A single-center, randomized, double-blind, placebo-controlled, parallel-group studie investigating the safety, tolerability and pharmacokinetics of single- and multiple-ascending subcutaneous doses of TA-46 in healthy volunteers

TA-46 is a new compound that may eventually be used for the treatment of
achondroplasia. People with achondroplasia have a short stature and
achondroplasia is a common cause of dwarfism. Achondroplasia is caused by an
alteration in the gene (hereditary predisposition) for a protein called
Fibroblast Growth Factor Receptor 3 (FGFR3). FGFR3 plays an important role in
bone growth and FGFR3 causes shorter bones. In achondroplasia the altered form
of FGFR3 is overly active and this leads to very short bones. FGFR3 is
activated by binding specific proteins called fibroblast growth factors. TA-46
is constructed to resemble FGFR3. TA-46 is a decoy protein. When TA-46 is to be
administered to humans a large part of the fibroblast growth factors will bind
to the decoy protein TA-46 instead of FGFR3 whereby FGFR3 will be less
activated. It is hoped for that the overly active FGFR3 will be inhibited in
achondroplasia, thus increasing bone growth and thereby increasing height. In
this way, TA-46 may be used as a treatment of dwarfism from achondroplasia.

The study will be conducted in 94 healthy male and female volunteers. The study
consists of 3 parts: Part A, Part B and Part C.
Part A will be conducted in 40 healthy male and female volunteers divided into
5 groups with 8 volunteers each.
Part B will be conducted in 32 healthy male and female volunteers divided into
6 groups with 8 volunteers each.
Part C will be conducted in 6 healthy male and female volunteers.
Part D will be conducted in 24 healthy male and female volunteers.


The aim of this research is to find out how safe TA-46 is and how well it is
tolerated when given to healthy volunteers. TA-46 has not been administered to
people before. It has been tested in the laboratory and also on animals. TA-46
is tested in various strengths.

It will also be investigated how quickly and to what extent TA-46 is absorbed
and excreted in the body (this is called pharmacokinetics).

TA-46 will be compared with a placebo (part A and part B). A placebo is a
substance with no active ingredient, a 'fake' medicine.

This is a single-center, randomized, double-blind, placebo-controlled,
parallel-group study in 70 healthy male and female volunteers.
The duration of the study for an individual volunteer is 8, 12, or 10 weeks
respectively for Part A, Part B, or Part C.

For Part A, the study consists of 1 period in which the volunteer will stay in
the PRA research center at the location of the Martini Hospital for 5 days (4
nights) . This is followed by 6 short visits to the research center. These
short visits take place on Day 5 and 8, 10, 12, 14 and 22 (Day 22 is applicable
for Group A5 only and only if the volunteers of this group agree upon attending
the additional visit)

For Part B the study consists of 7 periods: in period 1 and 7 the volunteer
will stay for 6 days (5 nights) in the PRA research center at the location of
the Martini Hospital. This is followed by 5 short periods during which the
volunteer will stay in the research center for 1 night. This is followed by 4
short visits to the research center. These short visits take place on Day 31,
33, 35 and 39.
For Group B3: the volunteers will stay 5 days (4 nights) for period 7 and
period 7 is followed by 5 short visits to the research center. These short
visits take place on Day 30, 33, 36, 38 and 46.

For Part B3-B6 the study consists of 2 periods of 5 days (4 nights).
Furthermore there will be 2 short periods during which the volunteer will stay
in the research center for 1 night.

For Part C the study will consist of 2 periods during which the volunteers will
stay in the PRA research center at the Martini Hospital location for 5 days (4
nights). In each period this will be followed by 5 days during which you will
visit the research center for a short visit. These short visits will
take place on Days 6, 9, 12, 16, and 22.

For Part D the study will consist of 1 period during which the volunteers will
stay in the research center for 5 days (4 nights). This will be followed by
short visits on 6 days. These will take place on Days 5, 8, 10, 12, 14 and 22.

Part A: Each group consists of 8 volunteers with 6 subjects receiving TA-46 as
a subcutaneous injection / infusion and the 2 subjects receiving a single dose
placebo.
Part B: Each group consists of 8 volunteers with 6 subjects receiving TA-46 as
multiple doses (1 time per week for 4 weeks) as a subcutaneous injection /
infusion and 2 subjects receiving placebo as multiple doses.
Part C: The study will consist of 2 periods during which the volunteers will
receive TA-46 once per period. TA-46 will be administered as 2 different
preparations with the same dose of TA-46 and these preparations will be given
under the skin (subcutaneous) in the abdomen as 1-2 injection(s) for one
preparation and an infusion for the other preparation. The duration of the
infusion will depend on the volume to be administered, but will not exceed a
period of 1 hour.
Part D: The study will consist of 1 period during the volunteers will receive
which TA-46 (as the 120 mg/ml formulation) as a single dose. TA-46 will be
given under the skin (subcutaneous) in the abdomen as an infusion.

As TA-46 will be administered to humans for the first time in this study, side
effects of TA-46 in humans have not been reported to date. However, TA-46 is
specifically developed for children with abnormal growth as result of an
alteration in cartilage cells accountable for the growth of long bones. These
cells have disappeared in adulthood hence we expect no effect on the volunteers
growth. TA-46 has been studied in mice and monkeys and a proportion of the
animals developed antibodies. It is possible that the volunteer may develop
antibodies against TA-46. Based on experience with TA-46 it is not expected
that the presence of these antibodies will have consequences for the volunteers
health. In mice TA-46 often caused an allergic reaction. Allergic reactions are
seen often in mice, when human proteins like TA-46 are recognized as foreign by
their immune system. Since TA-46 has the potential to induce immune reactions,
the volunteer will be monitored for this, though such reactions are not
expected. In some monkeys receiving 30 and 100 mg/kg TA-46, transiently swollen
eyelids were seen. Because of the important role of FGFR3 in wound healing of
the skin, in phosphate levels and in vitamin D levels, you will be monitored
for changes in these as well.

Infection, pain, minor bleedings, possibly an infection.