Novel biologic to treat chemotherapy-induced neuropathic pain

治疗化疗引起的神经性疼痛的新型生物制剂

• 批准号: 10546418
• 负责人: Yakov Kogan
• 金额: $ 100万
• 依托单位: RAFT PHARMACEUTICALS, LLC
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-19 至 2024-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10546418
• 关键词: Anticonvulsants; Apolipoprotein A-I; Binding Proteins; Biological; Biological Assay; Cancer Patient; Canis familiaris; Cell membrane; Cells; Chemotherapy-induced peripheral neuropathy; Cholesterol; Chronic; Cisplatin; Clinical; Clinical Research; Cyclic GMP; Data; Dependence; Development; Development Plans; Dose; Drug Kinetics; Endotoxins; Ensure; Epidemic; Excision; Formulation; Future; Healthcare; Helping to End Addiction Long-term; Immune response; Inflammation; Inflammatory; Injury; Mediating; Membrane Microdomains; Methods; Microglia; Modeling; Monitor; Mus; NOEL; National Institute of Neurological Disorders and Stroke; No-Observed-Adverse-Effect Level; Nociceptors; Non-Steroidal Anti-Inflammatory Agents; Opioid; Organ; Outcome; Pain; Pain management; Patients; Peripheral Nerves; Pharmaceutical Preparations; Pharmacodynamics; Pharmacologic Substance; Pharmacology; Phase; Phenotype; Preparation; Process; Proteins; Quality of life; Rattus; Regulation; Research; Risk; Rodent; Safety; Small Business Innovation Research Grant; Spinal; Spinal Ganglia; Spinal nerve root structure; Sterility; Surface; TLR4 gene; Therapeutic; Toxic effect; Toxicology; Translating; United States National Institutes of Health; addiction; biobank; cGMP production; cancer therapy; chemotherapy; chronic pain; clinical development; design; drug standard; effective therapy; experimental study; first-in-human; ganglion cell; human study; lead candidate; macrophage; manufacturing process; manufacturing scale-up; medication safety; meetings; neuroinflammation; non-opioid analgesic; nonhuman primate; novel; novel strategies; opioid misuse; pain relief; painful neuropathy; particle; preclinical evaluation; preclinical study; process optimization; programs; research clinical testing; response; safety study; scale up; side effect; success; systemic toxicity

PROJECT SUMMARY Chemotherapy-induced peripheral neuropathy (CIPN) has a profound negative impact on quality of life of nearly 70% of cancer patients receiving chemotherapy. While systemic administration of opiates, NSAIDs, and anticonvulsants can relieve pain for short intervals, they are not suitable for chronic therapy. Aside from efficacy, many of the potent agents are beset with limiting side effects and issues related to dependence and addiction. RAFT Pharmaceuticals (RAFT) proposes a Direct-to-Phase 2 SBIR proposal presenting a novel approach to reversal of preexisting neuropathic pain via regulation of lipid rafts in spinal and dorsal root ganglia (DRG) cells. Our lead candidate, RFT1081, which is a modified apoA-I binding protein (AIBP), promotes removal of cholesterol selectively from the plasma membrane of activated and inflammatory cells. This targeting is due to AIBP binding to Toll-like receptor 4 (TLR4), which is highly expressed on the surface of inflammatory microglia, macrophages and activated DRG nociceptors. RFT1081-mediated disruption of lipid rafts harboring activated TLR4 abrogates the facilitatory cycle of neuroinflammation and nociceptors’ spontaneous activity and alleviates chronic pain phenotypes. In a prior project, we developed a non-GMP scaled-up upstream and downstream manufacturing process for RFT1081 and conducted its detailed characterization; conducted pharmacokinetics studies of spinally delivered RFT1081 in mice and designed pharmacodynamics assays to evaluate RFT1081 target engagement; established dose-dependent efficacy profile for AIBP treatment in CIPN mice; and conducted a non-GLP dose-range tolerability study of RFT1081 in rats. These data provide support and justify further development of RFT1081 in the proposed Direct-to-Phase 2 SBIR studies. In this milestones-driven project, we plan to manufacture a RFT1081 drug product lot for toxicology studies using a cGMP-compatible process and analytical assays. The RFT1081 drug product lot, conforming to RAFT’s specifications and in optimized formulation will be thoroughly characterized for storage and in-use stability. The initial single-dose toxicology studies will be performed in rats. We will then also evaluate the pharmacology, local and systemic toxicity, and immune response to repeated i.t. administration of RAFT1081 in rats, dogs and non-human primates to further study the safety of the drug and to select a pharmacologically relevant non-rodent species for further IND- enabling preclinical evaluation. RFT1081 will also be evaluated in a model of cisplatin cancer therapy to ensure it does not interfere with chemotherapy action. The project will conclude with developing a detailed synopsis of an integrated first-in-human study and an overall indication-supporting clinical strategy, followed by preparation for and conducting a pre-IND meeting with the FDA. We expect that this Phase 2 SBIR project outcomes will include: 1) successful scale-up of RFT1081 suitable for future cGMP manufacturing, 2) completion of dose- ranging toxicology studies and selection of a relevant non-rodent species, and 3) a viable IND-enabling and clinical development strategy vetted with the FDA to de-risk future steps of RFT1081 development.

