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

摘要： 有> 3700万美国人患有CKD，包括> 495，000名终末期肾病患者 需要血液透析（CKD-HD）的终末期肾病（ESRD）患者和> 1700万患有晚期CKD（3-5期）的患者， 透析依赖型（CKD-非HD）。约三分之一的CKD-HD和CKD-非HD患者经历 中度至重度慢性瘙痒尿毒症瘙痒症。强烈和全身性瘙痒与 睡眠质量差，抑郁，生活质量下降（QoL），感染风险增加， 死亡之值得注意的是，除了瘙痒，>50%的CKD-HD和CKD-非HD患者还 经历慢性疼痛，并且这些患者中的30-50%被处方阿片类药物，导致额外的 合并症和QoL降低。直到最近，在美国还没有批准用于尿毒症瘙痒症的药物， 仍然没有批准的非成瘾性镇痛剂来代替阿片类药物用于CKD相关的慢性疼痛。 Difelikefalin是一种外周限制性和短效四肽KOR激动剂，最近被批准用于治疗糖尿病。 FDA将其用于CKD-HD患者的中度至重度尿毒症性瘙痒。它是第一个也是唯一一个被批准的药物， 这一迹象在美国。地非利克福林具有显著的缺点，包括肾介导的清除和 在肾脏功能正常的患者中半衰期短，限制了其在CKD-HD患者人群以外的发展。 使用专有的肽-抗体偶联物（PAC）技术，我们已经产生了PAC-KOR激动剂， 独特的目标产品概况（TPP），其特征在于以下关键特征：（i）有效和选择性的KOR 激动剂，以确保疗效，同时最大限度地减少剂量和商品成本（COGS），（ii）外周限制，以避免 CNS副作用，并确保安全性，和（iii）半衰期长，能够每周一次至每月一次皮下给药 (SC)通过自动注射器给药，以最大限度地提高便利性、依从性、暴露量和功效。本申请寻求 确认我们的临床候选药物的药效学（PD）和药代动力学（PK）特征，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