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.
Cystic Fibrosis is one of the most common life-shortening inherited disorders with no cure and a huge lifetime financial burden. Ninety percent of cases of CF result from one or two F508del mutations in CFTR and there is no approved pharmaceutical to repair this mutation. Our application addresses the need for correctors of the most common F508del mutation to assist it in trafficking to the plasma membrane, by a randomized, double- blind, placebo-controlled, Phase 1-2 multicenter trial of glycerolphenylbutyrate as a corrector of F508del CF.
