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

描述(申请人提供)：尼曼-皮克C(NPC)是一种罕见的神经退行性脂肪堆积性疾病。大约95%的疾病是由NPC1突变引起的，NPC1是一种晚期内小体/溶酶体(LE/Ly)膜蛋白，在脂蛋白来源的胆固醇输出中发挥作用。受影响的人通常在儿童早期出现共济失调和运动和智力功能的进行性损害，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方法。最近，我们发现用某些组蛋白脱乙酰酶抑制剂(HDACi)处理人NPC1突变细胞，包括Vorinostat(SAHA，Zolinza™)，可以清除LE/Ly中多余的胆固醇和其他脂质，并纠正了胆固醇调节的整体缺陷。在其他 在未发表的工作中，我们发现，在被检查的80个NPC1突变体中，有60个在使用HDACi治疗后显示出显著的胆固醇清除，这表明大多数或NPC1患者可能从HDACi治疗中受益。作为一种NPC1治疗药物，威力诺是一种极好的临床测试候选药物，因为它是口服的，中枢神经系统渗透性的，并且是FDA批准的。我们这项研究的目标是在治疗NPC1疾病的第一阶段临床试验中检查Vorinostat。为了实现这一目标，我们将开展一项Vorinostat在青少年晚期和成年NPC1疾病患者中的第一阶段、首例人类、开放标签、单中心、剂量递增研究，以确定Vorinostat用于治疗这种疾病的安全性。12名NPC1患者(18岁及以上)将被招募参加研究。研究参与者最初每天服用200毫克，连续三个月，然后剂量增加到每天400毫克，连续三个月。将获得血浆和脑脊液的药代动力学，毒性监测，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记物在Vorinostat第一阶段剂量递增研究中指导治疗的有效性。主要的结果指标将是脑脊液3？，5-α，3？-胆三醇，这是一种胆固醇氧化产物，在NPC1疾病中特异性升高，并随着神经元胆固醇储存的缓解而降低。次要结果指标将包括血浆24(S)-羟基胆固醇，一种中枢神经系统特有的氧固醇，在纠正神经元胆固醇运输缺陷后升高；脑脊液神经鞘脂标志物；脑脊液蛋白(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。这些结果指标可能在未来的2/3期HDACi试验中作为替代结果指标。

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 In other unpublished work, we found that 60 of the 80 NPC1 mutants examined show significant cholesterol clearance upon treatment with the HDACi, indicating the majority or NPC1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.