A Phase 3, Randomized, Double-Blind, Placebo-Controlled, Crossover Study to Evaluate the
Efficacy and Safety of Ivacaftor and VX-661 in Combination With Ivacaftor in Subjects Aged
12 Years and Older With Cystic Fibrosis, Heterozygous for the F508del-CFTR Mutation, and a
Second Allele With a CFTR Mutation Predicted to Have Residual Function

Cystic fibrosis is an autosomal recessive genetic disease caused by a defect in
the gene
encoding the CF transmembrane conductance regulator (CFTR), an epithelial
chloride ion
(Cl*) channel activated by cyclic adenosine monophosphate-dependent protein
kinase A that
is responsible for aiding in the regulation of salt and water absorption and
secretion in
various tissues. This function is defective in patients with CF due to a loss
of either cell
surface expression and/or function.
More than 1900 mutations in the CFTR gene have been identified. Mutations in
the CFTR
gene have been classified based on the molecular and functional consequence of
the mutation
on the CFTR protein and can be generally considered to reduce the quantity of
functional
CFTR protein that reaches the epithelial cell surface or reduce the function of
CFTR protein
located at the cell surface. CFTR gene mutations that affect the quantity of
functional cell
surface CFTR protein include defects that reduce CFTR protein synthesis and
defects that
impede the cellular processing and delivery of CFTR proteins to the cell
surface. VX-661 is a compound developed by Vertex Pharmaceuticals Incorporated
(Vertex) that has
been shown to have CFTR corrector properties.

To evaluate the efficacy of VX-661 in combination with ivacaftor and ivacaftor
monotherapy through 8 weeks of treatment in subjects with cystic fibrosis (CF)
who are heterozygous for the F508del mutation on the CF transmembrane
conductance regulator (CFTR) gene and a second allele with a CFTR mutation
predicted to have residual function.

This is a Phase 3, randomized, double-blind, placebo-controlled, 2-period,
3-treatment, crossover, multicenter study in subjects aged 12 years and older
with CF, heterozygous for the F508del-CFTR mutation, and a second allele with a
CFTR mutation predicted to have residual function.
This study includes the following:
- Screening Period (Day *28 through Day *1)
- Treatment Period 1 (Week 1 Day 1 through Week 8 ± 5 days)
- Washout Period (Week 9 through Week 16 ± 7 days); a safety evaluation visit
will be conducted at Week 12 (± 5 days).
- Treatment Period 2 (Week 17 through Week 24 ± 5 days)
- Safety Follow-up Visit (28 days ± 7 days after the last dose of study drug)
Subjects will be stratified by age at the Screening Visit (<18 versus *18 years
of age), FEV1 severity determined during the Screening Visit (<70% versus *70%
predicted), and type of residual function mutation on the second CFTR allele
(Class V non-canonical splice mutation versus Classes II to IV residual
function mutation), and then randomized (1:1:1:1:1:1) to 1 of the following 6
treatment sequences:
- Sequence 1: VX-661/ivacaftor in Treatment Period 1*washout* ivacaftor
monotherapy in Treatment Period 2
- Sequence 2: ivacaftor monotherapy in Treatment Period 1*washout*
VX-661/ivacaftor in Treatment Period 2
- Sequence 3: VX-661/ivacaftor in Treatment Period 1*washout* placebo in
Treatment Period 2
- Sequence 4: placebo in Treatment Period 1*washout* VX-661/ivacaftor in
Treatment Period 2
- Sequence 5: ivacaftor monotherapy in Treatment Period 1*washout* placebo in
Treatment Period 2
- Sequence 6: placebo in Treatment Period 1*washout*ivacaftor monotherapy in
Treatment Period 2
A minimum of 25% of enrolled subjects will carry a Class II to IV mutation on
the second CFTR allele. Stratification of enrollment will be managed through
the interactive web response system (IWRS). Enrollment into the non-canonical
splice strata will be limited to no more than 75% of total enrollment.

The first dose of the study drug will be administered after randomization on
Day 1.
Clinic visits will occur on Week 1 (Day 1 of Treatment Period 1), Week 2 (± 3
days), Week 4 (± 5 days), Week 8 (± 5 days), Week 12 (± 5 days), Week 17 (Day 1
of Treatment Period 2), Week 18 (± 3 days), Weeks 20 and 24 (± 5 days), and the
Safety Follow-up Visit (28 days ± 7 days after the final dose of study drug).
Subjects who prematurely discontinue study drug treatment will continue to
complete all the other scheduled study visits for assessments of efficacy
(spirometry, sweat chloride, and CFQ-R) and other endpoints (SF-12 and other
events related to outcome [hospitalizations, pulmonary exacerbations, etc.]).

Cystic fibrosis (CF) affects an estimated 70,000 children and adults worldwide
and is the
most common fatal genetic disease in persons of European descent. Based on the
size of the
population, CF qualifies as an orphan disease. Despite progress in the
treatment of CF with
antibiotics and mucolytics, the predicted median age of survival for a person
with CF is in
the mid-30s. Although the disease affects multiple organs, most morbidity and
mortality
are caused by progressive loss of lung function.
Ivacaftor (also known as VX-770) is the first CFTR modulator to show an
improvement in
CFTR function and clinical benefit in patients with CF. Results from several
Phase 3 studies
showed that ivacaftor is effective in the treatment of patients with CF who
have mutations
that result in gating defects as evidenced by sustained improvements in CFTR
channel
function (measured by reduction in sweat chloride concentration) and
corresponding
substantial, durable improvements in lung function, respiratory symptoms, and
weight gain.
Ivacaftor was also well tolerated, as evidenced by the rates and reasons for
premature
discontinuation and results of safety assessments.
Common adverse events in studies of CF subjects, who took VX-661, ivacaftor, or
VX-661 in combination with ivacaftor are Infective pulmonary exacerbation of CF
(temporary worsening of lung function due to an infection or inflammation),
Cough, Headache, Nausea, Sputum increased
Fatigue, Upper respiratory tract infection (common cold), Oropharyngeal pain
(sore throat), Nasal congestion (stuffy nose), Nasopharyngitis (inflammation of
the nose and pharynx), Abdominal Pain, Diarrhea, Rash, Dizziness (feeling
faint).