Development of an intranasal, direct to nerve treatment for headache disorders

PROJECT SUMMARY According to the US Centers for Disease Control, 14.2% of US adults report experiencing migraine symptoms within any

given 3-month period, making it the second most disabling illness in the world. Diagnosed migraine is typically categorized as either episodic (2 – 14 days per month) or chronic (15 or more days per month), with each attack accompanied by a

combination of debilitating pain and symptoms that persist between 4 - 72 hours. There is no absolute cure for migraine, and the overall financial burden associated with these disorders is more than $72B annually in the US and Europe. For individuals affected, however, the personal “costs” go well beyond financial and physical pain and are reflected in

decreased relationship satisfaction, increased dependency on caregivers, and loss of work and social productivity. Despite increased recognition of parasympathetic activation of the trigeminovascular system through the SPG, the majority of acute migraine therapies target downstream effects of trigeminovascular activation, including CGRP receptors and 5-HT

receptors. Nonspecific pain medications used in migraine (acetaminophen, NSAIDs, opioids) may have a more direct anti- nociceptive effect on the trigeminovascular system, but they either lack adequate potency for severe migraine symptoms

or cause significant adverse effects. Sphenopalatine ganglion (SPG) block procedures directly target the trigeminal nerve and have been identified as an effective, in-clinic method for reducing migraine symptoms that can be administered as often as needed without the potential for severe or addictive side effects. To date, these procedures have not been

considered a strong alternative to front-line medications due to their 1) Necessity for administration by a trained

healthcare professional, 2) Difficult and uncomfortable route of administration, and 3) High supply and procedural costs compared to single-dose medication. In response to the increasing clinical need for alternative migraine therapies, our

team comprised of migraine care specialists, device and drug developers, and clinical research specialists has created a technology for accurately delivering medication to the upper-posterior nasal cavity, enabling development of a self- administered SPG block combination product that provides rapid pain relief without the harsh and addictive side effects

of existing medications. The Principal Objectives of this Phase I SBIR, separated into two distinct Aims, are to establish

technical efficacy and evaluate commercial design feasibility for self-administration – a critical component for treatment

efficacy. In the first aim, components affecting nasal spray characteristics will be designed and prototyped. Benchtop and in vitro performance testing will be conducted using a surrogate nasal cast and laser diffraction techniques to measure

and optimize droplet size, distribution patterns, drug substance delivery rate, total drug substance delivered, and nasal

cavity deposition to ensure local drug application to the SPG while meeting specifications for function and safety based on current recommendations for drug delivery devices. Aim 2 will focus on the creation of system-level designs for the

delivery device through formative human factors evaluations that will bring together diverse groups of migraine patients, clinical care professionals, and key opinion leaders. The conclusion of Aim 2 will be an FDA pre-IND meeting to obtain clarification on the regulatory pathway and preclinical and clinical testing to support a successful NDA application.