A Phase 1, Randomized, Double-blind, Placebo-Controlled, Single- and Multiple-Dose Escalation Study Evaluating Safety and Pharmacokinetics of VX-440 Alone and in Combination with VX-661/Ivacaftor, and Bioavailability and Food Effect of VX-440 in Healthy Adult Subjects

VX 440 is a new investigational compound that may eventually be used for the
treatment of cystic fibrosis (CF). CF is a
genetic disorder that causes the body to produce unusually thick mucus. The
thick mucus results in malfunction of organs
like the lungs, pancreas and liver.

In the human body, the cystic fibrosis transmembrane conductance regulator
(CFTR; this is a protein that can be found on
the membrane of cells) plays an important role in the transport of salt and
water in and out of cells. In CF, this protein does
not work correctly or it is not produced sufficiently. As a result, the
transport of salt and water in and out of cells is disturbed and mucus will
become unusually thick. VX-440 is thought to improve CFTR functioning by
modifying folding of the protein structure. VX-440 is not registered as a drug
and has not been given to humans before

The purpose of Part A is to investigate how safe the study compound VX-440 is
and how well the study compound is
tolerated. The study will also investigate how quickly and to what extent the
compound is absorbed into and eliminated
from the body (this is called pharmacokinetics). In addition, safety and
pharmacokinetics of VX-440 will be compared for
two different oral dosage forms of VX 440 (suspension and tablet) and the
effect of taking the tablet dose with food will be
investigated during this part of the study.

The purpose of Part B is to investigate how safe the study compound VX-440 is
and how well the study compound is
tolerated after multiple dosing. The study will also investigate how quickly
and to what extent the compound is absorbed
into and eliminated from the body (this is called pharmacokinetics). In
addition, the effects of VX-440 on lung function and
on the amount of chloride in sweat will be investigated (this is called
pharmacodynamics).

The purpose of Part C is to investigate how safe the study compound VX-440 is
and how well the study compound is
tolerated when it is administered in combination with VX-661 and ivacaftor. The
study will also investigate how quickly and
to what extent the study compounds (VX-440, VX-661 and ivacaftor) are absorbed
into and eliminated from the body (this
is called pharmacokinetics). In addition, the effects of VX-440, VX-661 and
ivacaftor on lung function and the amount of
chloride in sweat will be investigated (this is called pharmacodynamics).

The purpose of Part D is to investigate how safe the study compound VX-4740 is
to how quickly and to what extent VX-440
is absorbed, distributed, metabolized (broken down) and eliminated from the
body (this is called pharmacokinetics). The
compound to be administered will be labeled with deuterium, a stable isotope,
and non-radioactive form of hydrogen
which is used as a tracer in human studies. This enables the investigator to
trace the compound in blood, urine and feces.
In addition, also VX-440 without deuterium will be administered during this
study.

Part A
For all groups, except one, the study will consist of 1 period during which you
will stay in the clinical research center in
Zuidlaren for 6 days (5 nights). One group is selected to stay in the clinical
research center for a second consecutive
period of 10 days (9 nights). This means that this group will stay in the
clinical research center for a total of 16 days (15
nights).
In Group 1 only, initially two volunteers will be dosed, one will receive
VX-440, and one will receive placebo. After dosing,
the safety and tolerability of VX-440 in these volunteers will be closely
monitored. If there are no concerns about the
safety and tolerability 24 hours after dosing, then the remaining six
volunteers (five will receive VX-440 and one will
receive placebo) will be dosed.
In all groups, on Day 1 of the study volunteers will receive VX-440 or placebo
as an oral suspension 30 minutes after the
start of breakfast followed by 240 milliliters of (tap) water. You will receive
a standardized breakfast which needs to be
finished within 20-25 minutes. The entire breakfast must be consumed. You are
not allowed to eat or drink for a minimum
of 8 hours (except water) before the start of the breakfast.
All volunteers in the group that will stay in the clinical research center for
a second period will receive the study compound
once on Day 1 of Period 2 without a standardized breakfast and once on Day 6 of
Period 2 with a standardized breakfast.
The study compound will be administered as a tablet followed by 240 milliliters
of (tap) water. On Day 1 you are not
allowed to eat or drink (except water) for a minimum of 8 hours before you
receive the study compound. On Day 1 drinking
water is not permitted from 1 hour prior to until 1 hour after study compound
administration. On Day 6 you will receive a
standardized breakfast which will have to be finished within 20-25 minutes. The
entire breakfast must be consumed. You
are not allowed to eat or drink (except water) for a minimum of 8 hours before
the start of the breakfast.
For all groups fasting will continue until 4 hours after administration of the
study compound, at which time you will receive
a lunch. You are allowed to drink water beginning 1 hour after administration
of the study compound. One of the
investigators will inspect your hands and mouth after the study compound intake.

