A Phase 3, Open-label Study Evaluating the Long-term Safety and Efficacy of VX-445 Combination Therapy in Subjects With Cystic Fibrosis (CF) Who Are Homozygous or Heterozygous for the F508del Mutation

Cystic fibrosis (CF) is an autosomal recessive chronic disease with serious
morbidities and frequent premature mortality. At
present, there is no cure. CF affects approximately 70,000 individuals
worldwide (approximately 30,000 in the US and 39,000 in
the EU). Based on its prevalence, CF qualifies as an orphan disease. CF is
caused by decreased quantity and/or function of the
Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) protein due to
mutations in the CFTR gene. The CFTR protein is
an epithelial chloride channel that aids in regulating salt and water
absorption and secretion and pH balance in sweat glands and
multiple organs, including the lungs, pancreas, and other gastrointestinal
organs. Despite progress in the treatment of CF with
antibiotics and mucolytics, the predicted median age of survival for a person
with CF is approximately 40 years. Progressive loss
of lung function is the leading cause of mortality. More effective treatments
are needed for CF. The most common disease-causing
CFTR mutation, F508del, accounts for 70% of the identified alleles in people
with CF, and approximately 40% of people with CF
are homozygous for F508del (F/F). 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
functional CFTR at the cell surface. Potentiators increase the channel open
probability of the CFTR protein delivered to the cell
surface to enhance ion transport. Depending on the amount of residual CFTR
channel activity in the membrane, and the
pathophysiology of that activity (reflecting the CFTR genotype of the patient
and possibly other factors), both approaches may be
required. The therapeutic activity of CFTR correctors and potentiators has been
established with products that were developed by
Vertex and approved for the treatment of CF: ivacaftor (IVA) monotherapy
(Kalydeco®), and lumacaftor (LUM) in combination with
IVA (Orkambi®). Kalydeco and Orkambi are approved to treat CF in patients with
specific CFTR genotypes. A second
corrector/potentiator combination, tezacaftor (TEZ)/IVA (Symdeko®) is now
approved in the US. An MAA has been submitted and
is under review. VX-445 is a next-generation CFTR corrector being developed for
administration in triple combination (TC) with
TEZ/IVA for the treatment of CF. The purpose of this study is to evaluate the
efficacy and safety of VX-445 in TC with TEZ/IVA in
subjects with CF who are heterozygous for F508del (F) and a second CFTR allele
carrying a minimal function (MF) mutation that is
non-responsive to TEZ, IVA, or TEZ/IVA. Patients with this genotype (F/MF)
usually have severe disease and lack approved CFTR
modulator therapy; previous studies with TEZ/IVA and lumacaftor (LUM)/IVA
failed to demonstrate efficacy in this patient
population. Due to this high unmet need, VX-445 is being developed in TC with
TEZ/IVA for F/MF subjects. The potential for
benefit in these patients is supported by in vitro data and clinical data in
F/MF subjects; in addition, the TC of VX 445/TEZ/IVA is
generally safe and well tolerated (please refer to VX-445 Investigators
Brochure, v3.0 dated 20 April 2018).

Primair eindpunt:
Evaluating the Long-term Safety and Efficacy of VX-445 Combination Therapy in
Subjects With Cystic Fibrosis (CF) Who Are Homozygous or Heterozygous for the
F508del Mutation.
Secundair eindpunt:
Evaluate the long-term efficacy of VX-445 in TC with TEZ and IVA
Evaluate the pharmacodynamics (PD) of VX-445 in TC with TEZ and IVA

This is a Phase 3, multicenter, open-label study for subjects who completed
the last Treatment Period visit in a parent study and meet eligibility
criteria. All subjects will receive the TC of VX-445/TEZ/IVAat the same dose
level as that evaluated in Study 445-102 and Study 445-103.
Duration of the study is 196 weeks: 192 weeks treatment period and subsequently
4 weeks of safety follow-up period.

Study drug refers to VX-445/TEZ/IVA. Study drugs will be orally administered as
2 fixed-dose combination (FDC) film-coated tablets (VX-445/TEZ/IVA) in the
morning and as 1film-coated IVA tablet in the evening. Active substance:
VX-445, TEZ (tezacaftor; VX-661), and IVA (ivacaftor; VX-770) Activity:CFTR
corrector, CFTR corrector, and CFTR potentiator (increased Cl* secretion)
Strength:100-mg VX-445/50mg TEZ/75mg IVA FDC tablet
Active substance: IVA (ivacaftor; VX-770) Activity: CFTR potentiator (increased
Cl- secretion) Strength: 150-mg tablet

To date, ELX/TEZ/IVA has been administered to more than 600 clinical trial
participants with cystic fibrosis age 6 years and greater. In addition, ELX 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%)
· Diarrhea (13%)
· Upper respiratory tract infection (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%)

Additional Risks associated with Elexacaftor (ELX)/Tezacaftor (TEZ)/Ivacaftor
(IVA) triple combination therapy (referred to as ELX/TEZ/IVA):

In some study participants treated with ELX/TEZ/IVA triple combination therapy,
high liver enzymes in the blood have been observed. Elevated liver enzymes may
be a sign of liver injury. These abnormal liver enzymes may get better after
Study Drug is stopped.

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 severe cases, significant liver injury can potentially become permanent and
even be life-threatening. In patients with advanced liver disease (for example,
cirrhosis and/or portal hypertension), there is a greater risk for worsening of
liver function. The worsening of liver function can lead to a need for liver
transplant.

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.

In some study participants treated with ELX/TEZ/IVA triple combination therapy,
increases in blood pressure have been observed.

In some study participants treated with ELX/TEZ/IVA triple combination therapy,
rash has been observed. In study participants treated with ELX/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 ELX/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 of interactions between medicines (drugs that interact with or work
against each other):
Almost all medicines can cause side effects. Many of these are mild, but some
can be life-threatening if they are not treated. The combination of the study
drug with other drugs, nutritional supplements, natural remedies or vitamins
could be harmful for you. It is therefore important that you inform your study
doctor during the study of all medicines, nutritional supplements, natural
remedies and vitamins (or changes in these).
There are certain herbal medicines, such as St John's Wort, and certain fruits
and fruit juices (such as grapefruit, and products made from these) that you
may not take, eat or drink during the study.

Unknown risks:
Side effects may occur that are not yet known.

Confidentiality:
There is a small possibility that your name or other personal information could
be seen by an unauthorized person.

Risks of the study procedures:
- Blood sample collection: When you have your blood taken with a needle, it may
feel like a pinch. It will hurt for a short time, and sometimes the place where
the needle was put might feel sore or look bruised. Some people may experience
dizziness, upset stomach, or fainting when their blood is drawn. There is a
small risk of infection.
- ECG: The stickers used for this test can cause skin irritation. Removing the
sticker can be unpleasant.
- Spirometry: When your lungs are tested, you may feel the need to cough, you
may feel short of breath or dizzy during or after the test.
- Sweat test: The sweat test can cause a tingling feeling in the skin at the
level of the sticky electrodes. In some cases, blister-like bumps may develop
and then disappear again within two to three hours. There is a chance of a mild
burn to the skin. This occurs in fewer than 1 in 50,000 persons. If this does
occur, it is usually minimal and heals within one to two weeks with little or
no scarring.