A randomized, double-blind, placebo-controlled study in two parts to investigate in Part 1 the safety, tolerability, pharmacokinetics and pharmacodynamics of multiple ascending dose of RO6799477 in healthy volunteers, and in Part 2 the safety, tolerability, pharmacokinetics and pharmacodynamics of multiple dose of RO6799477 in patients with type 2 diabetes mellitus.

RO6799477 is a selective partial agonist for TAAR1, which has been extensively
profiled in non-clinical procedures predictive of antipsychotic, procognitive,
antidepressant and anti-addictive activity with positive results. This leads to
the conviction that RO6799477 may constitute an effective drug of a completely
new class for the treatment of schizophrenia and mood disorders, targeting
symptoms in these diseases which currently are not treatable, such as residual
positive symptoms, cognition and negative symptoms, and substance abuse. TAAR1
partial agonists explore a fundamentally new mechanism of action based on the
modulation of dopaminergic neurotransmission and, potentially, glutamatergic
and serotonergic neurotransmission. In addition, due to its positive effect on
glucose metabolism and because it is anticipated that it will not need to
be associated with polypharmacology, RO6799477 has the potential to have a more
favorable tolerability profile than existing drugs and reduce the incidence of
metabolic syndrome in schizophrenia.

Main objective
Part 1: To assess the safety and tolerability of RO6799477 after multiple
ascending oral doses in healthy volunteers.
Part 2: To assess the safety and tolerability of RO6799477 after multiple oral
doses in patients with type 2 diabetes mellitus.

Secondary objectives:
Part 1:
- To investigate the pharmacokinetics of RO6799477 in plasma and in
cerebrospinal fluid;
- To investigate the pharmacodynamic effect of RO6799477 on CNS endpoints and
response to a standardized meal;
- To investigate brain penetration of RO6799477 by fMRI.

Part 2:
- To investigate the pharmacodynamic effect of RO6799477 on response to a
standardized meal and 24-h glycaemic profiles;
- To investigate the pharmacokinetics of RO6799477 after multiple oral doses in
patients with type 2 diabetes mellitus.

Part 1
Double-blind, randomized, placebo-controlled, sequential,multiple ascending
dose study.

Part 2
Double-blind, randomized, placebo-controlled, parallel group, multiple dose
study. The start of Part 2 will be contingent on the safety and pharmacodynamic
results of Part 1.

RO6799477 capsules (using combinations of 10 and 100 mg dosage strengths).
Part 1
In each cohort, subjects will receive daily oral administration of RO6799477 or
placebo for 14 days as in-clinic.
Tentative escalation scheme:
The tentative dose escalation scheme will include a minimum of 4 steps.
Cohort 1: 30 mg RO6799477 or matching placebo
Cohort 2: 100 mg RO6799477 or matching placebo
Cohort 3: 300 mg RO6799477 or matching placebo
Cohort 4: 600 mg RO6799477 or matching placebo
The study may be extended to accommodate for additional cohort(s) (e.g. cohort
5 at 900 mg RO6799477 or matching placebo) based on safety, pharmacokinetic
and/or pharmacodynamic results, without exceeding 48 subjects in total.

Part 2
Patients will receive daily oral administration of RO6799477 or placebo for 14
days as in-clinic.
• Group A: RO6799477 X mg or matching placebo.
• Group B: RO6799477 Y mg or matching placebo.
with 12 patients in each group (9 active; 3 placebo).
For all the treatment groups, the same number of capsules (mix of matching
placebo capsules and capsules of RO6799477 to obtain the chosen dose) will be
taken daily to ensure blinding.
The low dose (X mg) and a high dose (Y mg) of RO6799477 will be selected based
on Part 1 data. In any case, the high dose tested in Part 2 will not be higher
than the highest safe dose tested in Part 1.

Burden for subjects participating in this study:
- Multiple long in-house periods
- Questionnaires: POMS & ARCI49, and physical examinations
- Limited consunption of alcohol, grapefruit juice, food and beverages
containing cafeine as wellas use of tobacco
-subjects must refrain from strenuq¡s exercise on the two days preceding
admission
- Risk off side effects such as
. Mood changes, such as hyeractivity
. Mild anemia
. Changes in heart rhythm
. Too low blood sugar (hypoglycemia)
- Temporarely prolactin hormone increase.
- Unexpected side effect