Short Term Effects of Ivacaftor in Non-G551D Cystic Fibrosis Patients

Ivacaftor is a cystic fibrosis (CF)channel potentiator that is associated with decreased
sweat chloride concentration, improved lung function, and improved weight gain. It is
currently FDA approved for use only in CF patients with the G551D gating mutation. In vivo
data suggest that ivacaftor may potentiate CF channels coded for by many other mutations
associated with residual channel function, i.e., that some CF protein is present in the cell
membrane of affected cells. This includes all of the 9 other known gating mutations, but
ivacaftor also may be effective in CF patients with non-gating mutations, including some
associated with severe phenotype. Based on results from previous studies, we hypothesize
that non-G551D patients with signs of residual CF channel activity might respond favorably
to treatment with ivacaftor. This includes patients with any of the non-G551D gating
mutations, that are pancreatic sufficient, that have a sweat chloride concentration between
55 and 85 mmol, or that are much healthier than expected. Hence, select CF patients treated
with ivacaftor as compared to placebo will have a decrease in sweat chloride concentration
by greater than 20 mmol, improvement in FEV1, and weight gain. To test our hypothesis, we
will conduct a prospective double-blinded placebo-controlled crossover clinical study
comparing treatment with ivacaftor to placebo therapy (see details below). Our specific aims
are:

Specific Aim 1: To demonstrate a decrease in sweat chloride concentration by greater than 20
mmol from baseline after 14 days of ivacaftor as compared to placebo.

Specific Aim 2: To demonstrate improvement in lung function measures from baseline after 14
days of Ivacaftor as compared to placebo.

Specific Aim 3:To demonstrate weight gain from baseline after 14 days of Ivacaftor as
compared to placebo.

Study Design:

This is a prospective randomized double-blinded placebo-controlled crossover study of the
short-term effects of ivacaftor (aka VX-770 or Kalydeco) on sweat chloride concentration and
lung function in cystic fibrosis (CF) patients who fall outside current FDA approval.

We will enroll up to 30 CF subjects from the UCSF CF Center with a variety of genotypes and
phenotypes in which there is one or more signs of residual CFTR function. The signs of
residual CF channel function include: pancreatic sufficiency, sweat chloride concentration
less than 85 mmol, or milder than expected CF disease in a CF patient with a severe
genotype. We will exclude patients who are homozygous for the F508del mutation and have a
sweat chloride concentration greater 85 mmol, which is true of the majority of F508del
homozygotes. This population has been studied and found to be unresponsive to ivacaftor and
includes nearly half of all CF patients. However, even among F508del homozygotes about 15
percent have residual chloride secretion manifest as a lower than expected sweat chloride
concentration. The primary outcome measure will be the difference in sweat chloride
concentration measured in subjects on placebo and on ivacaftor. Secondary outcome measures
include variables obtained by spirometry and multi-breath washout testing.

Research Plan:

We will conduct a randomized double-blinded placebo-controlled crossover trial, in which all
subjects will be treated with 2 weeks of ivacaftor and 2 weeks of placebo with a 2-week wash
out period. Up to 30 subjects with one or more signs of residual CFTR function will be
randomized into the study. This includes subjects who are pancreatic sufficient, who have a
sweat chloride of 55 to 85 mmol, or who have mild CF disease in a setting of a severe CF
genotype.

Each subject will act as his/her own control in a prospective randomized double-blinded
crossover trial consisting of 14 days of ivacaftor or placebo, followed by a 14 day washout
period, followed by 14 days of placebo or ivacaftor. The primary outcome measure will be
sweat chloride concentration at baseline, 14 days, 28 days and 42 days. Secondary outcomes
include standard lung function measures: forced vital capacity (FVC), forced expiratory
volume at 1 second (FEV1), FEV1/FVC and mid-expiratory flow (FEF25-75), and multibreath
washout testing. Blood samples will be examined at baseline, 14 days, 28 days and 42 days
for evidence of drug toxicity (CBC with differential, liver function tests (AST, ALT),
non-fasting glucose, creatinine and BUN). For female subjects of child bearing age, a urine
pregnancy test will be done to assure they are not pregnant. If a female becomes pregnant
during the study, the trial will be stopped but we will continue to measure sweat chloride,
lung function, and blood work at the specified times. The effects of ivacaftor on the fetus
are not known at this time.

Results of all laboratory tests will be forwarded to a nurse practitioner not directly
involved with the study subjects, who will serve as the subject safety monitor. The nurse
practitioner will notify study investigators of any laboratory values consistent with an
adverse effect of study drug and will have the power to discontinue any subject in case of a
serious adverse event. The most common serious adverse event in previous ivacaftor trials
was mild elevation of liver tests. For this trial a serious adverse event sufficient to
warrant discontinuing a subject will include a liver function test (ALT or AST) more than
thrice the upper limit of normal, abnormal renal function or abnormal red or white cell
counts.

Inclusion Criteria:

- Two mutations known to cause cystic fibrosis and a sweat chloride concentration
greater than or equal to 55 mmol

- Greater than or equal to 6 years of age

Exclusion Criteria:

- Homozygous F508del with a sweat chloride greater than 85 mmol

- Taking medication known to interact with ivacaftor and chooses not to discontinue
that medication

- Is pregnant or planning to become pregnant during the study period

- Less than 6 years of age