A Phase I, Randomized, Single-Center Study to Investigate the
Safety, Tolerability, Pharmacodynamic and Pharmacokinetic Profiles of Single and Multiple Doses of R924548 in Healthy Human Subjects

The study drug to be given, R548, is a new investigational drug that may
eventually be used for the treatment of immune-mediated diseases such as
rheumatoid arthritis. R548 is a study drug that will convert in the body into
an inhibitor of Janus kinase 1 (JAK1) and Janus kinase 3 (JAK3), which are
enzymes that contribute to the development of inflammation in rheumatoid
arthritis.

This new study drug is not registered and approved for sale as a drug and this
is the first time that this study drug is being given to humans.

Primary:
to investigate the safety and tolerability in healthy subjects of single and
multiple ascending oral doses of R548 formulated and dosed as an aqueous
suspension or aqueous solution

Secondary:
- to characterize the single dose and steady state pharmacokinetic (PK)
profiles of R548 and its active metabolite R507
- to characterize the single dose PK profiles of R548 and its active metabolite
R507 in R548 formulated as an immediate release and an enteric-coated tablet.
- to characterize the food effect on the PK of R548 formulated as an immediate
release tablet.
- to characterize the single dose and steady state pharmacodynamics (PD)
profile of R548
- to evaluate the potential PK interaction between a CYP1A2 substrate
(caffeine) and R548 at steady state in healthy human subjects
- to profile the metabolites of R548 in the plasma, urine and feces

Design
Part A: a randomized, placebo-controlled, single-ascending dose study with four
groups of four healthy male subjects (Groups A1-A4) each receiving a single
oral dose of R548 or placebo (three active and one placebo); two groups of
eight healthy male subjects (Groups A5-A6) each receiving a single oral dose of
R548 or placebo (six active and two placebo; Group A1 will be sub-divided in
two groups of two subjects (one active and one placebo in the first group, and
two active in the second group, which will therefore be single-blind) separated
by a minimum of two days.

Part B: a randomized, placebo-controlled, multiple-ascending dose study with
two to three groups of eight healthy male subjects each receiving a single dose
of R548 or placebo (six active and two placebo) on Days 1 and 7 and an oral
dose of R548 or placebo twice daily on Days 2-6.

Part C: a randomized, placebo-controlled, multiple dose study with one to two
groups of ten healthy male and post-menopausal/surgically sterile female
subjects each receiving a single dose of R548 or placebo (eight active and two
placebo) on Days 1 and 14 and an oral dose of R548 or placebo twice daily on
Days 2-13

Part D: A randomized, open-label (not placebo-controlled), five-treatment
period study in 12 healthy male subjects consisting of four-way crossover,
followed by a fifth period in which subjects will be randomized to one of two
formulations. The four-way crossover component will employ a Williams design
with three subjects randomized to receive a different R548 formulation in each
period: aqueous suspension in fed state, immediate release 100 mg tablets in
fed state, immediate release 100 mg tablets in fasted state, and enteric coated
100 mg tablets in fasted state. In the fifth period, six subjects will be
randomized to receive immediate release 200 mg tablets in fasted state, and six
subjects will receive enteric coated 200 mg tablets in fasted state. All Part
D doses will be 400 mg R548.

Study Medication
Active substance: R548
Activity: janus kinase 1 (JAK1) and janus kinase 3 (JAK3)
Dosage form: aqueous suspension or aqueous solution

Treatments
Part A (SAD)
Group A1: a single oral dose of 50 mg R548 aqueous suspension or placebo on Day
1
Group A2: a single oral dose of 100 mg R548 aqueous suspension or placebo on
Day 1
Group A3: a single oral dose of 200 mg R548 aqueous suspension or placebo on
Day 1
Group A4: a single oral dose of 100 mg R548 aqueous solution or placebo on Day 1
Group A5: a single oral dose of 350 mg R548 aqueous suspension or placebo on
Day 1
Group A6: a single oral dose of 500 mg R548 aqueous suspension or placebo on
Day 1

Part B (MAD)
Group B1: a single oral dose of 200 mg R548 on Days 1 and 7 and an oral dose of
200 mg R548 twice daily on Day 2-6, a single oral dose of 150 mg caffeine in
the morning of Days -1 and 6
Group B2: a single oral dose of 400 mg R548 on Days 1 and 7 and an oral dose of
400 mg R548 twice daily on Day 2-6, a single oral dose of 150 mg caffeine in
the morning of Days -1 and 6

Part C (multiple dose)
Group C1: a single dose of 400 mg R548 on Days 1 and 14 and an oral dose of 400
mg R548 twice daily on Day 2-13

Part D
four times a single oral dose of 400 mg R548 on days 1, 4, 7, 10 and 13, as a
suspension (once) or a tablet (four times)

not applicable