Safety, Tolerability and Comparative Bioavailability of a Novel Intranasal DHE Product (INP104)

July 26, 2018

Abstract

Migraine remains a serious cause of disability.1,2 Up to 42% of migraineurs still report dissatisfaction with their treatment,3 over a third (37%) with the speed of effect and half (50%) were dissatisfied that their pain recurred.

Dihydroergotamine (DHE) is effective for acute migraine and is recommended as an alternative to triptans.4 DHE is available in multiple formulations: SC, IM, limited by slow absorption; nasal spray formulations limited by low bioavailability, and IV administration limited by difficulty self-administering and high rates of adverse events.5 MAP Pharmaceuticals developed an inhaled DHE product (MAP0004, Levadex®, Semprana®) with encouraging PK6 which
was successful in clinical studies at relieving migraine7,8 but the NDA was rejected three times by 2014 due to CMC issues9 which remained unresolved in 201710. Separating drug (DHE) from propellant (HFA) and delivering to the upper nasal cavity may avoid these issues and provide an improved route of administration for DHE.

Drug absorption via the nasal cavity is an underutilized route for systemic drug delivery, primarily because of difficulty with achieving significant and consistent absorption through the ciliated, pseudostratified columnar (respiratory) epithelium in the lower nasal space.11 The Precision Olfactory Delivery or POD® device is a nasal drug delivery platform designed to deliver drugs to the upper turbinate region and upper nasal cavity in a consistent and predictable manner for improved biodistribution, which should yield improved clinical outcomes.

INP104 is an innovative drug-device combination product that consists of a liquid DHE formulation administered by the I123 POD device that addresses the low bioavailability and high variability in nasal administration observed with traditional nasal sprays. By delivering the drug to the upper nasal cavity, INP104 may improve systemic availability and reduce reported adverse events of taste disturbance and avoid drug dripping out of the nose or into the nasopharynx after nasal administration, reported with traditional nasal sprays.

Impel NeuroPharma is developing INP104 to provide migraine patients with a non-injectable and user-friendly DHE delivery option. This study compared the safety, tolerability, and bioavailability of DHE following single dose administration of INP104 1.45 mg to that of IV DHE 1.0 mg and DHE nasal spray 2.0 mg in healthy adult subjects.