A randomized, double-blind, placebo-controlled, safety, tolerability, pharmacokinetic, and pharmacodynamic study of MET409 after single and multiple ascending oral dose administration in healthy male subjects

MET409 is a new compound that may eventually be used for the treatment of
non-alcoholic steatohepatitis (NASH). NASH is a chronic liver disease which is
characterized by inflammation and the build-up of fat in the liver. The
farnesoid X receptor (FXR) is a protein that is present at high levels in the
liver and intestine where it has an important role in various metabolic
functions (i.e., bile acid synthesis, carbohydrate and lipid metabolism).
MET409 is a FXR agonist, so it binds to FXR and then activates the receptor. By
activating FXR, the inflammation and the build-up of fat in the liver may be
reduced in patients with NASH.

This study will be performed in 124 healthy male volunteers. The study will be
performed in 2 parts, Part A and Part B.

Part A will be performed in 64 healthy male volunteers divided over 8 groups of
8 volunteers each.
Part B will be performed in 60 healthy male volunteers divided over 6 groups of
10 volunteers each.

The purpose of this study is to investigate how safe the new compound MET409 is
and how well it is tolerated when it is administered to healthy volunteers.
MET409 has not been administered to humans before. It has been previously
tested in the laboratory and on animals. MET409 will be tested at various dose
levels.

It will also be investigated how quickly and to what extent MET409 is absorbed
by and eliminated from the body (pharmacokinetics). In addition, the effect of
MET409 on certain blood markers will be investigated (pharmacodynamics).

MET409 will be compared with a placebo.

Part A:
The study will consist of 1 period during which the volunteer will stay in the
research center UMCG location for 5 days (4 nights).

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 4 of the study.

On 7 - 14 days after the end of the study the health of the volunteer will be
checked for the last time.

Part B:
The study will consist of 1 period during which the volunteer will stay in the
research center UMCG location (Group B1) or Martini Hospital location (Groups
B2-B6) for 18 days (17 nights).

Day 1 is the first 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
first day of administration of the study compound (Day -1). The volunteer will
leave the research center on Day 17 of the study.

On 7 - 14 days after the end of the study the health of the volunteer will be
checked for the last time.

Part A:
The study will consist of 1 period during which you will receive MET409 or
placebo as a single dose. MET409 and placebo will be given as oral tablets with
240 mL of tap water (or up to 480 mL of tap water, if needed, for Groups A7 and
A8 [400 and 800 mg MET409] because of the large amount of tablets the
volunteers need to swallow).

When MET409 or placebo is administered, the volunteer should have fasted for at
least 10 hours (no eating and drinking). Also, after administration of the
study compound, the volunteer will be required to fast for 4 additional hours
on Day 1. Then the volunteer will be served lunch. During fasting the volunteer
is allowed to drink water, except during 2 hours before and 1 hour after
administration of the study compound.

One of the investigators will inspect volunteers hands and mouth after the
study compound intake.

Whether the volunteer will receive MET409 or placebo will be determined by
chance (randomized study). Per group, 6 volunteers will receive MET409 and 2
volunteers will receive placebo. Neither the volunteer nor the responsible
doctor knows if MET409 or placebo will be administered (double-blinded study).
However, if it is important for volunteers health, for example in case of a
serious side effect, this information will be looked up during the study.

For safety reasons, initially 2 volunteers will receive the study compound in
Group A1. One volunteer will receive MET409, and 1 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 24 hours after administration, then the remaining 6 volunteers
(5 will receive MET409 and 1 will receive placebo) will receive the study
compound.

We refer to the table below to see the planned dose levels for the groups.

Group Day Treatment How often
A1 1 20 mg MET409 or placebo Once
A2 1 30 mg MET409 or placebo Once
A3 1 50 mg MET409 or placebo Once
A4 1 100 mg MET409 or placebo Once
A5 1 150 mg MET409 or placebo Once
A6 1 200 mg MET409 or placebo Once
A7 1 400 mg MET409 or placebo Once
A8 1 800 mg MET409 or placebo Once

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 responsible doctor, unacceptable side effects appear.

Part B:
The study will consist of 1 period during which you will receive MET409 or
placebo once daily for 14 consecutive days (Day 1 to Day 14). MET409 and
placebo will be given as oral tablets with 240 mL of tap water (or up to 480 mL
of tap water, if needed, for Groups B5 and B6 [up to 400 and 800 mg MET409]
because of the large amount of tablets the volunteers need to swallow).

When MET409 or placebo is administered, the volunteer should have fasted for at
least 10 hours (no eating and drinking). Also, after administration of the
study compound, the volunteer will be required to fast for 4 additional hours
on Day 1 and on Day 14. Then the volunteer will be served lunch. On all other
dosing days (Days 2 to 13) the volunteer will receive a standard breakfast 1
hour after administration of the study compound. During fasting the volunteer
is allowed to drink water, except during 2 hours before and 1 hour after
administration of the study compound.

One of the investigators will inspect volunteers hands and mouth after the
study compound intake.

Whether the volunteer will receive MET409 or placebo will be determined by
chance (randomized study). Per group, 8 volunteers will receive MET409 and 2
volunteers will receive placebo. Neither the volunteer, nor the responsible
doctor knows if MET409 or placebo will be administered (double-blinded study).
However, if it is important for the health of the volunteer, for example in
case of a serious side effect, this information will be looked up during the
study.

We refer to the table below to see the planned dose levels for the groups.

Group Days Treatment How often
B1 1 to 14 20 mg MET409 or placebo Once daily
B2 1 to 14 50 mg MET409 or placebo Once daily
B3 1 to 14 100 mg MET409 or placebo Once daily
B4 1 to 14 200 mg MET409 or placebo Once daily
B5 1 to 14 400 mg MET409 or placebo Once daily
B6 1 to 14 800 mg MET409 or placebo Once daily

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 responsible doctor, unacceptable side effects appear.

All potential drugs cause side effects; the extent to which this occurs
differs. Since MET409 will be administered in humans for the first time, side
effects of MET409 in humans are currently not known. MET409 has been
investigated in animals. In monkeys and rats, MET409 was well tolerated and a
few side effects were seen. There were no safety concerns and in particular no
effects on cardiac, pulmonary and neurologic function.

There is limited information on other FXR agonists that are under development:
it is known that up to now they have generally shown to be safe. However, the
occurrence of pruritus has been reported in several FXR agonists, e.g. with the
registered drug Ocaliva®.

The volunteer should be aware that the aforementioned side effect and possibly
other, still unknown side effects, may occur during the study. However, with
the doses used in this study no serious side effects are expected. The
volunteer will be immediately informed if relevant safety and tolerability
information of the study compound becomes available during the conduct of the
study.

Tests
Drawing blood and/or insertion of the indwelling cannula may be painful or
cause some bruising. In total, we will take about 200 milliliters (part A) and
435 milliliters (part B) of blood from the volunteer. This amount does not
cause any problems in adults. To compare: a blood donation involves 500
milliliters 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 arms and legs. Prolonged use of these
electrodes can cause skin irritation (rash and itching).

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