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

外周限制性长效生长抑素受体 4 (LA-SSTR4) 激动剂治疗疼痛

• 批准号: 10022491
• 负责人: Pierre Riviere
• 金额: $ 141万
• 依托单位: PEPTIDE LOGIC, LLC
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-01-01 至 2022-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10022491
• 关键词: Acute; Adverse effects; Agonist; Analgesics; Animals; Antibodies; Autopsy; Award; Biological; Biological Assay; Biological Availability; Brain; Chemistry; Chronic; Chronic inflammatory pain; Clinical; Clinical Pathology; Conjugated Carrier; Constipation; Dependence; Development; Disease; Dose; Drug Kinetics; Endocrine; Enzyme-Linked Immunosorbent Assay; Evaluation; Female; Freund' s Adjuvant; Generations; Government; Half-Life; High Pressure Liquid Chromatography; Human; Intravenous; Investigational Drugs; Investigational New Drug Application; Iodoacetates; Lead; Light; Logic; Malignant Bone Neoplasm; Mass Spectrum Analysis; Medial; Mediating; Methodology; Methods; Modeling; Molecular Sieve Chromatography; Monoclonal Antibodies; Morphine; Mus; National Institute of Drug Abuse; Neuraxis; Opioid; Pain; Pain management; Pancreas; Patients; Penetration; Peptide Synthesis; Peptide antibodies; Peptides; Peripheral; Persons; Pharmacology; Phase; Pituitary Gland; Plasma; Postoperative Pain; Production; Quality of life; Rattus; Reaction; Reaction Time; Reporter Genes; Research Design; Risk; Route; SSTR1 gene; SSTR2 gene; SSTR4 gene; SSTR5 gene; Safety; Side; Small Business Innovation Research Grant; Societies; Solid; Somatostatin; Statistical Data Interpretation; Structure; Substance Use Disorder; Surgical incisions; Tachyphylaxis; Technology; Testing; Therapeutic; Toxicokinetics; Toxicology; Validation; Ventilatory Depression; active control; addiction; analytical method; animal pain; antibody conjugate; base; cancer pain; chronic pain; clinical candidate; clinical development; cross reactivity; design; experimental study; follow-up; good laboratory practice; improved; lead series; male; nonhuman primate; novel; opioid epidemic; opioid sparing; osteoarthritis pain; pain model; prescription opioid; prevent; programs; response; safety practice; small molecule; somatostatin receptor 4; subcutaneous; success; tumor

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 &

项目总结/摘要 拟议的SBIR第二阶段计划旨在选择一流的，外围限制的，长效的 生长抑素受体4（LA-SSTR 4）激动剂作为新型非成瘾性药物开发临床候选物 镇痛剂能够替代阿片类药物，用于治疗中度至重度慢性疼痛。该计划是基于 强有力的科学证据表明，外周SSTR 4的激活产生广谱止痛剂， 活动，并追求独特的治疗策略。LA-SSTR 4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结构： [（肽）-（间隔子）-（接头）]2-[抗体载体]。所述肽模块赋予外周SSTR 4激动剂活性， 而抗体载体提供延长的作用持续时间和外周选择性。这些独特 这些功能将使我们能够在功效、安全性等方面实现显着差异化和上级的产品概况， 和方便性。扩展 半衰期将使每周一次至每月一次皮下给药成为可能，从而使便利性最大化， 合规性和功效。缺乏中枢神经系统（CNS）的渗透将防止不必要的 以及与CNS中大量表达的SSTR 4的不期望的相互作用，消除CNS介导的任何风险。 SSTR 4不良反应，从而最大限度地提高安全性。与阿片类药物不同，SSTR 4激动剂不会诱导便秘， 呼吸抑制、依赖、成瘾或滥用。最后，与SSTR 2和SSTR 5不同，SSTR 4表达 在垂体和胰腺中的表达非常低，支持选择性SSTR 4激动剂不太可能干扰 外周内分泌功能先前的SBIR第一阶段计划已经确定了以下可行性： 将短效、强效和选择性肽SSTR 4激动剂缀合至所述抗体载体。所得 LA-SSTR 4激动剂先导系列对SSTR 4具有高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 现有电极导线系列并选择临床候选产品进行开发，目标2：确认并优先考虑 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灵长类动物中的药代动力学和安全性/毒理学特征， 设计后续的研究性新药（IND）启动研究。假设成功的电流 建议，后续IIb期计划将建立良好的生产规范（GMP）生产， 临床候选人，并完成药物非临床研究质量管理规范（GLP）安全性/毒理学研究所需的 IND申请。影响和