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

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.2, Although the
disease affects multiple organs, most morbidity and mortality is caused by
progressive loss of lung function.
CF is an autosomal recessive genetic disease caused by a defect in the gene
encoding the cystic fibrosis transmembrane conductance regulator (CFTR).
Lumacaftor (VX 809) is a compound developed by Vertex Pharmaceuticals
Incorporated (Vertex) that has been shown to have CFTR corrector properties.

Primary Objective
To evaluate the efficacy of lumacaftor in combination with ivacaftor throughat
Week 24 in subjects with cystic fibrosis (CF) who are homozygous for the
F508del CFTR mutation on the CF transmembrane conductance regulator (CFTR) gene

Secondary Objectives
* To evaluate the safety of lumacaftor in combination with ivacaftor at Week 24
* To investigate the pharmacokinetics (PK) of lumacaftor and its metabolite, M28
(M28-lumacaftor) and ivacaftor and its metabolites, M1 and M6 (M1-ivacaftor and
M6-ivacaftor)

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 is designed to evaluate the efficacy and safety of
lumacaftor in combination with ivacaftor. This study will evaluate 2 dose
levels of lumacaftor in combination with ivacaftor.
This study includes a Screening Period, a Treatment Period, and a Safety Follow
up Visit. Approximately 500 subjects will be randomized, stratified by age (<18
versus *18 years of age), sex (male versus female), and FEV1 severity collected
at the Screening Period (<70% versus *70% predicted), and then randomized
(1:1:1) to 1 of the 3 treatment arms as shown in Figure 9 1.
Subjects who complete the Treatment Period will be offered the opportunity to
enroll in the Treatment Cohort of a rollover safety study of lumacaftor in
combination with ivacaftor (VX12 809 105 [Study 105]). Subjects who choose not
to enroll in the Treatment Cohort and subjects who discontinue prematurely
after having received at least 4 weeks of study drug will be offered enrollment
in the Observational Cohort of Study 105.

Dosage Day 1 through week 24, Study drug should be administered every 12 hours
(±2 hours).
* Treatment Arm A: 600 mg lumacaftor daily (qd) + 250 mg ivacaftor every 12
hours
(q12h)
* Treatment Arm B: 400 mg lumacaftor q12h + 250 mg ivacaftor q12h
* Treatment Arm C: lumacaftor placebo q12h + ivacaftor placebo q12h
Standard 12-lead ECG recordings
Ambulatory ECGs
Vital signs
Safety laboratory assessments and PK sampling
Spirometry will be performed according to the American Thoracic Society
Guidelines
Weight and BMI

Other Events Related to Outcome: These assessments (pulmonary exacerbations,
administration of antibiotic therapy for sinopulmonary signs and symptoms, and
hospitalizations) are other outcomes used to assess efficacy in therapies
targeting
improvement in CF disease.

Exploratory Assessments: (Optional)
A single optional blood sample (DNA Sample A) will be collected on Day 15
A second optional blood sample (DNA Sample B) will be collected on Day 15
Optional blood samples for blood biomarker analysis will be collected on Day 1,
Week 24, and ET Visit (if applicable)
Optional sputum samples will be collected on Day 1,Week 24, and ET Visit (if
applicable)

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.2, Although the
disease affects multiple organs, most morbidity and mortality is caused by
progressive loss of lung function.
CF is an autosomal recessive genetic disease caused by a defect in the gene
encoding the cystic fibrosis transmembrane conductance regulator (CFTR).

In the USA, almost 87% of patients with CF have at least 1 copy of the
F508del-CFTR mutation, and about 47% have 2 copies.11 In the European Union,
approximately 83% of patients with CF have 1 or 2 copies of the F508del-CFTR
mutation, and approximately 38.7% of patients with CF in the United Kingdom
have 2 copies.12 The mucus build-up obstructs the airways and predisposes the
patient to chronic lung infections.

Lumacaftor (VX 809) is a compound developed by Vertex Pharmaceuticals
Incorporated (Vertex) that has been shown to have CFTR corrector properties.
Ivacaftor (also known as VX-770) is a compound developed by Vertex that has
been shown to have CFTR potentiator properties.
Both approaches may be required to ameliorate lung disease in patients with CF
Details about the lumacaftor and ivacaftor development programs can be found in
the Investigator's Brochures