The FDA has accepted a filing for approval of Impel NeuroPharma’s INP104 for the acute treatment of migraine. If approved, INP104 will become the first commercial product based on Impel’s technology for delivering therapeutics to the upper nasal space.
Impel has developed metered dose devices for delivering liquids and powders to the upper nasal space. The decision to deliver molecules to this area is underpinned by evidence its vasculature is more permeable than the more commonly targeted lower nasal cavity. Impel thinks the permeability will translate into more consistent dosing and uptake, improved efficacy and faster onset of action.
INP104 is a proving ground for the approach. The product delivers dihydroergotamine, a decades-old drug originally given intravenously, for the acute treatment of migraine headaches with or without aura in adults. The FDA is set to decide whether to approve INP104 in the indication by the first week of September.
The filing for approval is based on data from a phase 3 trial that assessed the safety and tolerability of chronic intermittent usage of INP104 by 360 migraine sufferers. Most participants used INP104 for 24 weeks. A subset of subjects continued in a 28-week treatment extension period after the end of the main trial.
No participants suffered drug-related serious adverse events over the entire 52-week study. Most treatment-emergent adverse events were mild and transient. Nasal congestion and nausea were the most common adverse events.
The clinical trial was primarily designed to test safety and tolerability, but it also featured exploratory efficacy endpoints. Two-thirds of participants reported pain relief. Half of subjects reported freedom from their most bothersome migraine symptom two hours after taking their first dose of INP104.
Impel’s use of the 505(b)(2) pathway has enabled it to seek approval on the basis of that limited set of data. Physicians have used intravenous dihydroergotamine to treat migraine for decades. In 1997, Novartis won approval for a nasal formulation of dihydroergotamine mesylate, Migranal. The product is now sold by Bausch Health and faces competition from generics from companies including Cipla.
Migranal delivers dihydroergotamine to the lower nasal cavity. If Impel is right, INP104 will get more of the drug to the upper nasal region, changing the pharmacokinetic profile in ways that improve on the exposure achieved by Migranal while keeping plasma concentrations well below the levels seen in patients who receive dihydroergotamine intravenously.
Impel is one of a number of companies that have tried to improve the delivery of dihydroergotamine. The FDA rejected three applications for approval of an orally inhaled dihydroergotamine filed by MAP Pharmaceuticals and Allergan due to manufacturing and delivery problems. Satsuma Pharmaceuticals’ dihydroergotamine nasal powder failed in phase 3 last year, although the company is yet to give up on the asset.