A SINGLE-CENTER, RANDOMIZED, DOUBLE-BLIND, PLACEBO-CONTROLLED, ASCENDING DOSE STUDY TO INVESTIGATE THE PHARMACOKINETICS, PHARMACODYNAMIC EFFECTS, SAFETY AND TOLERABILITY OF REPEATED DOSING OF RO5459072 IN HEALTHY SUBJECTS

RO5459072 is a new investigational compound that may eventually be used for the
treatment of autoimmune diseases such as lupus nephritis and Sjögren*s
syndrome. Lupus nephritis and Sjögren*s syndrome are diseases of the immune
system where the defense mechanisms can damage any part of the body (skin,
joints, and/or organs inside the body). Lupus nephritis is a damage of the
kidneys due to this disease. Sjögren*s syndrome is a damage of the saliva and
tear glands due to this disease, leading to dry mouth and dry eyes. RO5459072
is a compound that inhibits the enzyme cathepsin S. This enzyme naturally
occurs in the body and plays an important role in the immune system. In the
latter autoimmune diseases, cathepsin S may be overactive. RO5459072 is not
registered as a drug but has been given to humans before.

The purpose of the study is to investigate to what extent RO5459072 is safe and
well tolerated.
It will also be investigated how quickly and to what extent RO5459072 is
absorbed, distributed to and removed from the body (this is called
pharmacokinetics). In addition, it will be investigated how degradation
products (metabolites) of RO5459072 are removed from the body. Furthermore, the
effect of the compound on cathepsin S activity, white blood cells and on other
proteins in the blood will be investigated (this is called pharmacodynamics).
The subject will also undergo a delayed-type hypersensitivity (DTH) test twice
to investigate your immune response.

The actual study will consist of one period during which you will stay in the
clinical research center in Groningen for 12 days (11 nights).

During the study the subject will receive RO5459072 or placebo with 240
milliliters of tap water. In Groups B, C and D, an additional 240 mL of tap
water may be permitted (since the number of capsules to take may be higher). On
Days 1 and 9 the subject will be dosed within 30 minutes after the start of
breakfast. Lunch will be served approximately 4 hours after dosing, followed by
an optional snack at approximately 7 hours after dosing and dinner
approximately 10 hours after dosing. In between meals the subjects are allowed
to drink water, except for 1 hour before and 1 hour after study drug
administration. On Day 1 the subject will follow same meal schedule as on Days
1 and 9. On all other days, meals (including breakfast, lunch, an optional
snack and dinner) may be served at convenience.

This study will be performed in maximally 36 healthy volunteers, divided over
up to 4 groups (Groups A, B, C and D). Each group will contain 9 volunteers.
The subjects can participate in one group only.

All potential drugs cause adverse events; the extent to which this occurs
differs. Single dose administration of RO5459072 has been studied previously in
17 healthy male and female volunteers. The most frequently observed adverse
effects were: frequency micturition increased, feeling heaviness lower limbs,
loose stools, bloating, inflammation of the hair follicles (folliculitis),
headache, nervousness, dizziness, pain lower back, and sleepiness. Most of the
adverse events reported were mild in intensity, and judged as not related to
the study compound by the Principal Investigator in charge of the study conduct.

The injections under the skin of the subject's arm during the skin test are
slightly painful and may cause a raised, thickened local area of skin and
redness. As a result of the skin test, there is a very small chance that the
subjects will have a severe hypersensitivity reaction or that the subjects will
develop a small scar on the injection spots.