Novel Treatment for Hermansky-Pudlak Syndrome Pulmonary Fibrosis

赫曼斯基-普德拉克综合征肺纤维化的新疗法

基本信息

批准号：
10470637
负责人：
Sharie Haugabook
金额：
$ 107.1万
依托单位：
NATIONAL CENTER FOR ADVANCING TRANSLATIONAL SCIENCES
依托单位国家：
美国
项目类别：
财政年份：
资助国家：
美国
起止时间：
至
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10470637
关键词：
Adult Animal Model Bioavailable Biogenesis Biological CNR1 gene Cessation of life Chronic Cicatrix Clinical Clinical Data Complex DNA Sequence Alteration Development Drug Kinetics Fibrosis Formulation Hermanski-Pudlak Syndrome Human In Vitro Inherited Investigational New Drug Application Lead Lung Lung Inflammation Lysosomes Magnetic Resonance Imaging Metabolism Mus NOS2A gene National Human Genome Research Institute National Institute on Alcohol Abuse and Alcoholism Neuraxis Oral Organelles Pathogenesis Pathway interactions Patients Peripheral Pharmaceutical Preparations Phase Phase II Clinical Trials Process Pulmonary Fibrosis Rare Diseases Receptor Inhibition Rodent Scientist Structure of parenchyma of lung Symptoms Therapeutics for Rare and Neglected Diseases Tissues Treatment Efficacy United States Food and Drug Administration comparative efficacy design drug candidate improved in vivo inhibitor/antagonist lung development neuropsychiatry new therapeutic target novel novel therapeutics pre-clinical premature rare genetic disorder research clinical testing rimonabant side effect treatment strategy

项目摘要

Hermansky-Pudlak syndrome is a rare genetic disorder primarily of lysosome-related organelle biogenesis. There are 10 different types of HPS, depending on which genetic mutation is inherited. Patients with HPS-1, HPS-2 or HPS-4 develop pulmonary fibrosis. In the absence of a Food and Drug Administration (FDA)-approved therapy for HPS-PF, there is an urgent need to identify new therapeutic targets and treatment strategies. It has been shown that the cannabinoid-1 receptor (CB1R) is overactivated in fibrotic lung tissue of mice and humans with HPS. In previous studies, rimonabant, a CB1R antagonist, demonstrated a modest ability to mitigate fibrosis in animal models. However, neuropsychiatric side effects of CB1R inhibition in the central nervous system (CNS) led to rimonabant being withdrawn from all clinical use. Additionally, the activity of inducible nitric oxide synthase (iNOS) is also increased in PF, promoting lung inflammation and progression of fibrosis. Because the pathogenesis of HPS-PF is complex, targeting multiple pathways has been recommended as an approach to improve therapeutic efficacy. To target these independent drivers of PF simultaneously in HPS, the novel drug candidate MRI-1867 was designed as a dual inhibitor of both CB1R and iNOS. To avoid the CNS side effects, MRI-1867 was designed to be restricted to only the peripheral tissues. MRI-1867 is orally bioavailable, and in chronic treatment in animal models of PF it provided increased antifibrotic efficacy compared with targeting either CB1R or iNOS alone. TRND scientists developed a synthetic process for GMP manufacturing of the development compound, S-MRI-1867, including conduct of pre-formulation studies. Studies to evaluate metabolism in vitro, and in vivo metabolite identification and pharmacokinetic analysis in rodents were also completed. MRI-1867 is being developed in parallel for another rare disease indication. The IND-enabling preclinical and Phase I clinical data from those studies are expected to be leveraged to enable the submission of an Investigational New Drug application with the FDA to initiate a pivotal Phase II clinical trial in HPSPF patients.

Hermansky-Pudlak综合征是一种罕见的遗传疾病，主要是与溶酶体相关的细胞器生物发生。有10种不同类型的HP，具体取决于遗传突变的遗传。 HPS-1，HPS-2或HPS-4患者患有肺纤维化。在没有食品和药物管理局（FDA）批准的HPS-PF疗法的情况下，迫切需要确定新的治疗靶标和治疗策略。已经表明，大麻素-1受体（CB1R）在小鼠的纤维化肺组织中过度活化，并具有HPS。在先前的研究中，CB1R拮抗剂Rimonabant表现出适度的减轻动物模型纤维化的能力。然而，中枢神经系统（CNS）中CB1R抑制的神经精神副作用导致Rimonabant从所有临床使用中撤回。另外，PF中诱导型一氧化氮合酶（INOS）的活性也增加，从而促进肺部炎症和纤维化进展。由于HPS-PF的发病机理是复杂的，因此建议将多种途径靶向以提高治疗疗效的方法。为了同时针对HPS中PF的这些独立驱动因素，新型药物MRI-1867被设计为CB1R和INOS的双重抑制剂。为避免CNS副作用，MRI-1867被设计为仅限于外围组织。 MRI-1867是口服生物可利用的，在PF动物模型中，与仅针对CB1R或INOS相比，在慢性治疗中，它提供了增加的抗纤维化功效。 TRND科学家开发了用于开发化合物S-MRI-1867的GMP生产的合成过程，包括进行前制定研究。还完成了评估体外代谢的研究，还完成了啮齿动物中体内代谢产物鉴定和药代动力学分析。 MRI-1867正在并行开发，以供另一种罕见的疾病指示。预计将利用来自这些研究的临床前和I期临床数据，以使与FDA的研究新药应用能够在HPSPF患者中启动一项关键的II期临床试验。