A Double-Blind, Placebo-Controlled, Randomized, Multiple Ascending Oral Dose Study to Investigate The Safety, Tolerability, Pharmacokinetics And Pharmacodynamics of JNJ-26070109 In Healthy Subjects

The study has three objectives. Firstly, we will study the safety and
tolerability of JNJ-26070109 after the administration of multiple doses of the
drug. Secondly, we will investigate the maximum tolerated concentration of the
drug in the body. Thirdly, we will study the speed at which the drug is
absorbed in the body, as well as the degree of elimination of the drug after
multiple doses.

JNJ-2607019 is an investigational drug being developed for gastroesophageal
reflux disease (GERD) to reduce the complaints of abdominal pain and heartburn
in people with this disease. JNJ-26070109 inhibits the gastrin receptor in the
stomach. The gastrin receptors are small particles in the stomach. When the
gastrin receptor is triggered the stomach will produce acid. In people with
GERD the acid in the stomach is the cause for the abdominal pain and heartburn.
By blocking the gastrin receptor the acid production will decrease and the
complaints of pain and heartburn will diminish.

This is a single center study in healthy male and female subjects, and consists
of 3 parts.
Part One is a double-blind, randomized, placebo-controlled multiple ascending
dose design. Subjects will participate in one of four (4) cohorts (n = 10) and
will receive either JNJ 26070109 oral suspension (n = 7) or placebo (n = 3)
daily for 14 consecutive days. Blinded data arising from the previous level(s),
based on the concentrations of study drug in blood, safety and tolerability
will be reviewed.
Dose escalations will continue if all these data are found acceptable.
It will continue until maximum tolerated dose (MTD) is reached per the dose
limiting toxicity (DLT) described in Section (4.6.6). Each dose escalation will
not exceed 3 fold of the previous dose and the dose will not exceed 1000 mg.
In Part Two of the study, based on safety, the concentration of study drug in
blood and tolerability data of Part 1, two doses will be selected. 2 Satellite
cohorts, each with 20 healthy male subjects, will be dosed in order to measure
24-hour intragastric pH as a pharmacodynamic endpoint. Each cohort in Part Two
will receive one of these two doses of JNJ-26070109 (n=15 per cohort) or
placebo (n=5 per cohort) daily for 14 consecutive days and will be evaluated in
a similar fashion to Part One. Commencement of Part Two may occur in parallel
with Part One but only after completion of the in-life phase in the 10 subjects
in Part One at the same selected dose. The staggered start of subjects in Part
Two by at least 2 weeks from Part One at the selected doses provides an added
level of safety for any adverse effects that may be reported over the 14-day
treatment period in Part One. The only difference in procedures and assessments
for subjects enrolled in Part One and Part Two is that intragastric pH will be
measured for 24 hours on Days -1 (day before dosing), 1, 7 and 14 in subjects
in Part Two and a Helicobacter Pylori breath test will be taken.
Part Three, Upon completion of the dose escalation in males in Part One, a
cohort of 10 healthy females not of childbearing potential will be dosed with
JNJ-26070109 (n=7 per cohort) or placebo (n=3 per cohort) daily for 14
consecutive days and will be evaluated in a similar fashion to Part One. The
dose and regimen of JNJ-26070109 will be no greater than the highest dose that
has been shown to be tolerable in males.
The total duration per subject is 68 days at a maximum. The study will include
a medical examination, one admission period of 20 days, one visit and finally a
follow-up. The following assessments will be taken; physical exam, blood-and
urine sample collections, alcohol breath test, blood sample for DNA-assessment,
vital signs, ECG*s and continuously hearth rhythm (telemetry) . For part 2,
also intra gastric pH monitoring will be assessed for 24 hours at Day -1, Day
1, Day 7 and Day 14 and a Helicobacter pylori breath test will be taken.

Every subject is only allowed to participate after randomization to one of the
cohorts. Per treatment subjects will receive the study drug for 14 consecutive
days.
Part 1:
Treatment A 50 mg JNJ-26070109 suspension or placebo qd
Treatment B 150 mg JNJ-26070109 suspension or placebo qd
Treatment C 400 mg JNJ-26070109 suspension or placebo qd
Treatment D 1000 mg JNJ-26070109 suspension or placebo qd
Part 2:
This part was initially designed to have 2 cohorts of 20 healthy male subjects
each.
After completion of Part one and the first 10 subjects of Part two it was
confirmed that JNJ-26070109 exposure on day 1 was up to 40% lowwer compaired
with exposures observed in the SAD (C-2006-003) study at the higher dose level
of 400 mg and 1000 mg suspension. The next three cohorts will receive
JNJ-260720109 in hard gel capsule formulaion.
cohort 1 400 mg JNJ-26070109 suspension or plavebo qd
cohort 2 100 mg JNJ-26070109 in hard gel capsule formulation or placebo qd.
cohort 3 300 mg JNJ-26070109 in hard gel capsule formulation or placebo qd.
cohort 4 based on PK, pH and safety/tolerability data of previous 2 cohorts, a
dose level which will no exeed 500 mg JNJ-26070109 in hard gel capsule
formulation or placebo qd.
Part 3:
Upon completion of the dose escalation in males and dependent on the observed
safety of the preceeding cohorts and PK-exposure data a cohort of 10 females
may be dosed with JNJ-27070109 hard gel capsules or placebo qd.

The associated risks to this study are the occurrence of possibility side
effects of the use of JNj-26070109. The burden of the subjects are the
confinement period in the unit, venipuncture, the insertion of the cannula and
connection of the telemetry equipment. For Part 2 also the insertion of the
gastric tube. All subjects will be carefully monitored regarding possible
adverse events by experienced study personnel and physicians