A Phase 3b, Randomized, Placebo-Controlled Study Evaluating the Efficacy and Safety of Elexacaftor/Tezacaftor/Ivacaftor in Cystic Fibrosis Subjects 6 Through 11 Years of Age Who Are Heterozygous for the F508del Mutation and a Minimal Function Mutation (F/MF)

Cystic fibrosis (CF) is an autosomal recessive chronic disease with serious
morbidities and frequent premature mortality. CF affects more than 70,000
individuals worldwide1 (approximately 31,000 in the US2 and 48,000 in the EU).
Based on its prevalence, CF qualifies as an orphan disease.
CF is caused by decreased quantity and/or function of the CFTR protein due to
mutations in the CFTR gene. CFTR is an ion channel that regulates the flow of
chloride and other ions across epithelia in various tissues, including the
lungs, pancreas and other gastrointestinal organs, and sweat glands. Decreased
CFTR quantity or function results in the failure to regulate chloride transport
in these tissues leading to the multisystem pathology associated with CF. In
the lungs, obstruction of airways with thick mucus, establishment of a chronic
bacterial infection in the airways, and damaging inflammatory responses are all
thought to play a role in causing irreversible structural changes in the lungs,
leading to respiratory failure. Progressive loss of lung function is the
leading cause of mortality.
The most common disease causing CFTR mutation is F508del. Approximately 85%
have at least 1 F508del allele.
Based on the understanding of the molecular defects caused by CFTR mutations, 2
complementary approaches have been developed to address the decreased quantity
and/or function of CFTR in order to enhance chloride transport in patients with
CF. Correctors facilitate the cellular processing and trafficking to increase
the quantity of CFTR at the cell surface. Potentiators increase the channel
open probability (channel gating activity) of the CFTR protein delivered to the
cell surface to enhance ion transport. With differing mechanisms of action, a
combination of correctors and potentiators increases F508del CFTR-mediated
chloride transport more than either type of modulator alone.

Primary Objective:
To evaluate the efficacy of ELX/TEZ/IVA in subjects 6 through 11 years of age
with CF, heterozygous for F508del and a MF mutation (F/MF)
Secondary Objectives:
• To evaluate the PD of ELX/TEZ/IVA
• To evaluate the safety of ELX/TEZ/IVA

This is a Phase 3b, Randomized, Placebo-Controlled Study of elexacaftor,
tezacaftor and ivacaftor.

The study consists of 3 periods:
- Screening Period
- Treatment Period
- Follow-up Period

Screening Period:
The screening period may be up to 4 weeks.

Treatment Period:
The treatment period can last up to 24 weeks.

Follow-up Period:
The follow-up period can last up to 4 weeks. The visit will take place around
28 (±7) days after the last dose of study drug.

Active substance: ELX (VX-445)/TEZ (VX-661)/IVA (VX-770)
Activity: CFTR corrector, CFTR corrector, and CFTR potentiator

Strength and route of administration:
• 50-mg ELX/25-mg TEZ/37.5-mg IVA fixed-dose combination (FDC) tablets for oral
administration
• 100-mg ELX/50-mg TEZ/75-mg IVA FDC tablets for oral administration

Active substance: IVA (VX-770)
Activity: CFTR potentiator

Strength and route of administration:
• 75-mg IVA tablet for oral administration
• 150-mg IVA tablet for oral administration

Study Drug should be taken every 12 hours (± 2 hours). Participant will take 2
tablets in the morning and 1 tablet in the evening. The Study Drug should be
taken within 30 minutes of the start of a meal or snack containing fat.

Risks associated with VX-445 (elexacaftor; ELX)/Tezacaftor (TEZ)/Ivacaftor
(IVA) triple combination therapy (referred to as VX-445/TEZ/IVA):

To date, ELX/TEZ/IVA has been administered to more than 500 clinical trial
participants with cystic fibrosis. In addition, LEX has been administered alone
or in combination with TEZ/IVA to approximately 200 healthy volunteers.

