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
基本信息
- 批准号:10546418
- 负责人:
- 金额:$ 100万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 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:
- 关键词:AnticonvulsantsApolipoprotein A-IBinding ProteinsBiologicalBiological AssayCancer PatientCanis familiarisCell membraneCellsChemotherapy-induced peripheral neuropathyCholesterolChronicCisplatinClinicalClinical ResearchCyclic GMPDataDependenceDevelopmentDevelopment PlansDoseDrug KineticsEndotoxinsEnsureEpidemicExcisionFormulationFutureHealthcareHelping to End Addiction Long-termImmune responseInflammationInflammatoryInjuryMediatingMembrane MicrodomainsMethodsMicrogliaModelingMonitorMusNOELNational Institute of Neurological Disorders and StrokeNo-Observed-Adverse-Effect LevelNociceptorsNon-Steroidal Anti-Inflammatory AgentsOpioidOrganOutcomePainPain managementPatientsPeripheral NervesPharmaceutical PreparationsPharmacodynamicsPharmacologic SubstancePharmacologyPhasePhenotypePreparationProcessProteinsQuality of lifeRattusRegulationResearchRiskRodentSafetySmall Business Innovation Research GrantSpinalSpinal GangliaSpinal nerve root structureSterilitySurfaceTLR4 geneTherapeuticToxic effectToxicologyTranslatingUnited States National Institutes of HealthaddictionbiobankcGMP productioncancer therapychemotherapychronic painclinical developmentdesigndrug standardeffective therapyexperimental studyfirst-in-humanganglion cellhuman studylead candidatemacrophagemanufacturing processmanufacturing scale-upmedication safetymeetingsneuroinflammationnon-opioid analgesicnonhuman primatenovelnovel strategiesopioid misusepain reliefpainful neuropathyparticlepreclinical evaluationpreclinical studyprocess optimizationprogramsresearch clinical testingresponsesafety studyscale upside effectsuccesssystemic toxicity
项目摘要
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.
项目总结
化疗所致周围神经病(CIPN)对近20年来老年人的生活质量有深远的负面影响
70%的癌症患者接受化疗。而阿片类药物、非甾体抗炎药和
抗惊厥药止痛时间短,不宜长期服用。除了功效之外,
许多强效药物都受到限制副作用以及与依赖和成瘾有关的问题的困扰。
RAFT制药公司(RAFT)提出了一项直接到第二阶段SBIR的建议,提出了一种新的方法
通过调节脊髓和背根神经节(DRG)细胞中的脂筏逆转先前存在的神经病理性疼痛。
我们的主要候选基因RFT1081是一种修饰的apoA-I结合蛋白(AIBP),它促进
胆固醇选择性地从激活的和炎性细胞的质膜中分离出来。这一目标是由于
AIBP与炎性小胶质细胞表面高表达的Toll样受体4(TLR4)结合,
巨噬细胞和激活的DRG伤害性感受器。RFT1081介导的脂筏破坏活性
TLR4取消了神经炎症和伤害性感受器自发活动的促进周期,并缓解了
慢性疼痛表型。在之前的项目中,我们开发了一个非GMP上下游放大的
RFT1081的制造工艺,并进行了详细的表征;进行了药代动力学研究
脊髓递送RFT1081在小鼠体内的研究及药效学研究
靶向参与;建立了AIBP在CIPN小鼠中治疗的剂量依赖疗效曲线;并进行了
RFT1081在大鼠体内的非GLP剂量耐受性研究这些数据提供了支持并进一步证明了这一点
在拟议的直接到第二阶段SBIR研究中开发RFT1081。在这个里程碑驱动的项目中,我们
计划使用与cGMP兼容的工艺生产用于毒理学研究的RFT1081药物产品批次,并
分析化验。RFT1081药品批次,符合RAFT规范,处于优化状态
将对配方进行彻底的表征,以确保储存和使用稳定性。最初的单剂量毒理学
研究将在大鼠身上进行。然后我们还将评估药理、局部和全身毒性,以及
对重复I.T.的免疫反应。RAFT1081在大鼠、狗和非人灵长类动物中的应用
研究该药物的安全性,并选择药理上相关的非啮齿动物物种进行进一步的研究。
启用临床前评估。RFT1081还将在顺铂癌症治疗模型中进行评估,以确保
它不会干扰化疗的作用。该项目最后将制定一份详细的概要
一项综合性的首个人体研究和全面的适应症支持临床策略,随后是准备
支持并与FDA召开IND前会议。我们预计这一第二阶段SBIR项目的成果将
包括:1)适合未来cGMP生产的RFT1081的成功放大;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)可行的支持IND和
与FDA一起审查了临床开发战略,以降低RFT1081开发的未来步骤的风险。
项目成果
期刊论文数量(0)
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Yakov Kogan的其他文献
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{{ truncateString('Yakov Kogan', 18)}}的其他基金
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 - 财政年份:2022
- 资助金额:
$ 100万 - 项目类别:
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