It’s a watershed moment. I’ve been a headache medicine doctor since 1986, and this is the most exciting time. What is happening in headache therapeutics is marvelous and I’m so happy for my patients. It’s truly the ground shaking under our feet.
With all of these new developments one might think that having a new formulation of DHE would be small potatoes. But having a new formulation of DHE is really important for our clinical practice. Having a reasonably priced, accessible home use DHE formulation that works similarly to intravenous and which has minimal adverse events would be enormously helpful for our patients. That’s why we were so excited about the MAP orally inhaled DHE and why we were so bitterly upset about the termination of that drug development.
The general neurologist will notice the magnitude of changes in headache treatment. They’re going to find out that as long as they get prior authorization, it’s going to be easy to prescribe monoclonal antibodies, the new categories are very helpful, and the new formulations of existing medications are going to be very useful. These developments will transform general neurology practice in terms of migraine management.
Transcript edited for clarity.