A PHASE 1, RANDOMIZED, DOUBLE-BLIND, SINGLE AND MULTIPLE ASCENDING DOSE STUDY TO INVESTIGATE THE SAFETY, TOLERABILITY, PHARMACOKINETICS AND PHARMACODYNAMICS OF RG2459 IN HEALTHY VOLUNTEERS, INCLUDING A SINGLE DOSE PROOF-OF-CONCEPT PART IN PATIENTS INFECTED WITH HEPATITIS C VIRUS, AND A DRUG INTERACTION PART WITH SIMEPREVIR (TMC435) IN HEALTHY VOLUNTEERS

RG2459 and simeprevir are new investigational compounds that may eventually be
used for the treatment of chronic hepatitis C infection. RG2459 and Simeprevir
work by inhibiting the replication of the hepatitis C virus via different
mechanisms. This is the first time that RG2459 is being given to humans.
Simeprevir is not registered as a drug but has been given to humans before.

The study will be performed in 4 parts, Parts A, B, C and D.
The purpose of the study is to investigate to what extent single doses of
RG2459 are tolerated in healthy volunteers and patients with a hepatitis C
infection and to what extent multiple doses of RG2459 are tolerated in healthy
volunteers. It will also be investigated how quickly and to what extent RG2459
is absorbed and eliminated from the body (this is called pharmacokinetics) when
given alone, or in combination with simeprevir. The pharmacokinetics of
simeprevir will also be investigated when given alone or in combination with
RG2459. In addition, the safety and tolerability of a single dose of RG2459
when given in combination with simeprevir will be investigated. The effect of
RG2459 on biomarkers in blood will be investigated (this is called
pharmacodynamics) in healthy volunteers and patients with a hepatitis C
infection. The effect of RG2459 on the intensity of the hepatitis C infection
will be investigated in patients with a hepatitis C infection.

During Part A, the effect of a single dose administration of RG2459 in healthy
volunteers will be studied. In Part B the effect of multiple doses of RG2459 in
healthy volunteers will be investigated. Part C will investigate the
interaction between RG2459 and simeprevir in healthy volunteers. In Part D,
single dose administrations of RG2459 will be investigated in patients with a
hepatitis C infection.

RG2459
Simeprevir (Part C only)

As RG2459 will be administered to man for the first time in this study, adverse
effects of RG2459 in man have not been reported to date. However, RG2459 has
been studied in animals. Generally RG2459 was well tolerated.

After single subcutaneous injections at levels up to 450 mg/kg in mice, a minor
decrease in cholesterol and minor increase in alkaline phosphatase (liver
enzyme) were observed. After 6 weekly subcutaneous injections at dose levels of
up to 45 mg/kg/week in mice, cholesterol lowering was seen as well as an
increased activity of liver enzymes. At the injection site, small bubbles in a
certain type of white blood cells (minimal macrophage vacuolation) were
observed, considered due to uptake of investigational compound RG2459 by the
macrophage.

After single subcutaneous injections at levels up to 150 mg/kg in cynomolgus
monkeys, increased liver enzyme activity, decreased cholesterol, increase in
blood clotting parameters (activated partial thromboplastin time duration and
fibrinogen concentration) were seen. Microscopic changes in the liver, kidney,
lymph nodes and injection site were observed, mainly vacuolation of
macrophage-like cells. On Day 14, minimal increase in size (hypertrophy) of
liver cells and minimal cell death (necrosis) occurred in the liver of male
monkeys at the 150 mg/kg dose. On Day 29 minimal cell death in the liver was
seen in female monkeys at the 150 mg/kg dose. Again vacuolation of macrophages
was seen.

Part C, Simeprevir:

The dose simeprevir used in this study, 150 mg, has been administered to humans
before. In a previous healthy volunteer single and multiple ascending dose
study, single doses up to 600 mg and multiple doses up to 400 mg once daily and
200 mg twice daily were generally safe and well tolerated. The most commonly
reported adverse effects in healthy volunteers were headache, photosensitivity
reaction (sunburn), diarrhea, abdominal pain (upper) and abdominal distension