A Phase 3, Randomized, Double-Blind, Placebo-Controlled, Parallel-Group Study to Evaluate
the Efficacy and Safety of VX-661 in Combination With Ivacaftor in Subjects Aged 12 Years and Older With Cystic Fibrosis, Homozygous for the F508del-CFTR Mutation

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 through 24
weeks of treatment in subjects with cystic fibrosis (CF) who are homozygous for
the F508del mutation on the CF transmembrane conductance regulator (CFTR) gene.

This is a Phase 3, randomized, double-blind, placebo-controlled,
parallel-group, multicenter study in subjects with CF who are homozygous for
the F508del-CFTR mutation.
This study includes the following:
- Screening Period (Day *28 through Day *1)
- Treatment Period (Day 1 through Week 24 ± 5 days)
- Safety Follow-up Visit (28 ± 7 days after the final dose of study drug)
Subjects will be stratified by age at the Screening Visit (<18 versus *18 years
of age), sex (male versus female), and FEV1 severity determined during the
Screening Period (<70% versus *70% predicted), and then randomized (1:1) to 1
of the following 2 treatment arms:
- VX-661/ivacaftor: 100 mg VX-661 once daily (qd) + 150 mg ivacaftor every 12
hours (q12h)
- Placebo: Placebo regimen with visually matched tablets

The first dose of the study drug will be administered after randomization on
Day 1.
- Clinic visits will occur on Day 1, Day 15 (± 3 days), and at Weeks 4, 8, 12,
16, and 24 (± 5 days), and during the Safety Follow-up Visit (28 ±7 days after
the final dose of study drug [Week 24]).
- Telephone contact will be made at Week 20 (± 5 days) to assess the subject's
status, any AEs, concomitant medications, treatments, and procedures.
Subjects who prematurely discontinue study drug treatment will continue to
complete all other scheduled study visits for assessments of efficacy
(spirometry, CFQ-R, sweat chloride, height, and weight), other endpoints
(CFRSD, SF-12, and PSQI), 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).