A Phase 1 Randomized, Double-Blind, Placebo-Controlled, Single Ascending Dose Study to Evaluate the Safety, Tolerability and Pharmacokinetics of NPT189 in Healthy Subjects

NPT189 is a new compound that may eventually be used for the treatment of
amyloidosis. Amyloidosis is a group of rare diseases characterized by a buildup
of abnormal proteins, called amyloids, in different organs. These proteins have
a somewhat different structure which allows them to stick together and prevents
the body from removing these proteins. There are different types of
amyloidosis, depending on the type of amyloid and where in the body the buildup
occurs. General symptoms include changes in skin color, severe fatigue, joint
pain, shortness of breath, severe weakness and tingling and numbness in legs
and feet. There is currently no cure for amyloidosis, and treatments only slow
the development of the disease and manage the symptoms. Especially when
amyloidosis affects your heart and kidneys it can be deadly. NPT189 binds to
these amyloid proteins and is thought to suppress the buildup of amyloid in
organs and is thought to break up these amyloid proteins so they can be cleared
from the body.

The purpose of this study is to investigate how safe the new compound NPT189 is
when it is administered to healthy subjects. NPT189 has not been administered
to humans before. It has been previously tested in the laboratory and on
animals. NPT189 will be tested at various dose levels.

It will also be investigated how quickly and to what extent NPT189 is absorbed
and eliminated from the body (pharmacokinetics).

The effects of NPT189 will be compared to the effects of a placebo.

The study will consist of 1 period during which the volunteer will stay in the
research center in Groningen, location Martini Hospital for 4 days (3 nights).
This will be followed by 3 days during which the volunteer will visit the
research center for a short visit. These short visits will take place on Day 7,
14 and 28.

Day 1 is the day of administration of the study compound. The volunteer is
expected at the research center at 14:00 h in the afternoon prior to the day of
administration of the study compound (Day -1). The volunteer will leave the
research center on Day 3 of the study.


During the short visits on Day 7, 14 and 28 of the study a physical examination
will be done including measurement of blood pressure, heart rate, number of
breath per minute and body temperature, a heart trace (on Day 7 only) and a
number of blood tests. The volunteer will also be asked about any possible
adverse effects and medication use.

On Day 49 of the study volunteers health will be checked for the last time.

NPT189 and placebo will be given as an intravenous infusion (solution of the
compound that will be administered directly in a blood vessel). The infusion
will take about an hour.

Whether the volunteer will receive NPT189 or placebo will be determined by
chance. Per group, 6 volunteers will receive NPT189 and 2 volunteers will
receive placebo, meaning that the volunteer will have 75% chance to receive
NPT189 and 25% chance to receive placebo. Neither the volunteer, nor the
responsible doctor knows if NPT189 or placebo will be dosed; *the study is
blinded*. However, if it is important for volunteers health, for example in
case of a serious adverse event, this information can be looked up during the
study.

Please refer to the table below to see the planned dose levels for the groups.
The dose for the groups 2 to 5 will only be increased if the lower dose of the
previous group was found to be well tolerated and in the case of no objection
by the Medical Research Ethics Committee. The investigation will be
discontinued if, in the opinion of the investigators, unacceptable adverse
effects appear. The doses of Groups 2 to 5 can be adjusted based on the results
of the previous group(s). The planned starting dose is 2.0 mg and the dose will
not be higher than 30.0 mg.

Verblijf (Dag -1 tot 3)

Group 1
Day 1 (Infusion): NPT189 0.2 mg/kg or placebo
Day 7, 14, en 28: Follow-up visit
Day 49: Last follow-up visit

Group 2
Day 1 (Infusion): NPT189 0.5 mg/kg or placebo
Day 7, 14, en 28: Follow-up visit
Day 49: Last follow-up visit

Group 3
Day 1 (Infusion): NPT189 1.5 mg/kg or placebo
Day 7, 14, en 28: Follow-up visit
Day 49: Last follow-up visit

Group 4
Day 1 (Infusion): NPT189 4.5 mg/kg or placebo
Day 7, 14, en 28: Follow-up visit
Day 49: Last follow-up visit

Group 5
Day 1 (Infusion): NPT189 12.0 mg/kg or placebo
Day 7, 14, en 28: Follow-up visit
Day 49: Last follow-up visit

Group 5
Day 1 (Infusion): NPT189 25.0 mg/kg or placebo
Day 7, 14, en 28: Follow-up visit
Day 49: Last follow-up visit

Each group will have 3 separate dosing groups. In the first dosing group only 2
volunteers will be dosed first. One volunteer will receive NPT189 and one
volunteer will receive placebo. In Group 1 and 2 these volunteers will be
continuously monitored during the first 8 hours following dosing for safety and
tolerability (presence of side effects). If there are no medical concerns in
the first 24-48 hours, the remaining volunteers will be dosed in 2 separate
dosing groups of 3 volunteers each approximately 24 hours apart. The volunteers
of each of the following dosing group will be closely monitored for safety and
tolerability during the first 24 hours following dosing. If there are no
medical concerns, the volunteers in the next dosing group will be dosed.

The study compound may cause side effects.

As NPT189 will be administered to humans for the first time in this study,
therefore, side effects of NPT189 in humans have not been reported to date.
However, NPT189 has been studied in animals.

Monkeys who received multiple doses of NPT218 showed no adverse effects with
respect to, for example body weight, appetite and clinical blood tests. Some
skin irritations have been observed in monkeys at the site of the infusion
after repeated infusions, but these resolved without the need for treatment.

It is possible that the volunteer has a reaction to NPT189 during or after its
administration, such as nausea, decreased blood pressure, difficulty breathing
or a rash. The volunteer should immediately contact the investigator if
volunteer develop nausea, vomiting, skin reactions, or breathing difficulties.

Other, as yet unknown risks, are also possible as NPT-189 has not previously
been administered to humans.

Tests
Drawing blood and/or insertion of the indwelling cannula may be painful or
cause some bruising.

In total, we will take about 122 milliliters of blood from the volunteer. This
amount does not cause any problems in adults. To compare: a blood donation
involves 500 ml of blood being taken each time.

To monitor the heart rate, electrodes (small, plastic patches) will be pasted
at specific locations on the chest and abdomen. Prolonged use of these
electrodes can cause skin irritation (rash and itching).

Procedures: pain, minor bleeding, bruising, possible infection.