A Randomized, Placebo-Controlled, Double-blind, Single Ascending Dose, First in Human Phase 1 Study to Evaluate the Safety, Tolerability, and Pharmacokinetics of QRL-101 in Healthy Participants.

QRL-101 is a new compound that may potentially be used for the treatment of
amyotrophic lateral sclerosis (ALS). ALS is a rare disease where nerve cells in
the brain and spinal cord that are responsible for movement are getting damaged
and die. This results in loss off coordination, muscle mass, muscle strength,
speaking, swallowing, and eventually respiratory function. ALS gets worse over
time and current treatments only bring about a small increase in lifespan.
There is no cure. QRL-101 is being developed as a potential treatment for ALS
as lab tests have shown that it can reduce the overactivation of cells.
Increased overactivation in nerve cells in brain and spinal cord is known to be
related to shortened lifespan in ALS patients.

In this study we will investigate how safe the new compound QRL-101 is and how
well it is tolerated when it is used by healthy subjects. A single dose of the
study compound will be given to each participant.

We will also investigate how quickly and to what extent QRL-101 is absorbed by,
transported through, and eliminated from the body.

We compare the effects of QRL-101 with the effects of a placebo. A placebo is a
compound without any active ingredient. Please note that when the term *study
compound* is used in this document, we mean QRL-101, placebo, or both.

This is the first study where QRL-101 is given to humans. QRL-101 has already
been extensively tested in the laboratory and on animals. QRL-101 will be
tested at various dose levels. There are multiple groups with ascending dose
levels, meaning the next group will receive a higher dose than the previous
group.

The study will take a maximum of 40 days from the screening until the follow-up
visit.
In total the volunteer will come to the research center 3 times:
- once for the screening.
- once for a stay in the research center of 4 days (3 nights).
- once for a follow-up visit on Day 10 (+/- 2 days).

A single dose of QRL-101 or placebo is given on Day 1.

The volunteer will be given QRL-101 or placebo as oral capsules with 240
milliliters (mL) of (tap) water or as an oral liquid of the study compound in
water (in total 240 mL). The study compound will be given after the volunteer
has fasted (no eating or drinking, except water) for at least 2 hours. Fasting
will continue until 1 hour after dosing. Drinking water is not allowed from 1
hour before dosing until 1 hour after dosing. If the study compound is given as
a liquid, the volunteer will receive a mint strip (e.g., Listerine strip)
before and after dosing to mask the taste of the study compound.

The table below shows an overview of the planned doses for each group where the
study compound is given as capsules.

Group Dose*
1 1 mg QRL-101 or placebo
2 2 mg QRL-101 or placebo
3 6 mg QRL-101 or placebo
4 12 mg QRL-101 or placebo
5 24 mg QRL-101 or placebo
6 # mg QRL-101 or placebo
7 # mg QRL-101 or placebo
8 # mg QRL-101 or placebo
9 # mg QRL-101 or placebo

*The doses to be used from Group 6 onwards will be decided based on the results
of the previous groups.

The table below shows the planned doses for each group where the study compound
is given as a liquid.
Group Dose*
A1 6 mg QRL-101 or placebo
A2 # mg QRL-101 or placebo
A3 # mg QRL-101 or placebo
A4 # mg QRL-101 or placebo
A5 # mg QRL-101 or placebo
A6 # mg QRL-101 or placebo
A7 # mg QRL-101 or placebo
* The doses to be used from Group A2 onwards will be decided based on the
results of the previous groups.

Blood draw
Drawing blood may be painful or cause some bruising. The use of the indwelling
cannula (a tube in a vein in the arm) 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 85 milliliters (mL) of blood from the volunteer
from screening to follow-up. This amount does not cause any problems in adults.
To compare: a blood donation involves 500 mL of blood being taken each time at
once. 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 (small, plastic patches) will be placed on
the volunteers arms, chest and legs. Prolonged use of these electrodes can
cause skin irritation (rash and itching).

Coronavirus test (only done when required per ICON policy)
Samples for the coronavirus test will be taken from the back of the volunteers
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 the volunteers throat may cause the volunteer to gag. When the
sample is taken from the back of the volunteers nose, the volunteer may
experience a stinging sensation and the volunteers eyes may become watery