The side effects associated with ELX/TEZ/IVA are listed or described in the
text below. For the listed side effects, the percentages of people with cystic
fibrosis in a large study who experienced these side effects are shown.

• Headache (17%)
• Diarrhoea (13%)
• Upper respiratory tract infection (common cold) (12%)
• Increased liver enzymes in blood (may be a sign of a liver problem) (11%)
• Rash (11%)
• Stomach ache (10%)
• Nasal congestion (9%)
• Increased blood enzyme called creatine phosphokinase (may be a sign of a
muscle problem) (9%)
• Runny nose (8%)

Drug Interaction Risks (medicines working with or against each other)
Almost all medicines can cause side effects. Many are mild, but some can become
life threatening if they are not treated. The combination of the Study Drug and
any other medications, dietary supplements, natural remedies, and vitamins
could be harmful. It is very important that participants tell their study
doctor about every medicine, dietary supplement, natural remedy, and vitamin
they are taking, or changes to what they are taking, while they are in the
study. There are certain herbal medications such as St. John*s Wort, and
certain fruits and fruit juices (such as grapefruit, or products made from
them) that participants must not take during study.

Unknown Risks
There may be side effects that are not yet known.

In some study participants treated with VX-445 (elexacaftor; ELX)/TEZ/IVA
triple combination therapy, high liver enzymes (called ALT or AST) in the
blood have been observed. These abnormal liver enzymes may get better after
Study Drug is stopped. In some severe cases, high liver enzymes may be a sign
of liver injury and can become permanent and even be life-threatening. The
participant will have their blood drawn to check their liver function during
the study.

Other than lab test changes, symptoms of liver injury are not specific and may
include loss of appetite, upset stomach, tiredness, pain in the right upper
belly, vomiting, dark urine, and/or yellowing of the eyes or skin.

In some children or adolescents treated with IVA-containing regimens,
abnormality of the eye lens (cataract) has been noted. A link between these
medicines and cataracts is uncertain but cannot be excluded. The study doctor
may perform eye examinations prior to and during treatment with Study Drug.

In some study participants treated with VX-445/TEZ/IVA triple combination
therapy, increases in blood pressure have been observed. Blood pressure will be
monitored during the study.

In some study participants treated with VX-445/TEZ/IVA triple combination
therapy, rash has been observed. In study participants treated with
VX-445/TEZ/IVA, rash was more commonly seen in women, especially those taking
hormones to prevent pregnancy. In some cases, the rashes were severe, required
treatment, or led to stopping of VX445-/TEZ/IVA. The rashes got better after
Study Drug was stopped.

The Study Drug may contain a very small amount of lactose, a sugar found in
dairy products. The amount of lactose in a single pill is roughly the same as
the amount in one teaspoon of milk. This amount of lactose is unlikely to cause
symptoms in people who have lactose intolerance.

Risks from tests
• Spirometry: When the lungs are tested, participants may feel the need to
cough, feel short of breath, or dizzy during or after the test.

• Blood sample collection: When participants have their blood taken with a
needle, it may feel like a pinch. It will hurt for short time, and sometimes
the place where the needle was put might feel sore or look bruised. Some
children may experience dizziness, upset stomach, or fainting when their blood
is drawn. There is a small risk of infection.

• ECG: It might hurt when the study doctor removes the sticky pads, like taking
off a bandage.

• Sweat chloride test: The sweat test may cause tingling on the skin where the
sticky pads are placed. In some cases, blister-like bumps may form, which will
go away within 2-3 hours. There is a chance of minor skin burn. This happens in
less than 1 in 50,000 people. When this happens, it is usually minor and gets
better within one to two weeks with little or no scarring.

• Multiple Breath Washout: There are no known risks associated with this test.
There are no known side effects to breathing pure oxygen. If participants feel
uncomfortable during the test, they can remove the nose clip and mouthpiece. If
this is the case, the test will be stopped, and no further testing will be
performed.