A Non-Randomized, Open Label, Adaptive, Single Center, Positron Emission Tomography (PET) Study to Assess Distribution of RO7248824 in the Central Nervous System Following Single Intrathecal Doses of [89Zr]-Labeled RO7248824 in Healthy Male Participants

RO7248824 is a new compound that may potentially be used for the treatment of
Angelman syndrome. Angelman syndrome is a rare genetic disorder that is present
at birth. People with AS have developmental problems that become noticeable by
the age of 6 to 12 months. Other common signs and symptoms usually appear in
early childhoods like walking and balance disorders, gastrointestinal issues,
seizures, and little to no speech. There is currently no cure for AS. People
with AS have genetic changes leading to a shortage of a protein called UBE3A
especially in the brain. In animal studies RO7248824 was able to increase the
UBE3A protein. It is hoped that treatment with RO7248824 will also increase the
level of UBE3A protein in people with AS, which could help to reduce the
symptoms of AS. The only way that RO7248824 can reach the brain is by an
injection into the fluid surrounding the spine, known as cerebrospinal fluid or
CSF in short.

The new compound RO7248824 is being developed for the treatment of Angelman
syndrome (AS). The purpose of this study is to find out how RO7248824 spreads
in the brain and spine after injection into the spinal canal (intrathecal
administration). This information is important for the design of clinical
trials for people with AS and to learn more about how other similar types of
drug can travel to the brain and spinal cord. It will also be investigated how
safe RO7248824 is and how well it is tolerated when it is administered to
healthy male volunteers.

Participation from screening until the follow-up visit will last up to 12 weeks
(3 months).

The volunteer will be given one single dose of 10 mg RO7248824 mixed with a
maximum of 100 µg of the labeled form of RO7248824 through an intrathecal
injection. The dose of tracer may be adapted during the study. If this happens,
the volunteer will be informed about this prior to receiving the dose.

The study will be performed in 2 parts, Part 1 and Part 2. the volunteer can
participate in 1 part only.
• In Part 1, RO7248824 will be administered in a similar way as in another
study ongoing in parallel. The dose of the labeled form of RO7248824 (which
determines the amount of radioactivity the volunteer will receive) is selected
to obtain good quality PET images and to restrict the amount of radioactivity
to acceptable limits and can be adapted if needed.
• Depending on the results from Part 1, different procedures for injection of
RO7248824, and/or different variations of the PET/CT scans may be tested in
Part 2. For each new procedure for injection, the dose of the labeled form of
RO7248824 could be adapted if needed to obtain good quality PET/CT images.
Which part of the study the volunteer participate in will depend on when the
volunteer is enrolled.

The volunteer will be given one single dose of 10 mg RO7248824 mixed with a
maximum of 100 µg of the labeled form of RO7248824 through an intrathecal
injection. The dose of tracer may be adapted during the study.

During an intrathecal injection, a thin needle is placed in a space between two
vertebrae in the lower back and the study compound will be injected into the
fluid of the spinal cord sac. We also call this fluid cerebrospinal fluid
(CSF). This intrathecal injection is popularly known as an epidural. The
procedure will be performed by a specialist in the UMCG.

Intrathecal injection

• In this study the volunteer will undergo an epidural, also known as an
intrathecal injection. The anesthetist will ask the to sit down and to arch the
back. With a very thin needle, the anesthetist just pierces the spinal
membranes and an amount of cerebrospinal fluid is taken. The study compound is
also administered via this thin needle.
• The skin where the epidural will be done is anesthetized beforehand. In
principle, people will therefore experience little pain during the epidural.
Some people experience a feeling of faintness when they get an injection.
• The spot where the volunteer got the epidural can sometimes be a little
sensitive. This will disappear after a while. If the volunteer have back pain
in a different place, this may be because the volunteer have been in the same
position for a long period of time during the procedure. This pain usually
disappears within a few days.
• While performing the epidural, the needle may sometimes touch a spinal nerve.
This can give a shock to the leg.
• Sometimes someone gets a bad headache after an epidural. The headache can
start immediately after the procedure, but also 24 hours afterwards. Usually
this headache disappears on its own within a week.
* If the volunteer does not respond to the standard *treatment* of bed rest,
fluid intake and time or pain medications and medications against vomiting and
nausea per the responsible doctor*s advice, the responsible doctor may decide
to perform an *epidural blood patch*. During this procedure a small volume of
the blood (approximately 15-20 milliliters that will be drawn from a vein in
the arm) will be injected in the epidural space of the spinal cord (space just
outside the meninges around the spinal cord) using an epidural needle. This
will be performed by an anesthesiologist under sterile conditions and with
local anesthesia. The volunteer will have to be in a sitting position with the
legs together. Relief of headache usually occurs swiftly after this procedure,
sometimes directly after administration of the blood patch, although a
transient sensation of *fulness* in the back is common. In some instances more
than 1 attempt may be required for relief of headache. After the procedure the
volunteer has to lie down on the back for another 1.5 - 2 hours to decrease the
risk of leakage of CSF.
* The volunteer may be asked to keep bed rest up to 3 days after the procedure
to reduce the risk of headache after an epidural. If you are taking pain
medications for the headache, your doctor may instruct you to taper them to
avoid the possibility of a rebound headache from sudden medication withdrawal.
• In rare cases, an epidural can cause infection or bleeding in the back. These
complications can lead to damage to the spinal nerves. Nerve damage often
causes pain, but can also result in movement and sensory disturbances.
Fortunately, these complications are rare.

