A phase 1, two-part, randomized, open-label study to evaluate the relative bioavailability and food effect of test formulations of VX-152 and Ivacaftor in healthy 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 in
development and is not registered as a drug but has been given to humans before.

Ivacaftor, the second study compound used in this study, is approved with the
brand name Kalydeco® in the U.S., the EU and some other countries for patients
who have certain CF abnormalities. If you would like to know in which
countries, age range, or for which genetic abnormalities Kalydeco® has been
approved, ask the study doctor. In this study Ivacaftor will, in some
instances, be administered in an experimental formulation that differs from the
approved Kalydeco® tablet.

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 4 different oral dosage forms
of VX-152 (suspension, liquid filled capsules and 2 kinds of tablets) and the
effect of taking 1 of the tablet doses with and without food will be
investigated during this part of the study.

The purpose of Part B is to investigate how safe the study compound ivacaftor
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 ivacaftor will be compared for 2 different oral dosage
forms (tablet and liquid filled capsule). Also the effect of taking the capsule
dose with and without food will be investigated during this part of the study.

Part A:
The study will consist of 1 period during which you will stay in the clinical
research center in Groningen for 22 days (21 nights).

Part B:
The study will consist of 1 period during which you will stay in the clinical
research center in Groningen for 16 days (15 nights).

Part A:
The study will consist of 1 period during which you will receive VX-152 5
times. VX-152 will be given orally as a suspension, a capsule and 2 tablet
dosage forms.

Part B;
The study will consist of 1 period during which you will receive ivacaftor 3
times. Ivacaftor will be given as a tablet and a liquid filled capsule.

Part A:
All potential drugs cause adverse effects; the extent to which this occurs
differs. As multiple doses of VX 152 will be administered to humans for the
first time in this study, adverse effects with multiple doses of VX 152 in
humans have not been previously reported. As of the date of this form single
doses of up to 800 mg have been administered to healthy volunteers in another
study.

VX 152 was generally well tolerated without safety concerns in these
volunteers, except for an event of hemolysis (spontaneous destruction of red
blood cells) 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 if VX-152 is administered.

To avoid inclusion of volunteers 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.

Generally, VX-152 was well tolerated in rats and dogs. In rats no VX-152
related adverse reactions were observed at the dose levels tested. When VX-152
was administered to dogs, adverse effects related to VX-152 were observed at
the highest dose level tested only. These adverse events included: increased
incidence of diarrhea and vomiting, loss of skin elasticity, lack of appetite,
and decreased activity. In addition, small body weight decreases (ie, the mean
body weight of the test group decreased less than 10%) were observed.

Part B:
All potential drugs cause adverse effects; the extent to which this occurs
differs. Ivacaftor has marketing authorization in a number of countries
including the EU. More than 35 studies of ivacaftor have been completed or are
ongoing in approximately 400 healthy adult subjects and 800 adult and pediatric
subjects with CF.

Common adverse events occurring in 10% or more of CF subjects:
- headache
- upper respiratory tract infection
- nasal congestion
- oropharyngeal pain
- abdominal pain
- diarrhea
- nasopharyngitis
- rash

Less common adverse events occurring in 5% to 10% of CF subjects:
- dizziness
- bacteria in sputum
- sinus congestion
- rhinitis

A few subjects with CF receiving ivacaftor as well as placebo have shown signs
of liver injury. In these cases, the liver injury was noticed as abnormalities
in blood tests which were monitored as part of the study. The very high levels
of these tests, called ALT and AST, led to stopping of the study compound. The
levels of ALT and AST got better after the study compound was stopped. Very
severe cases of liver injury can become permanent or be life-threatening.
Overall, the data does not support an association between ivacaftor and ALT and
AST elevations, although a possible link cannot be completely excluded based on
the available data.

The study compound 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.

Procedures: pain, mnor bleeding, bruising, possible infection