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

描述（由申请方提供）：尼曼匹克C型（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NPC 1突变引起的，NPC 1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起作用。受影响的个体通常在幼儿期出现共济失调和运动和智力功能的进行性损害，并且通常在青春期死亡。目前还没有FDA批准的治疗这种致命的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）（包括伏立诺他（SAHA，Zolinza™））处理人NPCl突变细胞导致从LE/Ly清除过量胆固醇和其他脂质，并且其校正胆固醇调节的总体缺陷。换句 在未发表的工作中，我们发现80个NPC 1突变体中的60个在用HDACi治疗后显示出显著的胆固醇清除，表明大多数NPC 1患者可以从HDACi治疗中受益。伏立诺他是临床试验作为NPC 1治疗剂的优秀候选者，因为它是口服可获得的，CNS渗透剂，并且FDA批准。我们研究的目的是在治疗NPC 1疾病的1期临床试验中检查伏立诺他。为了实现这一目标，我们将在患有NPC 1疾病的晚期青少年和成人中开展伏立诺他的I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。本研究将招募12例NPC 1患者（18岁及以上）。研究参与者最初将接受200 mg po每日给药，持续3个月，随后剂量递增至400 mg po每日给药，持续3个月。 将获得血浆和CSF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CSF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。主要结局指标将是CSF 3 α，5 α，3 α-胆固醇三醇，一种胆固醇氧化产物，在NPC 1疾病中特异性升高，并在神经元胆固醇储存缓解时降低。次要结果测量将包括血浆24（S）-羟基胆固醇，一种CNS特异性氧化固醇，其在神经元胆固醇运输缺陷校正后升高; CSF鞘脂标志物; CSF蛋白质（例如，钙结合蛋白D和FABP 3）;以及循环单核细胞中的组蛋白乙酰化和NPC 1蛋白水平。这些结局指标可能作为未来2/3期HDACi试验的替代结局指标。

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™)), 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 In other unpublished work, we found that 60 of the 80 NPC1 mutants examined show significant cholesterol clearance upon treatment with the HDACi, indicating the majority or NPC1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 3ß,5α,3ß- 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.