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

项目摘要/摘要 拟议的SBIR第二阶段计划寻求选择一流的、外围受限的和长效的 生长抑素受体4(LA-SSTR4)激动剂作为一种新型非成瘾性药物开发的临床候选药物 可替代阿片类药物治疗中重度慢性疼痛的止痛药。该计划是基于 关于激活外周SSTR4产生广谱止痛药的强有力的科学证据 并追求一种独特的治疗策略。LA-SSTR4激动剂是一种半合成生物制品 使用专有的多肽-抗体偶联(PAC)技术，并具有以下模块化结构： [(肽)-(间隔基)-(接头)]2-[抗体载体]。多肽模块在外周SSTR4处赋予激动剂活性， 而抗体载体提供了延长的作用时间和外周选择性。这些独特的 这些功能将使我们能够在有效性、安全性、 与短效和脑穿透的小分子SSTR4激动剂相比，它更方便。扩展后的 半衰期将实现每周一次至每月一次的皮下给药，从而最大限度地方便， 依从性和有效性。缺乏对中枢神经系统(CNS)的穿透将防止不必要的 以及与中枢神经系统中大量表达的SSTR4的不良相互作用，消除了中枢神经系统介导的任何风险 SSTR4的不利影响，从而最大限度地提高安全性。与阿片类药物不同，SSTR4激动剂不会导致便秘， 呼吸抑制、依赖、上瘾或滥用。最后，与SSTR2和SSTR5不同，SSTR4表达式 在脑垂体和胰腺中的含量非常低，支持选择性SSTR4激动剂不太可能干扰 外周内分泌功能。前面的SBIR第一阶段计划已经确定了 将短效、有效和选择性的多肽SSTR4激动剂偶联到抗体载体上。由此产生的 La-SSTR4激动剂铅系列对SSTR4具有很高的激动剂效力和选择性，并已证明 在动物疼痛模型中的抗伤害感受活性。拟议的SBIR第二阶段计划旨在：目标1：优化 现有的Lead系列，并选择临床候选进行开发，目标2：验证并确定优先顺序 使用与疾病相关的小鼠疼痛模型进行临床开发的适应症(S)，以及目标3：描述 临床候选药物在大鼠和非人灵长类动物中的药代动力学和安全性/毒理学概况 设计后续研究性新药(IND)使能研究。假设在当前形势下取得成功 建议，后续阶段IIb计划将建立良好的制造规范(GMP)生产 临床候选人并完成所需的良好实验室操作规范(GLP)安全/毒理学研究 IND应用程序。影响和

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 &