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.

该项目的长期目标是建立新型口服校正器的安全性和耐受性 - 甘油 最常见的CFTR突变F508DEL-CFTR。甘油苯丁酸是 4-苯基丁酸的甘油三酸酯促尿液（4pba，buphenyl®）。我们测试了4-PBA作为系统的校正器 CF中的F508DEL在一系列第1阶段和2次临床试验中。我们发现最大耐受的口服剂量为20克 每日划分的T.I.D.并最大程度地诱导了30上环状介导的鼻皮氯化物转运 通用每日划分的T.I.D.在治疗的第4天和第7天，为-10 mV的中位数。在这些条件下 汗水氯化物值或抗算机抑制的NPD无显着降低。我们将这些结果解释为 表示在没有潜在剂的情况下，仅校正治疗对于F508DEL不足。由于这些 出版物，Vertex Corporation在iVacaftor作为潜在者的发展（氯化物）方面取得了成功 G551D CFTR的频道开启器），并且单独研究了该药物并与校正器结合使用 LumAcaptor和VX-661用于纯合F508DEL CF。 ivacaftor和LumAcaptor的组合是 FDA供CF中考虑批准。尚不确定校正器的未来组合和 增强器将是安全有效的。新的4-苯基丁酸，甘油苯基丁酸或ravicti®的新型Pro-Proug （Hyperion）在2013年2月获得美国FDA批准。这个新公式是一种口头，odoless 无味的液体为每个分子的甘油苯基丁酸提供三个分子的4-PBA。胰 需要酶释放活性药物，必须用药物服用以释放4-PBA。 假设的说法：甘油苯基丁酸酯将部分恢复鼻上皮中的F508DEL CFTR F508DEL纯合的成人CF受试者项目的目标：目标1：建立安全和 甘油苯丁酸甘油CF的成年人的耐受性。目标2：确定有效性 胰腺酶滥用甘油苯丁酸甘油。目标3：建立最大可容忍的 研究药物的剂量。目标4：量化4天和7天的鼻上皮CFTR CFTR介导的氯化物转运 暴露于甘油苯丁酸或安慰剂中。目标5：选择一剂甘油苯丁酸 成人CF受试者中甘油苯丁酸苯甲酸苯甲酸苯酚和势剂（ivacaftor）组合的临床试验 F508DEL CFTR的纯合子。该研究将作为随机，双盲，安慰剂对照进行进行， 在CFTDN成员的三个地点进行剂量查找设计，并在CF试验的进行方面熟练 结果指标，包括鼻电差测试。