Long acting and peripherally restricted kappa-opioid receptor agonists for acute migraine treatment

摘要： 偏头痛是一种高度流行和致残的疾病，影响着美国第一线约4700万人。 治疗包括急性治疗，如非类固醇抗炎药(NSAIDs)、Triptans、Ditans 不幸的是，急性治疗在许多患者中往往效果不佳。只有大约20%-30%的 患者在使用这些药物类别的任何一种药物治疗后2小时内实现疼痛自由。3-11无反应者 有频繁发作偏头痛的急性疗法是预防性治疗的潜在候选者，2包括 新近研制的抗降钙素基因相关肽及其受体的单抗 (GGRPR).12-16 CGRP和CGRPR单抗每月可将偏头痛天数减少50%-40%-60% 患者，12-16人，因此仅实现了应答者的部分缓解，并使一大批无应答者 进步。总体而言，偏头痛仍有大量未得到满足的医疗需求，特别是新奇和广泛的 有效的急诊治疗。 我们最近证实外周kappa-阿片受体(KOR)是治疗急性偏头痛的新靶点。 治疗。我们发现，外周受限的KOR激动剂达菲凯法林可以逆转已建立的偏头痛-- 直接激活伤害性传入与炎性介质的混合物所致的小鼠疼痛 (IM)应用于硬脑膜。我们的数据表明，外周受限的KOR激动剂有可能 对急性偏头痛的治疗具有广泛的疗效和较高的疗效。 该计划的目标是开发长效、外周受限的、因此不会上瘾的kappa-阿片类药物。 受体(KOR)激动剂作为新的、安全和广泛有效的急性偏头痛治疗药物。建议的SBIR 第一阶段计划将选择一种能够治疗偏头痛并适用于 每日一次，作为静脉(IV)制剂在住院环境中使用或作为口服片剂使用 在门诊环境中。 影响和

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