An intranasal formulation of dihydroergotamine (DHE) for the acute treatment of migraine is safe and well tolerated, new research suggests.
Initial results from the phase 3 STOP 301 trial were presented last year at the virtual annual meeting of the American Headache Society.
Additional findings were published online August 7 in Headache ahead of the Prescription Drug User Fee Act date on September 6 for the DHE formulation known as INP104 (Impel NeuroPharma).
The open-label safety and tolerability trial included more than 300 patients who self-administered INP104 for up to 52 weeks. Results showed that 37% reported INP104-related treatment-emergent adverse events (TEAEs). However "no new safety signals" were observed for the delivery system, the researchers note.
In addition, an exploratory analysis showed treatment efficacy for outcomes such as pain relief and freedom from the most bothersome symptom.
"No one else has gone into the upper nasal space," co-investigator Sheena K. Aurora, MD, vice president of medical affairs at Impel NeuroPharma, Seattle, Washington, told Medscape Medical News.
"We had to establish that DHE would be safe there," Aurora added.
The STOP 301 trial included 354 patients with episodic migraine with or without aura. After a baseline period, patients were trained to use the Precision Olfactory Delivery (POD) technology that delivers the drug to the upper nasal space.
For 24 weeks, participants self-administered INP104 using the POD technology during migraine attacks. Afterward, a subset of participants entered a 28-week treatment continuation period.
About 68% of patients reported TEAEs during the 24-week period; and 36.7% reported TEAEs related to INP104, with the most common being nasal congestion (15%), nausea (6.8%), nasal discomfort (5.1%), and abnormal taste (5.1%). During the 52-week period, 45.2% of patients had INP104-related TEAEs.
Endoscopy results showed that patients had no significant changes in olfactory mucosal integrity. Nor did patients have problems with olfactory function.
Investigators also examined exploratory outcomes related to efficacy. Two hours after a single dose of INP104, 38% of patients reported pain freedom. Of this group, 7.1% reported migraine recurrence at 24 hours, and 14.3% reported migraine recurrence at 48 hours.
About 52% of patients reported freedom from their most bothersome symptom at 2 hours post-treatment; and 66.3% reported pain relief at 2 hours after their first INP104-treated attack.
The phase 3 study provides real-world data that compare participants' response to treatment with response to their best usual care at baseline, co-investigator Stephen B. Shrewsbury, MBChB, chief medical officer at Impel NeuroPharma, told Medscape Medical News.
The results showed that participants "consistently responded well to the product without intolerable side effects," he added.
"Clinicians are excited about having an at-home DHE," said Aurora. "There are a lot of patients who have a lot of unmet needs. They're looking for a non-oral route."
Atypical Study Population?
Commenting on the findings for Medscape Medical News, Amaal Starling, MD, associate professor of neurology at the Mayo Clinic in Scottsdale, Arizona, noted that the study's biggest strength "is truly that they're using a medication that we already know works."
Tolerability and patient acceptability have been the main barriers for DHE treatment. "Those are the unmet needs with this medication," said Starling, who was not involved with the research.
Neurologists need a formulation that patients find acceptable and doesn't cause significant side effects that result in discontinuation, she added.
Starling noted that open-label studies such as this one are vulnerable to bias, but the fact that investigators discussed the study with the US Food and Drug Administration (FDA) in advance is reassuring. "Otherwise, I would be worried that it would be a barrier for approval," she said.
Another concern is that the study population was limited to participants with two to 14 headache days per month.
"That may not be the typical population for whom we're using DHE," said Starling. "We're usually using DHE in our population that has more refractory migraine attacks."
This characteristic of the study population may explain why "there's not that significant of a difference" in efficacy between the study drug and patients' best usual care, said Starling.
"I suspect that if we looked at individuals for whom we typically use DHE, there would be more of a separation," she said. Patients with four or five migraine attacks per month are more likely to benefit from usual care than refractory patients, she added.
Likelihood of FDA Approval?
Also commenting on the findings for Medscape Medical News, Elizabeth W. Loder, MD, vice chair for academic affairs in the Department of Neurology, Brigham and Women's Hospital, Boston, Massachusetts, noted ethnic diversity of the population is a strength of the study.
"They have a sizeable percentage of participants who are Black or Hispanic," said Loder, who is also a professor of neurology at Harvard Medical School.
However, the 26% dropout rate during the 24-week treatment period is concerning, she noted. "I don't think it speaks to safety concerns so much as nuisance, side effects perhaps, and maybe lack of efficacy."
Starling said that the prospects for regulatory approval seem good, however.
"I think the likelihood of the FDA being favorable looking at the current data is high," she said. "I'm very hopeful that this will come to fruition and be available for us to prescribe for our patients that would benefit from this greatly."
However, given the study's inclusion criteria, it is possible that insurers will restrict coverage to patients with episodic migraine. That could mean the population most likely to benefit from the treatment would not be covered, said Starling.
Loder noted that adoption of nasal sprays for medicines such as sumatriptan and zolmitriptan has not been as widespread as expected, which is relevant for INP104. Most patients don't like putting things in their nose and would prefer to swallow a pill, she said.
"Obviously, they'd rather, in most cases, use a nasal spray, compared to injecting something, but I'm not so certain that the niche this is going to fill is all that big," she said.
In addition, the price of the treatment will affect its use significantly.
"The other concern I have is packaging old drugs in fancy new delivery systems and charging a huge amount for them," said Loder. DHE previously was inexpensive and widely used.
"Part of the drop-off in use is not really related to convenience, it's related to expense and difficulty getting the medication," she said.
Impel NeuroPharma, which is developing INP104, funded the study. Aurora and Shrewsbury are employees and stockholders of Impel NeuroPharma. Starling has received consulting fees from Allergan, Amgen, Axsome Therapeutics, Eli Lilly & Company, Everyday Health, Impel NeuroPharma, Lundbeck, Med-IQ, Medscape, Neurolief, Novartis, Satsuma, Teva, and Theranica. Loder has reported no relevant financial relationships.
Headache. Published online August 7, 2021. Full article
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Cite this: Intranasal DHE Safe, Well Tolerated for Acute Migraine: STOP 301 Published - Medscape - Aug 18, 2021.