As a phase III trial of DHE gets underway, the director of the Dartmouth Headache Clinic at Dartmouth-Hitchcock Medical Center spoke about its clinical history in the United States.
Stewart Tepper, MD
Last month, Impel Neuropharma announced that the first patient had been dosed in a phase III trial evaluating INP104, an intranasal dihydroergotamine (DHE) mesylate delivered via a precision olfactory delivery (POD) device, in acute migraine treatment.
Although DHE has had a longstanding place in migraine treatment, with the recent introduction of multiple new preventive agents in the space, much excitement has been building around the condition. Stewart Tepper, MD, 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 DHE agents. Tepper told NeurologyLive that a home-delivery system for DHE would be yet another agent to get excited about.
To provide some insight into the clinical background of DHE use, the professor of neurology at the Geisel School of Medicine at Dartmouth spoke about the history of its therapeutic use.
Stewart Tepper, MD: Ergots were derivatives of a mold, primarily a bread or a rye mold, called Claviceps purpurea. Early in the 20th century, it was found that ergots were oxytocics, and they clamp down the uterus after pregnancy, so derivatives of ergots were used for that purpose initially. Then, gradually, primarily at a lab in Switzerland—the Sandoz Lab—derivatives of ergots were created for other medicinal purposes, and these included ergotamine, which is currently available as Cafergot, dihydroergotamine (DHE), a variety of drugs for pituitary tumors and Parkinson’s such as bromocriptine and pergolide, and most infamously—and very closely related chemically to DHE—LSD or lysergic acid diethylamide. All of these ergots are chemically related, they all have pro- and anti-serotonin receptor effects, and they also interact with other receptors.
DHE, dihydroergotamine, was first released in the US around 1945 when it was called DHE-45. It was available in a paranal form, intravenous, intramuscular, and subcutaneously. Up until the 1990s, that was the only form of DHE in the US. In Europe, DHE was available orally to increase blood pressure. There is another ergot, ergonovine, which was used by cardiologists to induce cardiac vasospasm in people with Prinzmetal angina. Methylergonovine (Methergine) is still available in the US and is used specifically to constrict the uterus post-partum.
After DHE was synthesized by Sandoz, they synthesized the first designer drug for migraine prevention, which was an ergot called methysergide (Sansert). It was a very useful, very powerful migraine preventive agent, but it had an unfortunate adverse effect, which was that about 1 in 1,500 patients exposed to it for 6 months or longer developed idiopathic fibrotic complications, including fibrosis of coronary ostia, the lungs, or the GI tract. These fibrotic complications were life-threatening, and Sansert was removed from the market eventually. Ergotamine tartrate itself can cause fibrotic complications and is very habit-forming. DHE is probably not habit-forming, and with DHE the risk of fibrotic complications, if any, are rare. There have been 2 cases reported of people using oral DHE daily for years who developed fibrotic complications.
DHE became the chemical backbone from which the triptans were derived, and Pat Humphrey, PhD, DSc, who at that time was at GlaxoSmithKline, in the 1980s, took what he thought was the active portion of DHE and purified it and synthesized specific serotonin 1B/1D agonists, the triptans. The triptans were the first designer acute medications for migraine and were, therefore, derivatives of DHE.
In the US, we began to use DHE in the mid-1980s when Neil Raskin, MD, at the University of California San Francisco championed DHE use, although it had been used internationally for quite a while. We found in the 1980s that DHE could be used intravenously to terminate refractory migraine, migraine that wouldn’t quit, chronic migraine, and people who were in medication overuse. Intravenous DHE became a bridge to terminate bad migraine in the hospital and is still used this way. At Dartmouth, we still admit people every week or 2 to receive intravenous DHE to terminate difficult to treat migraine, to give us a tool, a bridge, to get people through withdrawal from overuse of medicines, or to stop or reduce chronic migraine so that we can get regular prevention on board. DHE also turned out to be effective in terminating cluster headache, and it is FDA approved for that as well.
Since the 1980s, we have taught patients how to inject subcutaneously or intramuscularly at home, but when the triptans became available they partially swept away DHE because they came in oral formulations. However, in the early 1990s, DHE was formulated by what Sandoz had become—Novartis—into a nasal DHE, and I was part of the trials for that nasal DHE. The currently available nasal DHE is a liquid with a nasal administrator spayed into the nose. It is called Migranal and is currently marketed by Valeant. Migranal is exceedingly expensive, even in its generic form, and is very often difficult for patients to get. It’s also very user unfriendly. It comes in a glass ampule with a tin top. Patients have to peel off the tin top, remove a rubber stopper, remove the bottom of the nasal applicator and screw it on, remember to take the top off the nasal applicator, spray it 4 times in the air to prime it, spray it in each nostril but not sniff it, wait 15 minutes and spray it again in each nostril. If they do all of these steps right, then Migranal can be effective at terminating migraine and can behave like a DHE injection. But it causes nasal stuffiness, it’s very inconvenient to use, and it is very difficult to obtain because it is usually prohibitive in price.
Clinically, as of September 2018, we use intravenous DHE, which is also very expensive, and we teach patients how to self-inject—there is no autoinjector. If the patients are lucky, they can get their hands on Migranal, and if they’re also lucky it doesn’t cause nasal stuffiness, and if they’re also lucky it works, and that is the current situation for DHE use at home.
A clinician may ask, why bother with DHE? We have 7 triptans, so why use this old drug? The answer is that DHE has some very unusual properties that differentiate it from triptans. Those properties include:
These reasons are why we really would like a home DHE that isn’t exorbitantly priced, that has a chance to work and is user-friendly. There have been multiple attempts to do this. Migranal was the first attempt, but the second was by a company in Northern California, a startup called MAP, who they created a novel inhaler and an inhalable DHE that worked great and met all of the 4 FDA-required primary co-endpoints. MAP was sold to Allergan, and there was a problem in the manufacturing of the inhaler, which was the end of DHE inhaler. This was very sad. I was one of the investigators on those trials, and that device worked well, and there were no concerns on safety or efficacy. The death of the orally inhaled DHE was entirely due to inhaler design/manufacturing issues.
Interestingly, 2 of those who helped develop the oral DHE inhaler are now trying to develop a new nasal DHE with a new startup company, Impel. There are 4 companies that I’m aware of that are developing different kinds of home-use DHE devices, of which Impel is the furthest along in development.
Transcript edited for clarity.