Part B
The actual study will consist of 1 period during which you will stay in the
clinical research center in Zuidlaren for 19 days
(18 nights).
Day 1 is the first day of administration of the study compound. On Day 1 to Day
14 you will receive VX-440 or placebo as
an oral suspension or as a tablet once or twice every day. A placebo is a
suspension or tablet without the active
ingredient.
The initial groups will receive VX-440 or placebo as an oral suspension. Dosing
with the tablet may only begin when
results from Part A are available.
During the study you will receive VX-440 or placebo 30 minutes after the start
of a standardized meal as an oral
suspension or as a tablet followed by 240 milliliters of (tap) water. You will
receive a standardized meal on all days you
receive study compound. The entire meal must be consumed and has to be finished
within 20-25 minutes.
If the study compound is administered once daily, then the standard meal will
be breakfast. If the study compound is
administered twice daily, then the standard meal will be standard breakfast and
standard dinner.
On Day 1 and Day 14 you are not allowed to eat or drink for a minimum of 8
hours (except water) before start of the
breakfast. Fasting on Day 1 and Day 14 will continue until at least 4 hours
after administration of the study compound in
the morning. During fasting you are allowed to drink water beginning 1 hour
after administration of the study compound.

Part C
The actual study will consist of 1 period during which you will stay in the
clinical research center in Zuidlaren for 19 days
(18 nights).
During the study you will receive VX-440, VX-661, ivacaftor or matching placebo
30 minutes after the start of a meal as an
oral suspension or as a tablet followed by 240 milliliters of (tap) water. You
will receive a standardized meal on all days
you receive study compound. The entire meal must be consumed and has to be
finished within 20-25 minutes.
If the study compound is administered once daily, then the standard meal will
be breakfast. If the study compound is
administered twice daily, then the standard meal will be standard breakfast and
standard dinner.
On Day 1, Day 2 and Day 14, you are not allowed to eat or drink for a minimum
of 8 hours (except water) before start of
the breakfast.
On Day 1, Day 2 and Day 14 fasting will continue until at least 4 hours after
administration of the study compound in the
morning. Then you will receive a lunch. You are allowed to drink water
beginning 1 hour after administration of the study
compound.

Part D
The actual study will consist of 1 period during which you will stay in the
clinical research center in Zuidlaren for 11 days
(10 nights).
Based on the results of Part A you may receive VX-440 either under fasted or
under fed conditions. The unlabeled study
compound will be administered as a tablet or oral suspension followed by 240
milliliters of (tap) water. The deuterium
labeled VX-440 will be administered as an intravenous infusion.
When you receive VX-440 under fasted conditions, on Day 1 and Day 6 you are not
allowed to eat or drink (except water)
for a minimum of 8 hours before you receive the study compound. Water is
allowed until 1 hour prior to study compound
administration.
When you receive VX-440 under fed conditions, on Day 1 and Day 6 you will
receive a standardized breakfast which will
have to be finished within 20-25 minutes. The entire breakfast must be
consumed. You are not allowed to eat or drink
(except water) for a minimum of 8 hours before the start of the breakfast.
Water is permitted until 1 hour prior to study
compound administration.
On Day 1 and Day 6 fasting will continue until at least 4 hours after
administration of the study compound. Then you will
receive a lunch. You are allowed to drink water beginning 1 hour after
administration of the study compound.

