A SINGLE-CENTER, RANDOMIZED, INVESTIGATOR/SUBJECT-BLIND, ADAPTIVE SINGLE-ASCENDING-DOSE (SAD), PLACEBO-CONTROLLED, PARALLEL STUDY TO INVESTIGATE THE SAFETY, TOLERABILITY, PHARMACOKINETICS (INCLUDING THE EFFECT OF FOOD AND THE EFFECT OF ITRACONAZOLE ON THE PHARMACOKINETICS OF A SINGLE ORAL DOSE OF RO7034067), AND PHARMACODYNAMICS OF RO7034067 FOLLOWING ORAL ADMINISTRATION IN HEALTHY SUBJECTS

RO7034067 is a new investigational compound that may eventually be used for the
treatment of spinal muscular atrophy (SMA).

SMA is a genetic disease that affects the control of muscle movement. It is
caused by a loss of specialized nerve cells, called motor neurons, in the
spinal cord and the part of the brain that is connected to the spinal cord (the
brainstem). The loss of motor neurons leads to weakness and wasting (atrophy)
of muscles used for activities such as crawling, walking, sitting up, and
controlling head movement. In severe cases of SMA, the muscles used for
breathing and swallowing are affected. There are many types of SMA
distinguished by the pattern of features, severity of muscle weakness, and age
when the muscle problems begin. SMA affects 1 in 11,000 live births and is the
leading genetic cause of mortality in infants and young children.

The survival motor neuron (SMN) protein is important for the maintenance of
motor neurons. In SMA, genes responsible for giving instructions to the body to
produce the SMN protein are not working correctly. This results in a shortage
of SMN protein levels in the body and thereby, a loss of motor neurons.
RO7034067 is thought to repair one of these genes (SMN2) and thereby restoring
SMN protein levels in the body.

RO7034067 is not registered as a drug and has not been given to humans before.

If you participate in Part 3 of this study, in addition to RO7034067, you will
also receive the antifungal compound itraconazole, which is a registered drug.

If you participate in Part 1 of this study, in addition to RO7034067, you may
receive the mouth wash solution Listerine®.

This study is not intended to improve your health, but is necessary for the
further development of RO7034067 .
The study will be performed in 3 parts, Parts 1, 2 and 3.
This document only refers to Part 1/2/3 of the study .

Part 1:
A single dose will be administered of RO7034067 or placebo (same formulation
but then without the active ingredient RO7034067). The purpose of Part 1 is to
investigate how safe RO7034067 is and how well RO7034067 is tolerated. Part 1
will also investigate how quickly and to what extent RO7034067 is absorbed
into, distributed in, and eliminated from the body (this is called
pharmacokinetics). In addition, the effect of RO7034067 on reparation of the
SMN2 gene as well as on SMN protein levels in the blood will be investigated
(this is called pharmacodynamics).

Part 1 will be performed in 6 groups (Groups 1 to 6) of which Group 1 will
consist of 5 healthy male volunteers and the other groups of 4 healthy male
volunteers each. Groups 2 to 6 may be expanded to a maximum of 16 healthy male
volunteers each, based on emerging results from this study. You will
participate in 1 of these 6 groups.

Part 2:
The purpose of Part 2 is to investigate the effect of food on the absorption,
distribution and elimination of RO7034067 in the body (this is called
pharmacokinetics) following a single dose of RO7034067. RO7034067 will be
administered twice, once with and once without food.

Part 2 will be performed in 1 group of 6 healthy male volunteers; the group may
be expended to to a maximum of 12 healthy male volunteers.

Part 3:
The purpose of Part 3 is to investigate the effect of multiple oral doses of
itraconazole on the absorption, distribution and elimination of RO7034067 in
the body (this is called pharmacokinetics) following a single dose of
RO7034067. RO7034067 will be administered twice, once alone and once in
combination with itraconazole. Itraconazole is known to inhibit proteins that
are involved in metabolizing compounds like RO7034067. In addition, the Part 3
will investigate how safe the study compound RO7034067 is and how well the
study compound is tolerated when it is given in combination with itraconazole.

Part 3 will be performed in 1 group of 8 healthy male volunteers; the group may
be expended to a maximum of 12 healthy male volunteers.

Part 1: The actual study will consist of one period where they will stay for 6
days (5 nights) in the clinical research center in Groningen: the afternoon of
Day-2 (two days before administration of study drug) on the morning of Day 4.
This is followed by three days (Day 5, 7 and 10) to which one applies a short
visit to the clinical research center in Groningen.
It can also be concluded that the volunteers should stay longer than three
days in the clinical research center (until the morning of Day 7). In this
case, the short visit will be scheduled on Day 5 and 7 will lapse.

Part 2: The actual study will consist of two periods of one every period for 6
days (5 nights) the volunteers will be staying in the clinical research center
in Groningen: the afternoon of Day-2 (two days before administration of study
drug) until tomorrow day 4. This is every period followed by three days (Day 5,
7 and 10) to which one applies a short visit to the clinical research center in
Groningen. Each period can also be determined that the volunteers should stay
longer than three days in the clinical research center (until the morning of
Day 7). In this case, the short visit will be scheduled on Day 5 and 7 will
lapse.

Part 3: In the first period they will stay for 4 days (3 nights) in the
clinical research center in Groningen: the afternoon of Day 1 (the day before
administration of study drug) on **the morning of Day 3. This is followed by 4
days (Day 4, 5, 7 and 10) to which one applies a short visit to the clinical
research center in Groningen. It can also be concluded that the volunteers in
the first period up to 3 days longer have to stay in the clinical research
center (until the morning of Day 6). In this case, the short visit will be
scheduled on Day 4 and 5 lapsed.

Second period
In the second period will be only stay for two days (one night) in the clinical
research center in Groningen: the afternoon of Day 1 (the day before
administration of study drug) on **the morning of Day 1. Then it will be for
seven days (6 nights) stay in the clinical research center in Groningen: the
afternoon of Day 3 until the morning of Day 9. This is followed by five days
(Day 10, 11, 13, 15 and 18) which one a short visit the clinical research
center in Groningen.Er can also be concluded that the free will keepers in the
second period up to 3 days longer have to stay in the clinical research center
(until the morning of Day 12). In this case, the short visit will be scheduled
on Day 10 and 11 lapse.

Part 1:
cohort 1 (0.6 mg): 5 (3 active + 2 placebo)
cohort 2 (2 mg): 4 (3 active + 1 placebo)
cohort 3 (6 mg): 8 (6 active + 2 placebo)
cohort 4 (20 mg): 8 (6 active + 2 placebo)
cohort 5 (60 mg): 8 (6 active + 2 placebo)
cohort 6 (200 mg): 8 (6 active + 2 placebo)

Part 2:
cohort 7: 12 subjects

Part 3:
cohort 8: 8 subjects

Pain, minor bleeding, bruising, possibly an infection.