A single-center, open-label, fixed-sequence Phase 1 trial to evaluate the effect of multiple
doses of pritelivir on the pharmacokinetics of substrates for CYP2C9, CYP2B6, CYP3A4
and OATP2B1

Pritelivir is a new compound that may potentially be used for the treatment of
skin infections caused by viruses such as the herpes simplex virus (HSV).
Infections with HSV are lifelong, with frequent and sometimes painful
recurrences, and carry the risk of serious complications in patients with a
weak immune system. Pritelivir can inhibit the replication of HSV and can
protect uninfected cells. It is being developed to treat patients with weak
immune systems where other treatments of HSV do not work.

In this study, the effect of pritelivir on various existing medications
(celiprolol, flurbiprofen, bupropion, and midazolam) will be evaluated. They
are substances that are acted upon by particular liver enzymes and
transporters. Based on earlier experiments, pritelivir may impact the activity
of these enzymes and transporters and as such may influence the presence of
these medications in the body when given simultaneously

Celiprolol is a beta-blocker and is used to treat high blood pressure.
Flurbiprofen is a drug that is used to reduce pain, swelling, and joint
stiffness in arthritis. Bupropion is an anti-depressant medication and is used
to treat major depressive disorders and to help people quit smoking. Midazolam
is a short-acting sedative used prior to a medical examination or procedure.
The dose levels of flurbiprofen, bupropion, and midazolam used in the current
study are far below the marketed dose levels. The dose level of celiprolol used
in the current study is similar to the marketed dose level.

In this study, we will investigate how quickly and to what extent the
investigational medicinal product pritelivir is absorbed, transported, and
eliminated from the body (this is called pharmacokinetics). In addition, we
will evaluate a possible interaction between pritelivir and various existing
medications. We will do this by investigating the effect of pritelivir on the
pharmacokinetics of celiprolol, flurbiprofen, bupropion, and midazolam. All
these compounds will be administered in this study.

We will also investigate how safe pritelivir is and how well it is tolerated
when it is used by healthy participants.

At last, we will look at the effect of your genetic information on the body*s
response to pritelivir (this is called pharmacogenetics)

For the study, it is necessary that the volunteers stays in the research center
for 1 period of 26 days (25 nights). Day 1 is the day when the volunteer
receive one of the study compounds (celiprolol) for the first time. The
volunteer is expected at the research center the day before the day of first
administration of the study compound, so on Day -1. The volunteers have to be
at the research center at approximately 6:00 pm. The time of entry may be
changed. If this happens, the volunteer will be informed about it in advance.
The volunteer will leave the research center on Day 25 of the study.

Below is an overview of the days you stay at the research center, or when you
visit the research center.
Screening 1 short visit between Day -28 and Day -2
In-house Period Day -1 up to Day 25
Follow-up 1 short visit between Day 28 and Day 35

The volunteer will be given pritelivir and celiprolol as tablets, flurbiprofen
and midazolam as a small drink, and bupropion as capsules via the mouth. The
volunteer will also be given 240 milliliters (mL) of water after each
administration.
One of the investigators will inspect the hands and mouth after administration
of the study compound. This it to check if the volunteers have taken the study
compound.

The volunteer will be given pritelivir and celiprolol as tablets, flurbiprofen
and midazolam as a small drink, and bupropion as capsules via the mouth. The
volunteer will also be given 240 milliliters (mL) of water after each
administration.

One of the investigators will inspect the hands and mouth after administration
of the study compound. This it to check if the volunteers have taken the study
compound.

In the table below the planned study compound administrations.
Day Study compound How much How often
1 Celiprolol 200
mg Once
2 -
- -
3 Flurbiprofen 10
mg Once
Bupropion 20
mg Once
Midazolam 1
mg Once
4 and 5 -
- -
6 Pritelivir 400
mg Once
7 Pritelivir 100
mg Once
8 Celiprolol 200
mg Once
Pritelivir 100
mg Once
9 to 18 Pritelivir 100
mg Once daily
19 Flurbiprofen 10
mg Once
Bupropion 20
mg Once
Midazolam 1
mg Once
Pritelivir 100
mg Once
20 and 21 Pritelivir 100
mg Once daily
22 to 25 -
- -

Pritelivir has been investigated in studies with healthy subjects receiving
single doses between 5 mg and 600 mg, and multiple doses between 5 mg/day and
400 mg/day for up to 21 days. A total of 202 patients with HSV infections with
recurrent genital herpes were treated with pritelivir up to 100 mg/day or 400
mg/week for up to 4 weeks.

The volunteer may experience none, some, or all of the adverse events described
below which have been reported as possibly being caused by pritelivir.

In Phase 1 single dose studies, 110 healthy subjects receiving pritelivir
reported 149 adverse events associated with pritelivir administration.
Reported adverse events considered to be commonly [>=1/100 and <1/10 (>=1% and
<10%)] related to pritelivir after single dose treatments were:
• increased liver functions tests in 7 subjects (6%), and
• headache in 4 subjects (4%).

In 68 healthy subjects receiving multiple doses between 5 mg/day and 400 mg/day
of pritelivir in Phase 1 studies for up to 21 days, a total of 267 adverse
events were reported.
Reported adverse events considered to be very commonly (>=1/10 [>=10%]) related
to pritelivir were:
• headache (26%),
• itching (19%),
• reddening of the skin (16%),
• rash (13%), and
• fatigue (12%).
Reported adverse events considered to be commonly [>=1/100 and <1/10 (>=1% and
<10%)] related to pritelivir were:
• increased liver functions tests (7%), and
• dry skin (4%).

These adverse events were mainly reported with multiple daily doses of 400 mg
pritelivir and were possibly observed as a result of a viral infection, but an
effect of treatment with pritelivir could also not be excluded.