Blood draw
• During this study, small amounts of blood will be drawn from a vein and by
finger prick and used for tests that allow the responsible doctor to see how
the volunteer is doing. Drawing blood may cause pain and there is a small risk
of bruising or infection at the place where the needle is inserted. Very
rarely, a blockage of the vein or a small nerve injury can occur, resulting in
numbness and pain. However, this will resolve with time. Some people experience
dizziness, upset stomach, or fainting when their blood is drawn.
• On Day 1, when several blood samples will be taken, we may use a cannula
inserted in the arm using a small needle. There is a small chance of infection
by placing the cannula in the arm, but every medical precaution will be taken
to avoid an infection.
• In total, we will take less than 500 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.

ECG
• The volunteer will have small, soft pads, placed stuck temporarily on
different parts of the body. There is no pain or discomfort during an ECG;
however the area of skin in which the ECG pads will be stuck may need to be
shaved, and the pads may cause a skin reaction such as redness or itching.
Taking the pads off may cause localized irritation to the skin and/or hair
loss, similar to having a plaster taken off.

PET scan / CT scan / MRI scan
• PET/CT and MRI scans are quite *closed in* and may be unpleasant for people
who have a fear (or strong dislike of) enclosed spaces. Because an MRI scanner
uses strong magnets, the volunteer cannot have any metal implants in the body
to have an MRI scan. People with a pacemaker, Implantable Cardioverter
Defibrillator (ICD) or with metal splinters, metal plate, pin, or other
metallic objects in their body may not be eligible for this study. If the
volunteer has certain tattoos, he/she might feel a little discomfort when they
have their MRI scan. Study personnel will ask questions to make sure the
volunteer can safely have an MRI scan. The MRI scan itself makes loud noises.
The volunteer will therefore receive earplugs and headphones. That muffles the
sound and protects the hearing. Sometimes the volunteer can listen to music.
Study personnel will ask questions to make sure the volunteer can safely have
the MRI and PET/CT scans.

Exposure to radiation
• This study involves using X-rays (PET/CT scan) and a radioactive tracer. The
additional amount of radiation (radiation burden) the volunteer will be exposed
to in this study is slightly less than 10 millisieverts. This is equivalent to
approximately 4 years of naturally occurring background radiation in the
Netherlands (~2.5 mSv per year). Background radiation is the radiation that
everyone is exposed to from sources such as the air we breathe, food we eat,
cosmic rays from the sun and space, as well as the ground and buildings around
us.
• Scientists disagree on whether radiation doses at these low levels are
harmful. A possible effect that could occur at doses associated with this study
is a slight increase in the risk of developing cancer later in life.

Coronavirus test
•Samples for the coronavirus test will be taken from the back of the 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 throat may cause the volunteer to gag. When the sample is taken from the
back of the nose, the volunteer may experience a stinging sensation and the
eyes may become watery.
• Participation in this study may expose you to viruses (including but not
limited to the seasonal flu, SARS-CoV-2, and common cold) and bacteria that
exist in the environment. While PRA will take all the possible steps to provide
safe and clean facilities, PRA cannot guarantee you will not be exposed to
these viruses and bacteria during the course of the study. Neither PRA nor the
Sponsor are responsible for any diagnosis or treatment related thereto. We do
not expect that participation in this study increases your risk of getting
exposed to viruses.