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

描述（由申请人提供）：尼曼-皮克C （NPC）是一种罕见的神经退行性脂质储存疾病。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，在脂蛋白源性胆固醇的输出中起作用。受影响的个体通常表现为儿童早期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去乙酰化酶抑制剂（HDACi），包括Vorinostat （SAHA, Zolinza(tm)）处理人类NPC1突变细胞，导致LE/Ly中多余的胆固醇和其他脂质被清除，并纠正了胆固醇调节的整体缺陷。在其他

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 In other unpublished work, we found that 60 of the 80 NPC1 mutants examined show significant cholesterol clearance upon treatment with the HDACi, indicating the majority or NPC1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