A single-center, randomized, double-blind, placebo-controlled, single ascending dose study to investigate the pharmacokinetics, pharmacodynamic effects, safety and tolerability of single doses of RO5459072 in healthy volunteers.

RO5459072 is a new investigational compound that may eventually be used for the
treatment of autoimmune diseases such as lupus nephritis. Lupus is a disease 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.
RO5459072 is a compound that inhibits the protein cathepsin S. This protein
naturally occurs in the body and plays an important role in the immune system.
In autoimmune diseases like Lupus, cathepsin S may be
overactive. This is the first time that this compound will be given to humans.

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, the effect of the compound on cathepsin S
activity and on other proteins in the blood will be investigated (this is
called pharmacodynamics). Furthermore, how metabolites (degradation products)
of RO5459072 are removed from the body and the effect of food on the compound*s
tolerability and pharmacokinetics may be investigated.

Before the study the volunteer will undergo a pre-study screening during which
they will be subjected to a number of medical examinations. Similar
examinations will be performed after the study at the post-study screening.

The actual study will consist of 4 periods during which the volunteers will
stay in the clinical research center for 5 days (4 nights) (Period 1) or 4 days
(3 nights) (Periods 2-4). The time interval between the different periods that
they will participate in will be at least 4 weeks.

The volunteers will be admitted to the clinical research center on Day -2
(Period 1) and on Day -1 (Periods 2-4) and will leave the clinical research
center on Day 3 of each period. Day 1 of each period is the day of
administration of study medication. The volunteers will be required not to have
consumed any food or drinks during the 4 hours prior to arrival in the clinical
research center (with the exception of water).
The post-study screening will take place 7-14 days after the last time you have
been administered study medication.
The participation to the entire study, from pre-study screening until the
post-study screening, will be approximately 22 weeks.

On Day 1 of each period the volunteers will receive a single dose of RO5459072
or placebo with 240 milliliters of tap water. For the higher dose levels an
additional 240 mL of tap water will be permitted (since the number of capsules
to take will be higher). In most cases they will receive the
medication after an overnight fast (no food or drinks with the exception of
water) of at least 8 hours. However, it is possible that the volunteers will
receive the study drug once after a standard high fat breakfast that they will
have to finish completely.
It will be determined during the study whether this will be the case and in
which period.

For all groups it is applicable that on Day 1 of each period fasting will
continue until 4 hours after study drug administration. Then the volunteers
will receive a lunch. During fasting before and after intake of the study
medication, they are allowed to drink water with the exception of the first 2
hours after study drug administration. One of the investigators will inspect
the volunteers hands and mouth after study medication intake.

This study will be performed in 16 healthy volunteers, divided over 2 groups,
which will participate in an alternating design. Volunteers in Group A will
participate in the 1st, 3rd, 5th and 7th periods and volunteers in Group B will
participate in the 2nd, 4th, 6th, and 8th periods.
Each group will contain 8 participants. The volunteers can participate in one
group only.

All potential drugs cause adverse events; the extent to which this occurs
differs. As RO5459072 will be administered to humans for the first time in this
study, adverse effects of RO5459072 in humans have not been reported to date.
RO5459072 has been studied in animals at high dose levels and administered
repeatedly for up to 13 weeks. In these studies in rats and monkeys, adverse
findings were observed only in animals receiving very high doses. At these dose
levels, the animals were exposed to RO5459072 blood levels that were more than
250 times higher than the concentrations that are thought to be needed for the
medication to be effective. The animal findings at these high doses included
changes in the
kidney, the heart and in the liver. In the animals with no adverse events, the
blood levels of RO5459072 were still at least 66 times higher than the blood
concentration expected to have clinical effects. From this data it is not
anticipated to see significant changes in humans at the dose
levels that will be given in this study; however your health will be closely
monitored throughout the study.
In a preliminary rat study , there was some evidence that RO5459072 at high
dose levels may cause birth defects. However, this was observed at dose levels
that were much higher than those that will be used in humans. In rabbits, no
birth defects were observed. This study will exclude
women who could become pregnant. Overall, data from animal studies do not
indicate particular safety risks associated with
RO5459072 treatment.