Safety, tolerability, pharmacokinetics and pharmacodynamics of single rising subcutaneous doses of BI 3006337 in healthy male subjects (single-blind, partially randomised within dose groups, placebo-controlled, parallel (sequential) group design)

BI 3006337 is a new compound that may potentially be used for the treatment of
non-alcoholic liver inflammation (NASH). NASH is a common liver disease that
occurs when the liver becomes inflamed due to the build-up of fat in the liver.
If the liver damage continues for a long time, scarring can develop in the
liver. This is also known as 'cirrhosis'. People with NASH have an increased
risk of developing liver cancer.

BI 3006337 combines the activity of 2 different hormone systems that are
naturally present in the body, the so called glucagon-like peptide 1 (GLP-1)
and fibroblast growth factor 21 (FGF21). GLP-1 is released in the intestines
and plays an important role in regulating the glucose metabolism. The hormone
FGF21 released by the liver plays a key role in the energy metabolism and
stimulates the burning of fat in the liver. It is assumed that the combined
effect of both hormones can have a positive impact on the above-mentioned NASH.

In this study we investigate how safe the new drug BI 3006337 is and how well
it is tolerated when used in healthy subjects.

We also investigate how quickly and to what extent BI 3006337 is absorbed,
transported and excreted by the body. We also look at the effect of BI 3006337
on certain biomarkers in the blood.

We compare the effects of BI 3006337 with the effects of a placebo.

BI 3006337 has not been administered to humans before. It has been extensively
tested in the laboratory and on animals. BI 3006337 is tested in different
strengths.

The study lasts a maximum of 9 weeks from the inspection to the follow-up check.

In total, volunteers visit the research center 10 times:

Once for the inspection
Once for a stay at the research center. For the research it is necessary to
stay in the research center for 1 period of 6 days (5 nights). We expect the
volunteer 2 days prior to the administration of the study drug at the study
center (Day -2).
Day 1 is the day on which the study drug is received.

One leaves the research center on Day 4 of the research.
After the stay in the research center there are 7 short visits to the research
center.
They come one more time for the check-up.

They will be given BI 3006337 or placebo as a subcutaneous injection into a
raised skin fold of your abdomen while lying down. After that, the volunteer
must also remain in bed for at least 30 minutes.

Group 1, Day 1, BI 3006337 0.2 mg (6 subjects) or placebo (2 subjects) once
Group 2, Day 1 BI 3006337 0.5 mg (6 subjects) or placebo (2 subjects) once
Group 3, Day 1 BI 3006337 1 mg (6 subjects) or placebo (2 subjects) once
Group 4, Day 1 BI 3006337 2 mg (6 subjects) or placebo (2 subjects) once
Group 5, Day 1 BI 3006337 4 mg (6 subjects) or placebo (2 subjects) once
Group 6, Day 1 BI 3006337 8 mg (6 subjects) or placebo (2 subjects) once
Group 7, Day 1 BI 3006337 15 mg (6 subjects) or placebo (2 subjects) once
Group 8, Day 1 BI 3006337 30 mg (6 subjects) or placebo (2 subjects) once
Group 9, Day 1 BI 3006337 50 mg (6 subjects) or placebo (2 subjects) once
Group 10, Day 1 BI 3006337 100 mg (6 subjects) or placebo (2 subjects) once
Group 11, Day 1 BI 3006337 150 mg (9 subjects) or placebo (3 subjects) once

Blood draw
Drawing blood may be painful or cause some bruising. The use of the indwelling
cannula can sometimes lead to inflammation, swelling, hardening of the vein,
blood clotting, and bleeding in the environment (bruising) of the puncture
site. In some individuals, a blood draw can sometimes cause pallor, nausea,
sweating, low heart rate, or drop in blood pressure with dizziness or fainting.

In total, we will take about 500 milliliters (mL) of blood from you from
screening to follow-up. This amount does not cause any problems in adults. If
the investigator thinks it is necessary for the safety of a subject, extra
samples might be taken for possible additional testing. If this happens, the
total amount of blood drawn may be more than the amount indicated above.

Heart tracing
To make a heart tracing, electrodes will be placed on your arms, chest and
legs. To monitor the electrical activity of your heart over a longer period,
electrodes will be placed on the chest and abdomen. Prolonged use of these
electrodes can cause skin irritation (rash and itching).

Fasting
If you have to fast for a prolonged time during the study, this may lead to
symptoms such as dizziness, headache, stomach upset, or fainting.

Coronavirus test
Samples for the coronavirus test will be taken from the back of your nose and
throat using swabs. Taking the samples only takes a few seconds, but can cause
discomfort and can give an unpleasant feeling. Taking a sample from the back of
your throat may cause you to gag. When the sample is taken from the back of
your nose, you may experience a stinging sensation and your eyes may become
watery.

Stomach emptying test
Drinking the paracetamol solution can lead to undesirable effects or
discomforts. Undesirable side effects observed to date include:
- Rare (1 to 10 in 10,000 patients treated): Increase in liver enzymes,
hypersensitivity reactions and bronchospasm (tightening of the airways) due to
sodium metabifulsite as an ingredient of the paracetamol solution.
- Very rare (less than 1 in 10,000 patients treated): Changes in the blood
count, such as thrombocytopenia (decrease in platelets) and agranulocytosis
(deficiency of specific white blood cells); severe skin reactions, partly with
blistering and peeling of the skin (drug-induced Stevens-Johnson syndrome,
toxic epidermal necrolysis, acute generalised exanthematous pustulosis);
bronchospasm (tightening of the airways due to drug induced asthma);
hypersensitivity reactions from simple reddening of the skin all the way to
urticaria (hives), Quincke's oedema (swelling mainly in the face) and
life-threatening anaphylactic shock (severe allergic reaction).

Sugar tolerance test
Drinking the sugar solution can lead to undesirable effects or discomforts.
Undesirable side effects observed to date include:
- Common (1 to 10 in 100 patients treated): Symptoms of hypoglycemia (low blood
sugar level) with an influence on wellbeing during the sugar tolerance test or
at a later point. Symptoms of hypoglycemia may also impair the ability to
react, thus limiting the ability to drive and use machines.
- Uncommon (1 to 10 in 1,000 patients treated): Gastric (stomach) pressure,
nausea or vomiting.
- Rare (1 to 10 in 10,000 patients treated): Allergic reactions, such as
reddening of the skin.