Migraine is a highly prevalent and disabling illness affecting about 47 million people in the US.1 First-linetherapies consist of acute treatments such as non-steroidal anti-inflammatory drugs (NSAIDS), triptans, ditansor gepants.2 Unfortunately, acute therapies are often poorly effective in many patients. Only about 20-30% ofpatients achieve freedom of pain at 2 hours post treatment with any of these drug classes.3-11 Non-respondersto acute therapies with frequent episodic migraine are potential candidates for preventive treatments,2 includingrecently 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% ofpatients,12-16 thus achieving only partial relief in responders and leaving a large group of non-responders withoutimprovement. Overall, there are still large unmet medical needs in migraine, specifically for novel, and broadlyeffective acute treatments.We recently demonstrated that the peripheral kappa-opioid receptor (KOR) is a novel target for acute migrainetreatment. 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 tobe 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-opioidreceptor (KOR) agonists as novel, safe, and broadly effective acute migraine treatments. The proposed SBIRPhase I program will select a clinical candidate for development able to treat migraine headache and suitable foronce-daily dosing, both as an intravenous (IV) formulation for use in inpatient settings or as an oral tablet for usein outpatient settings.Impact and
Public Health Relevance Statement: 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.
Project Terms: absorption ; Affect ; Aftercare ; After Care ; After-Treatment ; post treatment ; Albumins ; Amino Acids ; aminoacid ; Non-Steroidal Anti-Inflammatory Agents ; NSAIDs ; Non Steroidal Antiinflammatory Agents ; Nonsteroidal Anti-Inflammatory Agents ; Nonsteroidal Antiinflammatory Agents ; Nonsteroidal Antiinflammatory Drug ; non-steroidal anti-inflammatory drugs ; non-steroidal antiinflammatory drugs ; nonsteroidal anti-inflammatory drugs ; Monoclonal Antibodies ; Clinical Treatment Moab ; mAbs ; Biological Availability ; Bioavailability ; Biologic Availability ; Physiologic Availability ; Calcitonin Gene-Related Peptide ; Canis familiaris ; Canine Species ; Dogs ; Dogs Mammals ; canine ; domestic dog ; Pharmaceutical Preparations ; Drugs ; Medication ; Pharmaceutic Preparations ; drug/agent ; Dura Mater ; Dura ; Exhibits ; Fatty Acids ; Female ; Freedom ; Liberty ; Goals ; Half-Life ; Human ; Modern Man ; Inpatients ; Kidney ; Kidney Urinary System ; renal ; Chronic Kidney Failure ; Chronic Renal Disease ; Chronic Renal Failure ; chronic kidney disease ; Lead ; Pb element ; heavy metal Pb ; heavy metal lead ; male ; Transgenic Mice ; Molecular Weight ; Mus ; Mice ; Mice Mammals ; Murine ; Outpatients ; Out-patients ; Pain ; Painful ; Patients ; Peptides ; Drug Kinetics ; Pharmacokinetics ; Pruritus ; Itching ; Pruritic Disorder ; Pruritis ; itch sensation ; Quality of life ; QOL ; Serum Albumin ; Solubility ; Vertebral column ; Spinal Column ; Spine ; backbone ; Tablets ; Technology ; kappa opioid receptors ; kappa opiate ; kappa opioid ; κ opiate ; κ opioid ; κ opioid receptors ; κ-OR ; κOR ; Generations ; Migraine ; Migraine Headache ; Investigational New Drug Application ; base ; improved ; Peripheral ; Acute ; Phase ; Medical ; Series ; Chemicals ; Renal function ; kidney function ; Nociception ; nociceptive ; Inflammation Mediators ; inflammatory mediator ; Intravenous ; programs ; Hour ; Oral ; Receptor Protein ; receptor ; success ; pharmacophore ; Animal Models and Related Studies ; model of animal ; model organism ; Animal Model ; novel ; Modality ; Molecular Interaction ; Binding ; preventing ; prevent ; Dose ; Data ; Small Business Innovation Research Grant ; SBIR ; Small Business Innovation Research ; follow-up ; Active Follow-up ; active followup ; follow up ; followed up ; followup ; Development ; developmental ; triptans ; design ; designing ; innovation ; innovate ; innovative ; mouse model ; murine model ; prototype ; public health relevance ; standard of care ; screening ; Formulation ; Preventive treatment ; Preventative treatment ; clinical candidate ; Opioid agonist ; Opiate agonist ; Opiate receptor agonist ; Opioid receptor agonist ; lead optimization ; acute care ;