Part A;
In all groups you will receive a single dose of VX-440 or placebo as an oral
suspension. A placebo is a suspension or
tablet without the active ingredient. The group that will be selected to
continue on to a second period will receive a tablet
of VX 440 on Day 1 and Day 6 of Period 2.
Whether you will receive VX-440 or placebo will be determined by chance. In
each group, six volunteers will receive VX-
440 and two volunteers will receive placebo. Neither you nor the study doctor
will know if VX-440 or placebo will be dosed;
we call this *the study is blinded*. However, information on the administration
of the study compound will be present in the
clinical research center, in sealed envelopes, which can be opened in case of
emergency.

Only the start dose of Part A, group1 is set. This is 50 mg. The following
doses will be set based on the results obtained in
the previous cohorts. This is applicable for all parts of the study.

Part B:
On Day 1 to Day 14 you will receive VX-440 or placebo as an oral suspension or
as a tablet once or twice every day. A
placebo is a suspension or tablet without the active ingredient.
Whether you will receive VX-440 or placebo will be determined by chance. In
each group, six volunteers will receive VX-
440 and two volunteers will receive placebo. Neither you nor the study doctor
will know if VX-440 or placebo will be dosed;
we call this *the study is blinded*. However, information on the administration
of the study compound will be present in the
clinical research center, in sealed envelopes, which can be opened in case of
emergency.
The initial groups will receive VX-440 or placebo as an oral suspension. Dosing
with the tablet may only begin when
results from Part A are available.

Part C:
During the study you will either receive a combined treatment (with VX-661,
ivacaftor and VX 440), or treatment with
matching placebos only. The combined treatment starts on Day 1 with 1 tablet
containing a combination of VX 661 and
ivacaftor in the morning, followed by 1 tablet containing ivacaftor alone in
the evening. From Day 2 to Day 14 this regimen
will be continued and further combined with doses of VX-440 either once or
twice daily. The dose, dose regimen (once or
twice daily) and dosage form (tablet or oral suspension) of VX 440 will be
based on the results of Part A and Part B of this
study.
A placebo is a suspension or tablet without the active ingredient. Whether you
will receive VX 440 combined with VX-661
and ivacaftor or matching placebos (that means a placebo for each VX 440, VX
661 and ivacaftor) will be determined by
chance. In each group, 6 volunteers will receive VX 440 combined with VX-661
and ivacaftor and 2 volunteers will receive
matching placebos. Neither you nor the study doctor will know if VX-440, VX-661
and ivacaftor or triplicate placebo will be
dosed; we call this *the study is blinded*. However, information on the
administration of the study compound will be
present in the clinical research center, in sealed envelopes, which can be
opened in case of emergency.

Part D:
On Day 1 and Day 6 you will first receive a single oral dose of VX-440 without
deuterium. VX-440 will be dosed as a tablet
or as an oral suspension, depending on the results from Part A of the study. In
addition, 10 minutes after receiving the oral
dose you will receive deuterium labeled VX-440 via infusion (using a cannula)
on both Day 1 and Day 6. Depending on
results from Part A, VX-440 may be administered either after fasting for at
least 8 hours or after consumption of a meal.

Procedures: pain, light bleeding, heamatoma, possibly an infection.

As VX 440 is being administered to humans for the first time in this study,
adverse effects of VX 440 in humans have not been previously reported. As of
the date of this amendment of *Information Form and Statement of Willingness to
Participate*, single doses of up to 200 mg VX 440 have been administered to
healthy volunteers in Part A of the study (up to Cohort A3). VX 440 was
generally well tolerated without safety concerns in these volunteers. However,
in a study of a similar compound there was one event of hemolysis (spontaneous
destruction of red blood cells) leading to mild anemia (fewer red blood cells
than normal) in one volunteer and a possible event of milder hemolysis in a
second volunteer. These volunteers were found to have a genetic condition,
glucose-6-phosphate dehydrogenase (G6PD) enzyme deficiency. Volunteers with
this condition may be at risk of acute hemolysis with a small chance of kidney
damage when VX-440 is administered to them. To avoid inclusion of volunteers
with G6PD deficiency in this study, a blood test for G6PD deficiency will be
performed at screening.