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

该项目的长期目标是建立一种新型口腔矫正剂--甘油的安全性和耐受性 丁酸苯酯或Ravicti®--最常见的CFTR突变F508del-CFTR。苯丁酸甘油是一种 甘油三酯前体药物4-苯基丁酸酯(4PBA，丁苯®)。我们测试了4-PBA作为一种系统纠正剂 在一系列1期和2期临床试验中，F508del in CF。我们发现最大耐受量为20克 每日分时段TI.D.诱导环磷酰胺介导的鼻腔上皮氯离子转运的最大剂量为30 通用汽车每日分T.I.D.治疗第4天和第7天的中位数为-10 mV。在这种情况下， 汗氯化物值或阿米洛利抑制的NPD没有显著下降。我们将这些结果解释为 这意味着在没有增强剂的情况下，F508del仅靠矫正治疗是不够的。因为这些 Vertex公司已经成功地开发了作为增效剂(氯化物)的iVacaftor G551D CFTR的通道开放剂)，并单独研究了该药物，并与其矫正器联合研究 Lumacaftor和VX-661用于纯合子F508del CF.IVacaftor和Lumacaftor的组合是在 美国食品和药物管理局考虑在CF批准。目前还不能确定校正器和校正器未来组合 增效剂将是安全有效的。4-苯丁酸酯、苯丁酸甘油或Ravicti？ (Hyperion)于2013年2月获得美国FDA的批准。这种新配方是一种口服、无臭、 无味的液体，每一分子苯丁酸甘油提供三个4-PBA分子。胰腺 酶是释放活性药物所必需的，必须与药物一起服用才能释放4-PBA。 假设陈述：苯丁酸甘油可部分恢复鼻上皮细胞F508del CFTR F508del纯合子的成人CF受试者。项目目标：目标1：建立安全和 成人对苯丁酸甘油酯的耐受性。目标2：确定该方案的有效性 胰酶对苯丁酸甘油吸收的影响。目标3：确定最大容忍度 研究用药的剂量。目的4：定量测定第4天和第7天鼻腔上皮CFTR介导的氯离子转运 接触甘油、苯丁酸酯或安慰剂。目的5：选择合适剂量的苯丁酸甘油用于治疗 苯丁酸甘油与增强剂(异烟肼)联合应用治疗成人慢性纤维性心脏病的临床研究 F508del CFTR为纯合子。这项研究将以随机、双盲、安慰剂对照、 CFTDN成员中的三个地点的剂量发现设计，并熟练地进行CF试验和 结果测量包括鼻电势差测试。

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.