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ABSTRACT: Migraine is a highly prevalent and disabling illness affecting about 47 million people in the US.1 First-line therapies consist of acute treatments such as non-steroidal anti-inflammatory drugs (NSAIDS), triptans, ditans or gepants.2 Unfortunately, acute therapies are often poorly effective in many patients. Only about 20-30% of patients achieve freedom of pain at 2 hours post treatment with any of these drug classes.3-11 Non-responders to acute therapies with frequent episodic migraine are potential candidates for preventive treatments,2 including recently approved monoclonal antibodies (mAbs) for calcitonin gene-related peptide (CGRP) and its receptor (GGRPR).12-16 CGRP and CGRPR mAbs reduce the number of migraine days per month by 50% in 40-60% of patients,12-16 thus achieving only partial relief in responders and leaving a large group of non-responders without improvement. Overall, there are still large unmet medical needs in migraine, specifically for novel, and broadly effective acute treatments. We recently demonstrated that the peripheral kappa-opioid receptor (KOR) is a novel target for acute migraine treatment. We showed that the peripherally restricted KOR agonist difelikefalin reverses established migraine- like pain in mice resulting from direct activation of nociceptive afferents with a cocktail of inflammatory mediators (IM) applied to the dura mater. Our data suggest that peripherally restricted KOR agonists have the potential to be broadly effective and to achieve high efficacy for acute migraine treatment. The goal of this program is to develop long acting, peripherally restricted and hence non addictive, kappa-opioid receptor (KOR) agonists as novel, safe, and broadly effective acute migraine treatments. The proposed SBIR Phase I program will select a clinical candidate for development able to treat migraine headache and suitable for once-daily dosing, both as an intravenous (IV) formulation for use in inpatient settings or as an oral tablet for use in outpatient settings. Impact and PROJECT NARRATIVE: The goal of this program is to develop long acting, peripherally restricted and hence non addictive, kappa-opioid receptor (KOR) agonists as novel, safe, and broadly effective acute migraine treatments. The proposed SBIR Phase I program will select a clinical candidate for development able to treat migraine and suitable for once-daily dosing, both as an intravenous (IV) formulation for use in inpatient settings or as an oral tablet for use in outpatient settings. If successful, the proposed program has the potential to profoundly transform the standard of care for acute migraine treatment and to improve the quality of life for many patients.