Peripherally-Restricted Long-Acting Somatostatin Receptor 4 (LA-SSTR4) Agonists for Pain

项目概要/摘要 拟议的 SBIR 二期计划旨在选择一流的、外周限制的、长效的 生长抑素受体 4 (LA-SSTR4) 激动剂临床候选药物，作为一种新型非成瘾性药物进行开发 能够替代阿片类药物治疗中度至重度慢性疼痛的镇痛药。该计划基于 强有力的科学证据表明外周 SSTR4 的激活可产生广谱镇痛 活动并追求独特的治疗策略。 LA-SSTR4 激动剂是半合成生物制剂 使用专有的肽-抗体偶联物 (PAC) 技术并具有以下模块化结构： [(肽)-(间隔基)-(连接基)]2-[抗体载体]。肽模块赋予外周 SSTR4 激动剂活性， 而抗体载体提供了延长的作用持续时间和外周选择性。这些独特的 这些功能将使我们能够在功效、安全性、 与短效且具有脑穿透性的小分子 SSTR4 激动剂相比，具有更方便的特点。扩展的 半衰期将使每周一次到每月一次皮下给药成为可能，从而最大限度地提高便利性， 合规性和有效性。中枢神经系统 (CNS) 缺乏渗透性将阻止不必要的 以及与中枢神经系统中大量表达的 SSTR4 发生不需要的相互作用，消除了中枢神经系统介导的任何风险 SSTR4的不良影响，从而最大限度地提高安全性。与阿片类药物不同，SSTR4 激动剂不会引起便秘， 呼吸抑制、依赖性、成瘾或滥用。最后，与SSTR2和SSTR5不同，SSTR4表达 在垂体和胰腺中的水平非常低，支持选择性 SSTR4 激动剂不太可能干扰 外周内分泌功能。此前的SBIR第一期计划已经确立了以下项目的可行性： 将短效、强效、选择性的肽 SSTR4 激动剂与抗体载体缀合。由此产生的 LA-SSTR4激动剂先导系列对SSTR4具有高激动剂效力和选择性，并已证明 动物疼痛模型中的抗伤害活性。拟议的 SBIR 第二阶段计划旨在： 目标 1：优化 现有的先导系列并选择一个临床候选药物进行开发，目标 2：验证并优先考虑 使用疾病相关小鼠疼痛模型进行临床开发的适应症，以及目标 3：表征 临床候选药物在大鼠和非人类灵长类动物中的药代动力学和安全性/毒理学概况，以帮助 设计后续的研究性新药 (IND) 支持研究。假设当前成功 根据提案，后续的 IIb 阶段计划将为该产品建立良好生产规范 (GMP) 生产 临床候选人并完成良好实验室规范（GLP）所需的安全/毒理学研究 IND 申请。影响 ＆

PROJECT SUMMARY/ABSTRACT The proposed SBIR Phase II program seeks to select a first-in-class, peripherally-restricted, and long-acting somatostatin receptor 4 (LA-SSTR4) agonist clinical candidate for development as a novel non-addictive analgesic able to replace opioids for the treatment of moderate-to-severe chronic pain. The program is based on strong scientific evidence showing that activation of peripheral SSTR4 produces broad spectrum analgesic activity and pursues a unique therapeutic strategy. LA-SSTR4 agonists are semi-synthetic biologics created using a proprietary peptide-antibody conjugate (PAC) technology and having the following modular structure: [(peptide)-(spacer)-(linker)]2-[antibody carrier]. The peptide module confers agonist activity at peripheral SSTR4, whereas the antibody carrier provides extended duration of action and peripheral selectivity. These unique features will allow us to achieve a markedly differentiated and superior product profile in terms of efficacy, safety, and convenience compared to short-acting and brain-penetrating small molecule SSTR4 agonists. The extended half-life will enable once-weekly to once-monthly subcutaneous dosing, thereby maximizing convenience, compliance, and efficacy. The lack of penetration in the central nervous system (CNS) will prevent unnecessary and undesired interaction with abundantly expressed SSTR4 in the CNS, eliminating any risk of CNS-mediated SSTR4 adverse effects, thereby maximizing safety. Unlike opioids, SSTR4 agonists do not induce constipation, respiratory depression, dependence, addiction, or abuse. Finally, unlike SSTR2 and SSTR5, SSTR4 expression in the pituitary and pancreas is very low, supporting that selective SSTR4 agonists are unlikely to perturb peripheral endocrine functions. The preceding SBIR Phase I program has already established the feasibility of conjugating a short-acting, potent, and selective peptide SSTR4 agonist to the antibody carrier. The resulting LA-SSTR4 agonist lead series has high agonist potency and selectivity for SSTR4 and has demonstrated antinociceptive activity in an animal pain model. The proposed SBIR Phase II program seeks to: Aim 1: optimize the existing lead series and select a clinical candidate for development, Aim 2: validate and prioritize the indication(s) for clinical development using disease-relevant mouse pain models, and Aim 3: characterize the pharmacokinetics and safety/toxicology profile of the clinical candidate in rat and non-human primates to help design subsequent investigational new drug (IND)-enabling studies. Assuming success with the current proposal, the follow up Phase IIb program will establish good manufacturing practices (GMP) production for the clinical candidate and complete the good laboratory practices (GLP) safety/toxicology studies required for the IND application. IMPACT &