A phase I randomized, double-blind, placebo-controlled, multiple 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 makes it
difficult for the body to remove them. This often causes problems in the organs
in which these proteins are deposited. 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 the heart and kidneys it can be deadly. NPT189 binds to
these amyloid proteins and is being studied to understand whether it can
suppress the buildup of amyloid in organs and 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
and how well it is tolerated when it is administered to healthy volunteers.
NPT189 has been administered to humans before. It has also been previously
tested in the laboratory and on animals. NPT189 will be tested at various dose
levels.

The study will also investigate how quickly and to what extent NPT189 is
metabolized and eliminated from the body. In addition, the effect of NPT189 on
the body will be investigated.

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

The study will consist of 5 periods in the research center during which the
volunteer will stay in the research center for 4 days (3 nights). After the 5th
period the volunteer will return to the research center for 4 short visits.
These short visits will take place on approximately Day 35, 42, 56 and 84.

Day 1, 8, 15, 22 and 29 are the days of administration of the study compound.
The volunteer is expected at the research center at 10:00 h in the morning
prior to the day of each administration of the study compound. The volunteer
will leave the research center on the 3rd day after drug administration.

NPT189 or placebo will be given as an intravenous infusion (solution of the
compound that will be administered directly in a blood vessel), once per
period. 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. Neither the volunteer, nor the responsible doctor knows if
NPT189 or placebo will be administered; we call this a double-blinded study.
However, if it is important for the volunteers health, for example in case of a
serious side effect, this information can be looked up during the study.

For safety reasons, in each group initially 2 volunteers will receive the study
compound. One volunteer will receive NPT189, and 1 volunteer will receive
placebo. After administration, the safety and tolerability of the study
compound in these 2 volunteers will be closely monitored. If there are no
concerns about the safety and tolerability 48 hours after administration, then
the remaining 6 volunteers (5 will receive NPT189 and 1 will receive placebo)
will receive the study compound.

Please refer to the table below to see the planned dose levels for each group.
The doses of Groups 2 and 3 can be adjusted based on the results of the
previous group(s). However, the dose will not be lower than 2.0 mg/kg and not
higher than 12.5 mg/kg. The dose for the next group will only be increased if
the lower dose of the previous group was found to be well tolerated and in case
of no objection by the Medical Research Ethics Committee. The study will be
discontinued if, in the opinion of the investigators, unacceptable side effects
appear.

Group Dose
1 NPT189 2.0 mg/kg or placebo
2 NPT189 5.0 mg/kg or placebo*
3 NPT189 12.5 mg/kg or placebo*
* In case the dose level will be lower or higher than planned, you will be
informed verbally.

NPT189 or placebo will be given as an intravenous infusion (solution of the
compound that will be administered directly in a blood vessel), once per
period. 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. Neither the volunteer, nor the responsible doctor knows if
NPT189 or placebo will be administered; we call this a double-blinded study.
However, if it is important for the volunteers health, for example in case of a
serious side effect, this information can be looked up during the study.

For safety reasons, in each group initially 2 volunteers will receive the study
compound. One volunteer will receive NPT189, and 1 volunteer will receive
placebo. After administration, the safety and tolerability of the study
compound in these 2 volunteers will be closely monitored. If there are no
concerns about the safety and tolerability 48 hours after administration, then
the remaining 6 volunteers (5 will receive NPT189 and 1 will receive placebo)
will receive the study compound.

Please refer to the table below to see the planned dose levels for each group.
The doses of Groups 2 and 3 can be adjusted based on the results of the
previous group(s). However, the dose will not be lower than 2.0 mg/kg and not
higher than 12.5 mg/kg. The dose for the next group will only be increased if
the lower dose of the previous group was found to be well tolerated and in case
of no objection by the Medical Research Ethics Committee. The study will be
discontinued if, in the opinion of the investigators, unacceptable side effects
appear.

Group Dose
1 NPT189 2.0 mg/kg or placebo
2 NPT189 5.0 mg/kg or placebo*
3 NPT189 12.5 mg/kg or placebo*
* In case the dose level will be lower or higher than planned, you will be
informed verbally.

As multiple doses of NPT189 have not been administered to humans there could be
unknown side effects. In humans who received a single dose of NPT189 up to 25
mg, NPT189 was well-tolerated.

Monkeys who received multiple doses of NPT189 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 you
develop nausea, vomiting, skin reactions, or breathing difficulties.

The study compound may also have side effects that are still unknown.

Possible discomforts due to procedures

Drawing blood and/or insertion of the indwelling cannula (tube in an arm vein)
may be painful or cause some bruising.

In total, we will take about 400 milliliters (mL) of blood from the volunteer.

To make a heart tracing, electrodes (small, plastic patches) will be pasted at
specific locations on the volunteer arms, chest and legs.