A Phase 1, Randomized, Double blind, Placebo Controlled, Single and Multiple Dose Escalation Study Evaluating Safety and Pharmacokinetics of VX 152 Alone and in Combination with VX 661/Ivacaftor, and Bioavailability and Food Effect of VX 152 in Healthy Adult Subjects

VX 152 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-152 is thought to improve CFTR
functioning by modifying folding of the protein structure. VX-152 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-152 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-152 will be compared for two different oral dosage forms
of VX 152 (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-152 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-152 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-152 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-152, VX-661 and ivacaftor)
are absorbed into and eliminated from the body (this is called
pharmacokinetics). In addition, the effects of VX-152, 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-152 is
to how quickly and to what extent VX-152 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-152 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-152, and one will receive placebo. After dosing, the safety and tolerability
of VX-152 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-152 and one will receive
placebo) will be dosed.
In all groups, on Day 1 of the study volunteers will receive VX-152 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-152 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-152 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-152 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-152, 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-152 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-152 will be administered as an intravenous infusion.
When you receive VX-152 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-152 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-152 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 152 on Day 1 and Day 6 of Period 2.
Whether you will receive VX-152 or placebo will be determined by chance. In
each group, six volunteers will receive VX-152 and two volunteers will receive
placebo. Neither you nor the study doctor will know if VX-152 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-152 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-152 or placebo will be determined by chance. In
each group, six volunteers will receive VX-152 and two volunteers will receive
placebo. Neither you nor the study doctor will know if VX-152 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-152 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 152), 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-152 either once or twice daily. The dose, dose
regimen (once or twice daily) and dosage form (tablet or oral suspension) of VX
152 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 152 combined with VX-661 and ivacaftor or matching placebos
(that means a placebo for each VX 152, VX 661 and ivacaftor) will be determined
by chance. In each group, 6 volunteers will receive VX 152 combined with VX-661
and ivacaftor and 2 volunteers will receive matching placebos. Neither you nor
the study doctor will know if VX-152, 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-152 without
deuterium. VX-152 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-152 via infusion
(using a cannula) on both Day 1 and Day 6. Depending on results from Part A,
VX-152 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.

Single doses of up to 800 mg VX 152 or placebo were generally well tolerated
without safety concerns in healthy volunteers, except for an event of hemolysis
(spontaneous destruction of red blood cells) in one volunteer after a single
dose of 400 mg VX-152, and a possible event of milder hemolysis in a second
volunteer after a single dose of 200 mg VX 152. These volunteers were found to
have a genetic condition, glucose-6-phosphate dehydrogenase (G6PD) enzyme
deficiency. People with this condition are at risk of acute hemolysis, with a
small chance of kidney damage if VX-152 is administered. To avoid inclusion of
people with G6PD deficiency in this study, a blood test for G6PD deficiency
will be performed at screening. Furthermore, additional blood and urine samples
will be taken to improve the monitoring.

Single doses of 1200 to 2000 mg VX-152 or placebo were well tolerated by about
half of the volunteers but only moderately tolerated by some of the volunteers
due to loss of appetite, nausea and vomiting, and/or headache. A mild increase
in total and direct bilirubin was also observed in most volunteers who received
single doses of 1200 to 2000 mg VX-152 or placebo.

Multiple doses of up to 400 mg VX-152 or placebo twice daily were generally
well tolerated without safety concerns in healthy volunteers. Some volunteers
who received multiple doses of up to 800 mg VX-152 or placebo twice daily had
mild increase in total and direct bilirubin.

Multiple doses of 800 mg VX-152 or placebo twice daily were poorly tolerated
due to temporary nausea and vomiting, and high levels of blood test called ALT
and AST. Increases in ALT and AST can be a sign of liver inflammation or
injury. The abnormal blood tests were reversible, and the nausea and vomiting
got better after the study drug was stopped.

Very severe cases of liver injury can become permanent and even be
life-threatening. During the remainder of the study, the doses of study drug to
be taken by the subjects will be chosen to give predicted drug levels that are
substantially less than the drug levels measured in the subjects who had the
adverse effects described above. Also, you will have your blood drawn every 1 *
3 days to check for liver injury. If we detect evidence of liver injury through
your blood tests, we will stop your study drug.

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. You should
tell your doctor if you have any of these symptoms or anything else unusual.

Possible Risks Based Upon Chemical Profile and Animal Studies:

VX-152 has been studied in animals. VX-152 was generally well tolerated in rats
and dogs. When VX-152 was administered to dogs, effects observed at the highest
dose level tested included: increased diarrhea and vomiting, lack of appetite,
and decreased activity. In addition, small body weight decreases were observed.

In animals treated with VX-152 by mouth, study drug that goes into the skin may
absorb light and produce tissue damage. This damage might appear similar to a
sunburn. Animal studies are ongoing to define whether light exposure after
VX-152 treatment has effects on the skin. Until results are available, people
receiving VX 152 (or placebo) as part of human studies should take appropriate
measures against sun exposure or exposure to excessive UV-visible radiation.