Glycerol Phenylbutyrate Corrector Therapy For CF (Cystic Fibrosis)

We were the first to test 4-phenylbutyrate (Buphenyl) as a systemic corrector of these
defects in F508del under an investigator-initiated Investigational New Drug (IND)application
held by P. Zeitlin. In a series of Phase 1 and 2 trials we established the maximum tolerated
dose as 20 gm daily divided t.i.d. and the maximum induction of cyclic AMP (cAMP)-mediated
nasal epithelial chloride transport with 30 gm daily as a median of -10 millivolt (mV) on
days 4 and 7 of treatment.1;2 Under those conditions there was no significant decrease in
sweat chloride values or in amiloride-inhibited nasal potential difference (NPD). We
interpreted these results as a proof of concept of corrector therapy, but corrector therapy
alone was likely an insufficient therapy for this mutation in CF, and therefore closed the
IND for 4-phenylbutyrate.

In the ensuing years, Vertex Pharmaceuticals, Inc. has had success with the development of
ivacaftor3;3;4 (VX-770) as a potentiator of G551D CFTR and has studied the drug alone and in
combination with their corrector lumacaftor5 (VX-809) and VX-661. We at Johns Hopkins
University (JHU), University of Alabama at Birmingham (UAB) and Childrens' Hospital of
Philadelphia/University of Pennsylvania (CHOP/Penn) have participated in many of the clinical
trials and are pleased and encouraged by the success of VX-770. It is not yet certain that
future combinations of corrector(s) and potentiator(s) will be safe and effective, and it is
prudent to explore alternative correctors and potentiators. Furthermore, recent structural
investigations in a number of laboratories support the idea that more than one corrector may
be necessary to fully restore F508del to the trafficking pathway 6. Precedent for combination
of 4PBA with other CFTR modulators has been established in vitro 7;8 4-Phenylbutyrate tablets
are formulated for oral delivery, and we showed that the pharmacokinetics were similar in CF
to that in patients with urea cycle disorders. However the large number of tablets that had
to be ingested at each meal were somewhat daunting at the 30 gm daily dose. A new pro-drug of
4-phenylbutyrate, glycerol phenylbutyrate or Ravicti®(owned by Hyperion Pharmaceuticals,
Inc.) was approved in February 2013 by the US FDA. This new formulation is a significant
advance for patients with urea cycle disorders because it is an oral, odorless, tasteless
liquid, that contains 3 molecules of 4-phenylbutyrate for every molecule of the triglyceride.
Simple arithmetic would suggest that one mole equivalent of the pro-drug provides three moles
of active drug. However, pancreatic lipase enzymes are required to break the covalent bonds
and release the active drug in the intestines. Because most CF patients homozygous for
F508del are pancreatic-insufficient and already on enzyme therapy, we propose to test the
effectiveness of the combination of CF pancreatic enzyme replacement therapy (PERT) on
absorption of Ravicti® and subsequent restoration of nasal epithelial CFTR-mediated chloride
transport during the nasal potential difference (NPD) test.

Inclusion Criteria:

1. Male or female 18 years or older.

2. Confirmed diagnosis of CF based on the following criteria:

A genotype with two F508del CFTR mutations and one or more clinical features consistent
with the CF phenotype 3. Taking pancreatic enzyme replacement therapy (PERT). 4. Ability to
perform acceptable spirometry. 5. Ability to understand and sig a written informed consent
and comply with the requirements of the study.

6 FEV1 greater than 30% predicted normal for age, gender, height (Hankinson standards) pre
or post-bronchodilator at Screening.

7. Oxygen saturation by pulseoximetry 90% or greater breathing ambient air at screening and
day 1.

8. Hematology and clinical chemistry of blood and urine results with no clinically
significant abnormalities that would interfere with the study assessments (as judged by the
principal investigator) at screening. If electrolyte abnormality at screening, values must
be corrected prior to dosing.

9. Subjects on chronic inhaled antibiotic therapy are eligible if they can continue their
usual antibiotic regimen, or remain on their off-cycle period, for the duration of study
drug exposure.

10. Negative pregnancy test for women of child-bearing potential. Females of childbearing
potential must agree to practice one highly effective method of birth control, including
abstinence, from the time of consent through the Day 14 outpatient visit. Barrier
contraceptives such as the male condom or diaphragm are acceptable if used in combination
with spermicides or there is documentation of azoospermia vasectomy, hysterectomy, or tubal
ligation.(Orkambi)

Exclusion Criteria:

1. Current use of ivacaftor (Kalydeco), lumacaftor/ivacaftor combination, or other
corrector or potentiator (Symdeko) less than 30 days from Screening.

2 Any investigational drug or device within 30 days of Screening or within 6 half-lives of
the investigational drug (whichever is longer).

3. History of any illness or condition that in the opinion of the investigator could
confound the results of the study or pose additional risk to subjects.

4. Any acute infection, including acute upper or lower respiratory infections and pulmonary
exacerbations that require treatment within 4 weeks of Study Day 1.

5. Any change in chronic therapies for CF lung disease (e.g., Ibuprofen, Pulmozyme®,
hypertonic saline, Azithromycin, TOBI®, Cayston®) within 4 weeks of Study Day 1 6.
Pregnant, planned pregnancy or breast feeding 7. Clinically significant cardiac, liver or
kidney disease 8. Seizure disorder 9. Use of continuous 24 hour or nocturnal supplemental
oxygen therapy 10. Acute upper respiratory infection within 2 weeks or acute pulmonary
exacerbation requiring intravenous antibiotics within 4 weeks of Screening Visit 11. Sinus
surgery within 6 weeks of Screening Visit 12. Respiratory culture positive for Burkholderia
cepacia within 2 years of Screening 13. Abnormal renal function 14. Abnormal liver
function, defined as ≥3x upper limit of normal (ULN) of aspartate aminotransferase (AST),
alanine aminotransferase (ALT) or known cirrhosis.

15. Screening laboratory results which in the judgment of the investigator would interfere
with completion of the study 16. History of or listed for solid organ or hematological
transplantation