Ph 1-2 Study of Glycerolphenylbutyrate for Cystic Fibrosis IND 125,124 (12/5/15)

Ph 1-2 甘油苯基丁酸酯治疗囊性纤维化的研究 IND 125,124 (12/5/15)

• 批准号: 9322858
• 负责人: Pamela L. Zeitlin
• 金额: $ 12.5万
• 依托单位: NATIONAL JEWISH HEALTH
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-08-01 至 2021-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9322858
• 关键词: Ph; Study; Glycerolphenylbutyrate; Cystic; Fibrosis

The long term goal of this project is to establish the safety and tolerability of a novel oral corrector-- glycerol phenylbutyrate or Ravicti®.--of the most common CFTR mutation F508del-CFTR. Glycerol phenylbutyrate is a triglyceride pro-drug of 4-phenylbutyrate (4PBA, Buphenyl®). We tested 4-PBA as a systemic corrector for F508del in CF in a series of Phase 1 and 2 clinical trials. We found a maximum tolerated oral dose of 20 gm daily divided t.i.d. and the maximum induction of cyclicAMP-mediated nasal epithelial chloride transport on 30 gm daily divided t.i.d. as a median of -10 mV on days 4 and 7 of treatment. Under those conditions there was no significant decrease in sweat chloride values or in amiloride-inhibited NPD. We interpreted these results to signify that corrector therapy alone is insufficient for F508del in the absence of a potentiator. Since these publications, Vertex Corporation has had success with the development of ivacaftor as a potentiator (chloride channel opener) of G551D CFTR and has studied the drug alone and in combination with their correctors lumacaftor and VX-661 for homozygous F508del CF. The combination of ivacaftor and lumacaftor is before the FDA for consideration of approval in Cf. It is not yet certain that future combinations of corrector and potentiator will be safe and effective. A new pro-drug of 4-phenylbutyrate, glycerol phenylbutyrate or Ravicti® (Hyperion) was approved in February 2013 by the US FDA. This new formulation is an oral, odorless, tasteless liquid providing three molecules of 4-PBA for every molecule of glycerolphenylbutyrate. Pancreatic enzymes are required to release the active drug and must be taken with the drug to release the 4-PBA. Statement of Hypothesis: Glycerol phenylbutyrate will partially restore F508del CFTR in the nasal epithelium of adult CF subjects homozygous for F508del. Goals of the Project: Objective 1: To establish safety and tolerability in adults with CF of glycerol phenylbutyrate. Objective 2: To determine the effectiveness of pancreatic enzymes on absorption of glycerol phenylbutyrate. Objective 3: To establish the maximum tolerable dose of study drug. Objective 4: To quantify nasal epithelial CFTR-mediated chloride transport at 4 and 7 days exposure to glycerol phenylbutyrate or placebo. Objective 5: To select a dose of glycerol phenylbutyrate for a clinical trial of the combination of glycerol phenylbutyrate and potentiator (ivacaftor) in adult CF subjects homozygous for F508del CFTR. The study will be conducted as randomized, double-blind, placebo-controlled, dose finding design at three sites that are members of the CFTDN and skilled in the conduct of CF trials and outcome measures including nasal potential difference testing.

本项目的长期目标是确定一种新型口服校正剂-甘油的安全性和耐受性 苯基丁酸盐或Ravicti®。最常见的CFTR突变F508 del-CFTR。苯丁酸甘油酯是一种 4-苯基丁酸酯（4PBA，Buphenyl®）的甘油三酯前药。我们测试了4-PBA作为全身校正剂， F508 del在CF中的一系列I期和II期临床试验。我们发现最大耐受口服剂量为20克 每日分三次cyclicAMP介导的鼻上皮氯离子转运的最大诱导量为30 gm每日分三次治疗第4天和第7天的中位数为-10 mV。在这种情况下， 汗液氯化物值或阿米洛利抑制的NPD无显著降低。我们将这些结果解释为 表明在没有增效剂情况下，单独的校正剂治疗对于F508 del是不够的。由于这些 在出版物中，Vertex公司已经成功地开发了作为增效剂（氯化物）的依伐卡托 通道开放剂），并研究了单独的药物和与其校正剂的组合 鲁玛卡托和VX-661用于纯合F508 del CF。ivacaftor和lumacaftor的组合是在 FDA考虑批准Cf.目前尚不确定未来的校正器和 增强剂将是安全和有效的。4-苯基丁酸酯、苯基丁酸甘油酯或Ravicti®的新前药 2013年2月获得美国FDA批准。这种新配方是一种口服，无味， 无味液体，每分子甘油苯丁酸酯提供3分子4-PBA。胰腺 需要酶来释放活性药物，并且必须与药物一起服用以释放4-PBA。 假设声明：苯丁酸甘油酯将部分恢复鼻上皮中的F508 del CFTR F508 del纯合子的成年CF受试者。项目目标：目标1：建立安全和 苯丁酸甘油酯在CF成人中的耐受性。目标2：确定 胰酶对苯丁酸甘油酯吸收的影响。目的3：确定最大耐受量 研究药物剂量。目的4：在4天和7天时定量鼻上皮CFTR介导的氯离子转运 暴露于苯丁酸甘油酯或安慰剂。目的5：选择苯丁酸甘油酯的剂量， 苯丁酸甘油酯和增效剂（依伐卡托）组合在成人CF受试者中的临床试验 F508 del CFTR纯合子。本研究将以随机、双盲、安慰剂对照的方式进行， 在CFTDN成员和熟练开展CF试验的三个研究中心进行剂量探索设计， 结果测量包括鼻电位差测试。