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: 10706551
• 负责人: Yakov Kogan
• 金额: $ 105万
• 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/10706551
• 关键词: Anticonvulsants; Apolipoprotein A-I; Binding; Binding Proteins; Biological; Biological Assay; Cancer Patient; Canis familiaris; Cell membrane; Cells; Certification; 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; Macrophage; 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; Qualifying; Quality of life; Rattus; Regulation; Research; Risk; Rodent; Safety; Small Business Innovation Research Grant; Specific qualifier value; Spinal; Spinal Ganglia; Spinal nerve root structure; Sterility; Surface; TLR4 gene; Therapeutic; Toxic effect; Toxicology; Translating; United States National Institutes of Health; Vertebral column; 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; manufacture; manufacturing process; manufacturing scale-up; medication safety; meetings; neuroinflammation; non-opioid analgesic; nonhuman primate; novel; novel strategies; opioid misuse; pain relief; painful neuropathy; particle; pharmacologic; pre-Investigational New Drug meeting; 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.

项目摘要 化疗引起的周围神经病变（CIPN）对近100名患者的生活质量有着深远的负面影响。 70%的癌症患者接受化疗。虽然全身施用阿片类药物、NSAID和 抗惊厥药可以在短时间内缓解疼痛，但不适合长期治疗。除了功效， 许多有效的药剂受到有限的副作用以及与依赖性和成瘾性相关的问题的困扰。 RAFT Pharmaceuticals（RAFT）提出了一项直接进入2期SBIR提案，提出了一种新的方法， 通过调节脊髓和背根神经节（DRG）细胞中的脂筏逆转预先存在的神经性疼痛。 我们的主要候选物RFT 1081是一种修饰的apoA-I结合蛋白（AIBP），可促进 胆固醇选择性地从活化的和炎性细胞的质膜。这一目标是由于 AIBP与Toll样受体4（TLR 4）结合，TLR 4在炎症性小胶质细胞表面高度表达， 巨噬细胞和激活的DRG伤害感受器。RFT 1081介导的含有活化的脂筏的破坏 TLR 4消除了神经炎症和伤害感受器自发活动的易化周期， 慢性疼痛表型。在之前的一个项目中，我们开发了一个非GMP规模的上游和下游 RFT 1081的生产工艺，并对其进行了详细表征;进行了药代动力学 小鼠中经脊髓给药的RFT 1081研究和设计的评价RFT 1081的药效学试验 靶向接合;在CIPN小鼠中建立AIBP治疗的剂量依赖性功效曲线;并进行 大鼠中RFT 1081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 在拟定的直接至II期SBIR研究中开发RFT 1081。在这个里程碑驱动的项目中，我们 计划使用cGMP兼容工艺生产用于毒理学研究的RFT 1081制剂批次，以及 分析测定。RFT 1081制剂批次符合RAFT的质量标准，并进行了优化 将对制剂的储存和使用中稳定性进行彻底表征。最初的单剂量毒理学 将在大鼠中进行研究。然后，我们还将评估药理学、局部和全身毒性， 对重复i.t.在大鼠、狗和非人灵长类动物中施用RAFT 1081以进一步 研究该药物的安全性，并选择一种与临床研究相关的非啮齿类动物种属进行进一步IND- 从而能够进行临床前评估。还将在顺铂癌症治疗模型中评价RFT 1081，以确保 它不干扰化疗作用。该项目最后将制定一个详细的大纲， 一项综合的首次人体研究和一项支持适应症的总体临床策略，随后进行准备 并与FDA进行IND前会议。我们预计，第二阶段SBIR项目的成果将 包括：1）RFT 1081成功放大，适用于未来cGMP生产，2）完成剂量- 广泛的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使能和 FDA审查的临床开发策略，以降低RFT 1081开发未来步骤的风险。