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确定一种新型口腔矫正剂——甘油的安全性和耐受性 苯丁酸或 Ravicti®。——最常见的 CFTR 突变 F508del-CFTR。苯丁酸甘油酯是一种 4-苯基丁酸酯的甘油三酯前药（4PBA，Buphen®）。我们测试了 4-PBA 作为系统校正剂 F508del 在 CF 中进行了一系列 1 期和 2 期临床试验。我们发现最大耐受口服剂量为 20 克 每日划分 t.i.d.以及环腺苷酸介导的鼻上皮氯转运的最大诱导 30 GM每日划分t.i.d.治疗第 4 天和第 7 天的中位数为 -10 mV。在那些条件下有 汗液氯化物值或阿米洛利抑制的 NPD 没有显着降低。我们将这些结果解释为 表明在没有增效剂的情况下，单独的校正剂疗法不足以治疗 F508del。由于这些 出版物中，Vertex 公司成功开发了 ivacaftor 作为增效剂（氯化物） G551D CFTR 的通道开放剂），并单独研究了该药物以及与其校正剂的组合 lumacaftor 和 VX-661 用于纯合 F508del CF。 ivacaftor 和 lumacaftor 的组合是之前 FDA 考虑批准 Cf。目前还不确定未来校正器和 增效剂将是安全有效的。 4-苯基丁酸酯、苯基丁酸甘油酯或 Ravicti® 的新型前药 （Hyperion）于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，每个甘油苯丁酸酯分子提供三个 4-PBA 分子。胰 释放活性药物需要酶，并且必须与药物一起服用才能释放 4-PBA。 假设陈述：苯丁酸甘油酯将部分恢复鼻上皮中的 F508del CFTR F508del 纯合的成人 CF 受试者。项目目标： 目标 1：建立安全和 成人 CF 患者对苯丁酸甘油酯的耐受性。目标 2：确定有效性 胰酶对苯丁酸甘油酯吸收的影响。目标 3：确定最大容忍度 研究药物的剂量。目标 4：量化第 4 天和第 7 天时鼻上皮 CFTR 介导的氯离子转运 接触甘油苯丁酸酯或安慰剂。目标 5：选择苯丁酸甘油酯的剂量 苯丁酸甘油酯与增效剂 (ivacaftor) 联合用于成人 CF 受试者的临床试验 F508del CFTR 纯合。该研究将以随机、双盲、安慰剂对照的方式进行 在 CFTDN 成员且擅长进行 CF 试验的三个地点进行剂量发现设计 结果测量包括鼻电位差测试。