A Phase 1 Dose Escalation Study of Vorinostat in Niemann-Pick C1 Disease

伏立诺他治疗尼曼-匹克 C1 病的 1 期剂量递增研究

• 批准号: 8639788
• 负责人: Frederick R. Maxfield
• 金额: $ 36.02万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-01-10 至 2016-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8639788
• 关键词: 18 year old; Adolescence; Adolescent; Adult; Adverse effects; Affect; Animals; Ataxia; Biochemical; Biological Markers; Blood; Blood - brain barrier anatomy; Cells; Chemistry; Childhood; Cholesterol; Clinical; Clinical Treatment; Clinical Trials; Clinical assessments; Collaborations; Cutaneous; Cyclodextrins; Data; Defect; Disease; Disease Progression; Dose; Drug Kinetics; Effectiveness; Extramural Activities; FABP3 gene; FDA approved; Foundations; Future; Glycosphingolipids; Goals; Histone Acetylation; Histone Deacetylase Inhibitor; Hour; Human; Hydroxycholesterols; Individual; Infusion procedures; Intrathecal Injections; Laboratories; Lead; Life; Lipids; Lipoproteins; Lysosomes; Malignant neoplasm of brain; Measures; Membrane Proteins; Miglustat; Monitor; Mononuclear; Mus; Mutation; National Institute of Child Health and Human Development; Nerve Degeneration; Neurodegenerative Disorders; Neurons; Oral; Oral cavity; Outcome Measure; Participant; Patients; Peripheral; Pharmaceutical Preparations; Pharmacotherapy; Phase; Phase I Clinical Trials; Plasma; Proteins; Recruitment Activity; Regimen; Regulation; Reporting; Safety; Sampling; Schedule; Severities; Sphingolipids; T-Cell Lymphoma; Therapeutic; Therapeutic Effect; Time; Toxic effect; Treatment Efficacy; United States National Institutes of Health; Universities; Vorinostat; Washington; Zolinza; base; calbindin D; cholesterol trafficking; design; early childhood; medical schools; meetings; motor impairment; mutant; open label; oxidation; primary outcome; protein function; public health relevance; research clinical testing; response; safety testing; secondary outcome; unpublished works

DESCRIPTION (provided by applicant): Niemann-Pick C (NPC) is a rare, neurodegenerative, lipid storage disease. Approximately 95% of the disease is caused by mutations in NPC1, a late endosomal/lysosomal (LE/Ly) membrane protein that functions in export of lipoprotein-derived cholesterol. Affected individuals typically present in early childhood with ataxia and progressive impairment of motor and intellectual function, and usually die in adolescence. There are currently no FDA-approved therapies for this fatal neurodegenerative disorder. Recently, we found that treatment of human NPC1 mutant cells with certain histone deacetylase inhibitors (HDACi), including Vorinostat (SAHA, Zolinza(tm)), leads to clearance of excess cholesterol and other lipids from the LE/Ly, and it corrects the overall defect in cholesterol regulation. In other unpublished work, we found that 60 of the 80 NPC1 mutants examined show significant cholesterol clearance upon treatment with the HDACi, indicating the majority or NPC1 patients may benefit from HDACi therapy. Vorinostat is an excellent candidate for clinical testing as an NPC1 therapeutic because it is orally-available, CNS-penetrant, and FDA-approved. The goal of our study is to examine Vorinostat in a Phase 1 clinical trial for the treatment of NPC1 disease. To meet this objective, we will develop a Phase 1, first-in-human, open-label, single-center, dose escalation study of Vorinostat in late adolescents and adults with NPC1 disease to establish the safety of Vorinostat for treatment of this disorder. 12 NPC1 patients (18 years and older) will be recruited for the study. Study participants will initially be dosed with 200 mg po daily for three months, followed by dose escalation to 400 mg po daily for three months. Plasma and CSF pharmacokinetics will be obtained, toxicity monitored, and clinical assessments performed. We will further evaluate the utility of peripheral and CSF disease biomarkers to guide therapy in the Phase 1 Vorinostat dose-escalation study. The primary outcome measure will be CSF 3¿,5¿,3¿- cholesten-triol, a cholesterol oxidation product that is specifically elevated in NPC1 disease and decreases in response to alleviation of neuronal cholesterol storage. Secondary outcome measures will include plasma 24(S)-hydroxycholesterol, a CNS-specific oxysterol that is elevated following correction of the neuronal cholesterol trafficking defect; CSF sphingolipid markers; CSF proteins (e.g., Calbindin D and FABP3); and histone acetylation and NPC1 protein levels in circulating mononuclear cells. These outcome measures can potentially serve as surrogate outcome measures in future Phase 2/3 HDACi trials.

描述（由申请人提供）：Niemann-Pick C (NPC) 是一种罕见的神经退行性脂质沉积病。大约 95% 的疾病是由 NPC1 突变引起的，NPC1 是一种晚期内体/溶酶体 (LE/Ly) 膜蛋白，在脂蛋白衍生胆固醇的输出中发挥作用。受影响的个体通常在儿童早期出现共济失调以及运动和智力功能进行性损伤，并且通常在青春期死亡。目前尚无 FDA 批准的治疗这种致命神经退行性疾病的疗法。最近，我们发现用某些组蛋白脱乙酰酶抑制剂（HDACi）（包括 Vorinostat（SAHA，Zolinza(tm)）治疗人类 NPC1 突变细胞，可以清除 LE/Ly 中多余的胆固醇和其他脂质，并纠正胆固醇调节的整体缺陷。在其他方面 在未发表的研究中，我们发现所检查的 80 种 NPC1 突变体中有 60 种在使用 HDACi 治疗后显示出显着的胆固醇清除率，表明大多数 NPC1 患者可能受益于 HDACi 治疗。伏立诺他是作为 NPC1 治疗剂进行临床测试的绝佳候选者，因为它可口服、具有中枢神经系统渗透性且已获得 FDA 批准。我们研究的目的是在 NPC1 疾病治疗的 1 期临床试验中检查伏立诺他 (Vorinostat)。为了实现这一目标，我们将在患有 NPC1 疾病的青少年晚期和成人中开展伏立诺他的 1 期、首次人体、开放标签、单中心剂量递增研究，以确定伏立诺他治疗这种疾病的安全性。 12 名 NPC1 患者（18 岁及以上）将被招募参加该研究。研究参与者最初将每天口服 200 毫克，持续三个月，然后剂量逐步增加至每天 400 毫克，持续三个月。 将获得血浆和脑脊液药代动力学、监测毒性并进行临床评估。我们将进一步评估外周和脑脊液疾病生物标志物在 1 期伏立诺他剂量递增研究中指导治疗的效用。主要结果指标是脑脊液 3',5',3'- 胆固醇三醇，这是一种胆固醇氧化产物，在 NPC1 疾病中特别升高，并随着神经元胆固醇储存的缓解而降低。次要结果指标包括血浆 24(S)-羟基胆固醇，这是一种中枢神经系统特异性氧甾醇，在纠正神经元胆固醇运输缺陷后会升高；脑脊液鞘脂标记物； CSF 蛋白（例如 Calbindin D 和 FABP3）；循环单核细胞中的组蛋白乙酰化和 NPC1 蛋白水平。这些结果测量有可能作为未来 2/3 期 HDACi 试验的替代结果测量。