项目概要 化疗引起的周围神经病变（CIPN）对近乎生活质量产生深远的负面影响 70%的癌症患者在接受化疗的同时全身施用阿片类药物、非甾体抗炎药和药物。 抗惊厥药只能短期缓解疼痛，除了疗效外，不适合长期治疗。 许多有效的药物都受到有限的副作用以及与依赖性和成瘾相关的问题的困扰。 RAFT Pharmaceuticals (RAFT) 提出了一项直接进入 2 期 SBIR 提案，提出了一种新方法 通过调节脊髓和背根神经节（DRG）细胞中的筏来逆转先前存在的神经性疼痛。 我们的主要候选药物 RFT1081 是一种修饰的 apoA-I 结合蛋白 (AIBP)，可促进去除 胆固醇选择性地来自活化的炎症细胞的质膜。 AIBP 与 Toll 样受体 4 (TLR4) 结合，该受体在炎症小胶质细胞表面高度表达， RFT1081 介导的巨噬细胞和活化的 DRG 伤害感受器破坏了含有活化的脂筏。 TLR4 消除神经炎症和伤害感受器自发活动的促进循环并减轻 在之前的项目中，我们开发了一种非 GMP 放大的上游和下游。 RFT1081的生产工艺并进行了详细的药代动力学表征； 在小鼠中进行脊髓递送 RFT1081 的研究并设计药效学测定来评估 RFT1081 目标参与；建立并进行 CIPN 小鼠 AIBP 治疗的剂量依赖性疗效曲线； RFT1081 在大鼠中的非 GLP 剂量范围耐受性研究这些数据提供了支持并进一步证明了合理性。 在拟议的直接二期 SBIR 研究中开发 RFT1081 在这个里程碑驱动的项目中，我们。 计划使用符合 cGMP 的工艺生产用于毒理学研究的 RFT1081 药品批次，并且 RFT1081 药品批次，符合 RAFT 规范并经过优化。 将彻底表征制剂的储存和使用稳定性。 然后我们还将在大鼠中进行研究，评估药理学、局部和全身毒性以及 大鼠、狗和非人灵长类动物重复注射 RAFT1081 后的免疫反应 研究药物的安全性并选择药理学相关的非啮齿动物物种进行进一步的 IND- RFT1081也将在顺铂癌症治疗模型中进行评估，以确保能够进行临床前评估。 它不会干扰化疗作用，该项目将制定详细的概要。 综合首次人体研究和总体适应症支持临床策略，然后进行准备 我们预计第 2 阶段 SBIR 项目的成果将与 FDA 进行 IND 前会议。 包括：1）成功扩大适合未来 cGMP 生产的 RFT1081，2）完成剂量- 范围毒理学研究和相关非啮齿动物物种的选择，以及 3) 可行的 IND 支持和 FDA 审查了临床开发策略，以降低 RFT1081 未来开发步骤的风险。