Peptide-antibody conjugate kappa-opioid receptor (PAC-KOR) agonists for treatment of chronic itch

摘要： 有3700万美国人患有慢性肾脏病，其中包括495,000名终末期肾病患者 需要血液透析(CKD-HD)的(ESRD)和受晚期CKD(3-5期)影响的1,700万人 透析依赖(CKD-非HD)。大约三分之一的CKD-HD和CKD-非HD患者都经历过 中到重度慢性瘙痒，又名。尿毒症瘙痒。剧烈的全身性瘙痒与 睡眠质量差，抑郁，生活质量下降，感染风险增加，风险增加 对死亡的恐惧。值得注意的是，除了瘙痒，50%的CKD-HD和CKD-非HD患者也 经历慢性疼痛，其中30%-50%的患者服用阿片类药物，导致额外的 并存和生活质量下降。直到最近，在美国还没有被批准的治疗尿毒症瘙痒的药物，而且 目前还没有批准的非成瘾性止痛药来替代阿片类药物来治疗CKD相关的慢性疼痛。 DifelikeFalin是一种外周受限的短效四肽KOR激动剂，最近被美国国家药品监督管理局批准 FDA对CKD-HD患者中到重度尿毒症瘙痒的治疗。这是第一种也是唯一一种被批准用于 这一迹象在美国出现。Difelikefain有明显的缺点，包括肾脏介导的清除和 肾功能正常的患者的半衰期较短，限制了CKD-HD患者以外的发展。 使用专有的多肽-抗体偶联(PAC)技术，我们已经创造出具有 独特的目标产品概况(TPP)，其特征如下：(I)有效和有选择性的KOR 激动剂，以确保疗效，同时将剂量和商品成本降至最低(COGS)，(Ii)外围限制，以避免 CNS副作用并确保安全性，以及(Iii)较长的半衰期，可每周一次至每月一次皮下注射 (SC)通过自动注射器给药，以最大限度地提高便利性、粘附性、曝光性和有效性。此应用程序寻求 确认我们的临床候选人的药效学(PD)和药代动力学(PK)概况，并创建 稳定的细胞系，以支持未来的发展。 影响和

ABSTRACT: There are >37 million Americans suffering from CKD, including >495,000 patients with end stage renal disease (ESRD) requiring hemodialysis (CKD-HD) and >17 million affected by advanced CKD (stages 3-5) who are not dialysis dependent (CKD-nonHD). About one third of both CKD-HD and CKD-nonHD patients experience moderate-to-severe chronic itch a.k.a. uremic pruritus. Intense and generalized systemic itching is associated with poor sleep quality, depression, reduced quality of life (QoL), increased risk of infection, and increased risk of death. It is important to note that, in addition to pruritus, >50% of both CKD-HD and CKD-nonHD patients also experience chronic pain, and that 30-50% of these patients are prescribed opioids resulting in additional comorbidities and reduced QoL. Until recently, there was no approved drug for uremic pruritus in the US and there is still no approved non-addictive analgesic to replace opioids for CKD-associated chronic pain. Difelikefalin is a peripherally restricted and short-acting tetrapeptide KOR agonist that was recently approved by the FDA for moderate-to-severe uremic pruritus in CKD-HD patients. It is the first and only approved drug for this indication in the US. Difelikefalin has significant shortcomings, including kidney-mediated clearance and short half-life in patients with functioning kidneys limiting its development outside the CKD-HD patient population. Using a proprietary peptide-antibody conjugate (PAC) technology, we have created PAC-KOR agonists with a unique target product profile (TPP) characterized by the following key features: (i) potent and selective KOR agonist to ensure efficacy while minimizing dose and cost of goods (COGS), (ii) peripherally-restricted to avoid CNS side-effects and ensure safety, and (iii) long half-life enabling once-weekly to once-monthly subcutaneous (SC) dosing by autoinjector to maximize convenience, adherence, exposure, and efficacy. This application seeks to confirm the pharmacodynamic (PD) and pharmacokinetic (PK) profile of our clinical candidate and create stable cell lines to support future development. Impact and