A randomized, 2-part, placebo controlled phase 1 study to evaluate safety, tolerability, pharmacokinetics and immunogenicity following single ascending doses (Part 1) and multiple ascending doses (Part 2) of GBR 830 in adult healthy subjects

GBR 830 is a new investigational compound that may eventually be used for the
treatment of several autoimmune diseases. An autoimmune disease is an illness
that occurs when the body tissues are attacked by its own immune system. This
occurs for example in patients with rheumatoid arthritis (affecting the
joints), psoriasis (affecting the skin), and Crohn*s disease or ulcerative
colitis (affecting the intestines).

Antibodies are produced by our own body for host defense against for example
bacteria and viruses. However, antibodies can also be prepared in a custom made
way by pharmaceutical companies, so that they can be used for various
therapeutic applications and medical research. GBR 830 is an antibody designed
to specifically recognize, bind and block the function of particular receptors
on immune cells (e.g. the OX 40 receptor on T cells). A receptor is a protein
on the cell surface that can transmit a signal when molecule binds to that
receptor. GBR 830 acts on a type of white blood cells (so called T cells) that
play an important role in immune responses.

GBR 830 is in development and is not registered as a drug but has been given to
humans before.

The purpose of the study is to investigate to what extent GBR 830 is tolerated.
It will also be investigated how quickly and to what extent GBR 830 is absorbed
and eliminated from the body (this is called pharmacokinetics). In addition,
the effect of GBR 830 on the immune system will be investigated (this is called
pharmacodynamics) and the effect of GBR 830 on the body may be explored.

Part 1:

Before the study the volunteer will undergo a pre-study screening during which
the volunteer will be subjected to a number of medical examinations Similar
examinations will be performed after the study at the post-study screening.

Day 1 is the day of administration of GBR 830 or placebo. The volunteer is
expected at the clinical research center at 11:00 h in the morning prior to the
day of administration of study medication (Day -1). The volunteer will be
required not to have consumed any food or drinks during 4 hours prior to
arrival in the clinical research center (with the exception of water). He/she
will stay in the clinical research center in Groningen (location UMCG) for 4
days (3 nights: from Day -1 to Day 3).

The volunteer will return to the clinical research center (location Martini
Hospital) for 8 additional short visits: on Day 5, Day 7, Day 8, Day 15, Day
29, Day 43, Day 57 and Day 71 (the post study screening).

The participation to the entire study, from the pre-study screening until the
post study screening, will be a maximum of 99 days.

During the study the volunteer will receive a single dose of GBR 830 or placebo
as an iv infusion for 1 hour.

Part 2:

Before the study the volunteer will undergo a pre-study screening during which
the volunteer will be subjected to a number of medical examinations Similar
examinations will be performed after the study at the post-study screening.

Day 1 is the first day of administration of GBR 830 or placebo. The volunteer
is expected at the clinical research center at 11:00 h in the morning prior to
the day of each administration of the study compound. The volunteer will be
required not to have consumed any food or drinks during the 4 hours prior to
arrival in the clinical research center (with the exception of water). For each
dose, the volunteer will stay in the clinical research center in Groningen
(location UCMG) for 3 days (2 nights). Between the 1st and 2nd dose the
volunteer will return for two short visits on Day 3 and Day 5 and between the
4th and 5th dose he/she will return for two short visits on Day 24 and Day 26
(location Martini Hospital).

After the volunteer has received all 6 doses, he/she will return to the
clinical research center (location Martini Hospital) for 8 additional short
visits: on Day 38, Day 40, Day 42, Day 43, Day 50, Day 64, Day 78, and Day 92
(the post study screening).

There will be an option to stay overnight in the clinical research center
(location UMCG) from Day 2 to Day 3, from Day 23 to Day 24, and From Day 37 to
Day 38. The ambulant visits on Day 3, Day 24 and Day 38 will take place in the
clinical research center located at the Martini Hospital.

The participation to the entire study, from the pre-study screening until the
post study screening, will be a maximum of 120 days.

During the study the volunteer will receive GBR 830 or placebo as an iv
infusion for 1 hour once every week for 6 weeks.

Part 1:

Group Day Treatment (mg/kg) How often
1 1 20 mg/kg GBR 830 or placebo Once
2 1 40 mg/kg GBR 830 or placebo Once

Part 2:

Group Day Treatment (mg/kg) How often
3 1, 8, 15, 22, 29 and 36 10 mg/kg GBR 830 or placebo Once every week for 6
weeks
4 1, 8, 15, 22, 29 and 36 20 mg/kg GBR 830 or placebo Once every week for 6
weeks

All potential drugs can cause adverse effects; the extent to which this occurs
differs. GBR 830 has been studied in animals. In animals no abnormalities were
observed and the study medication was well tolerated.

GBR 830 has already been studied in healthy volunteers with dose levels up to
10 mg/kg intravenously. In this previous study that has also been conducted at
PRA, GBR 830 was well tolerated at all dose levels without clear adverse
effects.

In another study that has recently been completed at PRA, GBR 830 was
administered as an iv dose of 600 mg and compared to 75 mg and 600 mg of GBR
830 administered subcutaneously (sc). In this study, GBR 830 was generally well
tolerated. However, based on preliminary data there was one adverse event
(infusion reaction characterized by acute appearance of hives) that
necessitated early discontinuation of the infusion. This adverse event was of
mild intensity and resolved swiftly without medical intervention. In addition,
a serious adverse event occurred after sc administration of 75 mg GBR 830:
neuralgic amyotrophy; this volunteer suffered from acute and severe neck pain.
Although the neck pain was transient, it was followed by persistent paralysis
of the diaphragm which resulted in shortness of breath when lying flat. This
adverse event was of moderate intensity at occurrence and the cause of this
rare disorder was not known. As the first symptoms developed two weeks after
administration of the drug, a link with the recent administration of GBR 830
could not be definitely ruled out. On the other hand, it could have been a
coincidence as well. This serious adverse event is still ongoing but stable.

In another ongoing study, GBR 830 is being tested at a dose of 10 mg/kg in
patients with atopic dermatitis (a type of eczema). In this study GBR 830 has
been well tolerated so far.

GBR 830 is a so-called *biological*; with respect to the properties of these
drugs there is a chance that the volunteers body will develop antibodies
against GBR 830. This may induce development of a hypersensitivity or allergic
reaction to GBR 830 as described above and the volunteer may become more
susceptible to infections. Based on experience with GBR 830 (and other
monoclonal antibodies in general), the chance that the volunteer will develop
antibodies against the study compound is possible. If antibodies against the
new investigational compound are found in the volunteers blood, we expect that
with the current knowledge this will have no consequences for his/her health.
However, in case the volunteer would develop a condition that could be treated
with GBR 830 in the future, it cannot be predicted whether and how these
antibodies may influence the effect of treatment. GBR 830 is being developed
for autoimmune diseases like rheumatoid arthritis, ankylosing spondylitis,
axial spondyloarthritis, psoriatic arthritis, psoriasis, Crohn*s disease, and
ulcerative colitis. If the volunteer would need treatment for one of these
diseases, the volunteers doctor will suggest the best possible treatment for
him/her. As of today several medications are available or being developed for
the treatment of the conditions mentioned.

The volunteer should be aware that the aforementioned adverse events and
possibly other, still unknown adverse events, may occur during the study.