A Phase 1, Randomized, Double-Blinded, Placebo-Controlled, Single-Dose Escalation Study Followed by a Multiple-Dose Escalation Study and an Open-Label Relative Bioavailability and Food Effect Study of VX-787 in Healthy Subjects

VX-787 is a new investigational compound under development by Vertex who is the
Sponsor of this study. VX-787 is being investigated to determine if it may be
used for the treatment of influenza, a widespread and potentially deadly
infectious disease. VX-787 is not registered as a drug which means it is
experimental and not approved for commercial use. This is the first study where
this compound is being given to humans. The study was already started in the
USA, but was put on hold by the authorities in the USA. The authorities in the
USA requested additional information on results from ongoing animal studies,
before allowing the study to proceed. The authorities in The Netherlands feel
that these results are not needed at this drug development stage, and feel that
it is safe to proceed with the study in The Netherlands.

Primary:
Part A:
to evaluate the safety and tolerability of single oral ascending doses of
VX-787 administered to healthy male and female subjects (of non-childbearing
potential)

Part C:
to evaluate safety and tolerability of multiple oral ascending doses of VX-787
administered for 10 days to healthy male and female subjects (of
non-childbearing potential)

Secondary:
Part A:
to evaluate the pharmacokinetics (PK) of VX-787 and its metabolites (if
possible)
after administration of a single oral ascending doses of VX-787 to healthy male
and
female subjects (of non-childbearing potential)

Part C:
to evaluate the PK profile of VX-787 and its metabolites (if possible) after
administration of multiple oral ascending doses of VX-787 to healthy male and
female subjects (of non-childbearing potential)

This ia a randomized, double-blinded, placebo controlled single ascending dose
study with Five cohorts of eight volunteers each receiving a single oral dose
of VX-787 or placebo (six active, two placebo), followed by a multiple
ascending dose study with two cohorts of eight volunteers each receiving
multiple doses of VX-787 or placebo (six active, two placebo)

Procedures and assessments:
Screening and follow-up: demographics, medical history, physical examination,
height, weight, BMI, HBsAg, anti HCV, anti-HIV1/2, alcohol and drug screen,
vital signs, 12-lead ECG, clinical laboratory (including chemistry, hematology,
coagulation and urinalysis), creatine kinase, pregnancy test (females only),
adverse events and prior and concomitant medication

Throughout the study: physical examination, alcohol and drug screen, vital
signs, 12-lead ECG, clinical laboratory (including chemistry, hematology,
coagulation and urinalysis), creatine kinase, pregnancy test (females only),
adverse events and prior and concomitant medication

Blood sampling for pharmacokinetics of VX-787
Urine sampling for pharmacokinetics of VX-787

Part A:
a single dose of VX-787 or placebo administered as a capsule on Day 1 in the
fasted state

Part C:
multiple doses of VX-787 or placebo administered as a capsule; once or twice
daily and dietary status (fed or fasted) of subjects at the time of dosing will
be based on available data from the PK observed in Parts A and Part B

The possible adverse effects of the investigational procedures (e.g. the use of
the indwelling canula) are described in section 9 of the information booklet.
This si the first study in which the compound will be give to humans. This
study has already started in the US and will proceed in The Netherlands. VX-787
was administered in doses of 50mg and 100mg was given previously to humans and
no adverse effects related to the drug were seen in people who received the
100mg every day for 10 days. There were two subjects who had mild diarrhea at
the 50mg dose but none at the 100mg single dose. The starting dose in groep 3
will be 200 mg. The other doses will be determined based on the results of the
preceeding groups.

VX-787 has been studied in animals and was well-tolerated at doses up to 100
mg/kg in rats and 150 mg/kg in monkeys. Currently there is a study at even
higher doses in rats and monkeys and those results are still pending.

The occurrence of known or other effects cannot be excluded. All potential
drugs cause adverse events to some extent.

Registration af adverse effects: During the entire investigation all adverse
effect that are reported will be documented.

Blood draw, indwelling canula: During this study less then 500 ml of blood will
be drawn.
Part A: Blood will be drawn until 96 hours after administration of VX 787 or
placebo (thus until Day 5). It is anticipated that on Day -1 an indwelling
canula will be inserted for most of the blood sampling on Day 1 and 2. On the
other days during this study, blood will be drawn by direct puncture of the
vein.
Part C: Blood will be drawn until 96 hours after the last administration of
VX-787 (thus until Day 14). It is anticipated that on Day -1 and Day 9 an
indwelling canula will be inserted for most of the blood sampling on Day 1 and
2, and Day 10 and 11. On the other days during this study, blood will be drawn
by direct puncture of the vein.

Collection of urine:
Part A: Urine will be collected until 72 hours after administration of VX 787
(thus until Day 4).
Part C (Group 10 only): Urine may be collected on Day 10 and 11.

Heart trace (ECG*s):
Part A: ECG*s will be made regularly: specifically on Day 1.
Part C: ECG*s will be made regularly: specifically on Day 1 and Day 10.

Blood sample for DNA tests:
During the study, a blood sample will be taken and preserved for a maximum of
15 years for possible analyses on genetic material (DNA), relevant to this
study. Taking part in this genetic testing is completely voluntary. If a
subject does not wish to participate in this part of the study he/she can state
so on the form at the end of the ICF. Refusal to participate will involve no
penalty or loss of benefits to which the subject would otherwise be entitled.
At this very moment it is not yet exactly known which analyses are going to
take place. Moreover, new genetic tests might become available in the future,
which may be applied to your blood sample. The results from the above tests
will be coded, meaning that it will be ensured that the results cannot be
linked to the subjects personal identity. For the DNA test a blood sample of
8.5 mL will be taken. Subjects will not receive an additional reimbursement for
the DNA sample.

Meals:
If Part C is conducted under fed conditions, a high-fat, high-calorie breakfast
will be served 30 minutes before each dosing on Days 1 to 10. Evening meals
will be given 30 minutes before evening dose, if applicable. Subjects are
required to eat all of the pre-dose meals provided.
The high-fat, high-calorie breakfast consist of:
2 slices of wheat bread (70 g) with 15 g margarine
2 fried eggs (in 15 g butter/margarine) (approximately 100 g)
1 portion of bacon or brie (40 g)
1 portion of fried potatoes (115 g)
1 glass of high fat milk (240 mL)