In two Phase 2 studies, a total of 202 subjects were treated with pritelivir.

In the first Phase 2 study (AIC316-01-II-01), 103 subjects of the 125 treated
with pritelivir reported adverse events associated with pritelivir
administration. Those subjects were treated with 5 mg/day, 25 mg/day, 75
mg/day, or 400 mg/week. Treatment lasted for 4 weeks.
Very commonly reported adverse events were:
• headache (18%), and
• nausea (17%).
Commonly reported adverse events were:
• abdominal pain and -discomfort (8%),
• dizziness (6%),
• fatigue (5%), and
• rash (5%).

The incidence (how often an adverse event occurs) of the reported adverse
events in this study appeared to be comparable across treatment (= dose) groups.

In the second Phase 2 study (AIC316-01-II-02), 20 of the 77 subjects treated
with pritelivir 100 mg/day for 28 days reported adverse events associated with
pritelivir administration.
A very commonly reported adverse event was:
• headache (10%).
Commonly reported adverse events were:
• diarrhea (4%),
• nausea (4%),
• fatigue (4%),
• dizziness (3%) and
• vaginal itching (3%).

The incidence of the reported adverse events was comparable to valacyclovir, a
drug approved for this indication.

Pritelivir is inhibiting an enzyme called carbonic anhydrase, which may lead to
a number of adverse events including but not limited to urinary urgency (sudden
urge to urinate), deterioration of performance, hearing impairment, depression,
and hepatic impairment when used in therapeutic amounts. Increased liver
functions tests (hepatic impairment) and fatigue (deterioration of performance)
were detected in pritelivir Phase 1 trials as adverse reactions. However, it is
unclear whether these side effects were caused by an inhibition of the enzyme
carbonic anhydrase.

Study treatment related effects on male fertility were detected in rats after
several weeks of pritelivir dosing and also after higher doses compared to the
human dose. These effects were fully reversible after a period of several weeks
without treatment. These effects did not occur with chronic use of pritelivir
in monkeys at very high doses. Therefore, these findings are considered
unlikely to be relevant to humans.

Very common, common, and uncommon side effects of celiprolol, flurbiprofen,
bupropion, and midazolam are described below.

The following side effects have been reported for celiprolol.
Common Side Effects
• (Severe) depression
• Trembling, tingling, headache, weakness, drowsiness, dizziness
• Hot flashes, paleness of fingers or toes
• Vomiting, nausea, upper abdominal pain, dry mouth
• Excessive sweating, skin redness, rash, itching
• Impotence
Uncommon Side effects
• Insomnia
• Dry eyes, visual disturbances
• Palpitations
• Low blood pressure, cold blue limbs
• Shortness of breath
• Muscle cramp
Flurbiprofen

The following side effects have been reported for flurbiprofen.
Common
• Dizziness, headache
• Throat irritation
• Mouth ulcers, pain or numbness in the mouth
• A sore throat
• Discomfort (warm or burning sensation or tingling) in the mouth
• Nausea, diarrhoea
• Prickling and itching of the skin
Uncommon Side effects
• Drowsiness
• Blistering in the mouth or throat, numbness in the throat
• Stomach bloating, abdominal pain, flatulence, constipation, indigestion,
vomiting
• Dry mouth
• Burning sensation in the mouth, altered sense of taste
• Drowsiness or difficulty falling asleep
• Worsening of asthma, wheezing, shortness of breath
• Less sensation in the throat

The following side effects have been reported for bupropion.
Very Common Side Effects
• Sleeping problems
• Headache
• Dry mouth
• Nausea, vomiting
Common Side Effects
• Fever, dizziness, itching, sweating and rash
• Trembling, trembling, weakness, fatigue, chest pain
• Feeling anxious or restless
• Abdominal pain or other problems (constipation), changes in the taste of
food, loss of appetite (anorexia)
• Increased blood pressure (sometimes severe), sudden redness of the face and
neck
• Ringing in the ears, visual disturbances
Uncommon Side Effect
• Feeling depressed
• Feeling confused
• Concentration problems
• Elevated heart rate
• Weight loss

Midazolam
For the side effects of midazolam, it is not possible to determine the
frequency of occurrence with the available data. The following side effects
have been reported for midazolam.
Immune system disorders:
• General allergic reactions (skin reactions, heart and blood system reactions,
wheezing)
Mental disorders:
• Confusion
• Euphoria (excessive feeling of well-being or excitement)
• Hallucinations (seeing and possibly hearing things that are not there)
• Excitement (restlessness)
• Restlessness
• Hostility, anger or aggression
• Excitement (happiness)
Nervous system disorders:
• Drowsiness and prolonged sedation
• Decreased alertness
• Headache
• Dizziness
• Difficulty with muscle coordination
• Temporary amnesia
Cardiac and blood vessel disorders:
• Low blood pressure
• Slow heart rate
• Redness of the face and neck (flushing), fainting or headache
Gastrointestinal disorders:
• Nausea
• Vomit
• Blockage
• Dry mouth
Skin and subcutaneous tissue disorders:
• Result
• Hives with a rash
• Itch
Musculoskeletal and connective tissue disorders:
• Muscle spasms and tremors (muscle trembling without you being able to do
anything about it)
General disorders and administration site conditions:
• Fatigue
• Redness
• Swelling of the skin
Injuries, poisoning and procedural complications:
• There is a risk of falling and breaking bones in patients taking
benzodiazepine-type medicines. This risk is higher in the elderly and people
who also use other anesthetics (including alcohol)

Blood draw
Drawing blood may be painful or cause some bruising. On Days 1, 3, 8, 17, and
19, blood will be sampled very frequently using an indwelling cannula (a tube
in a vein in the arm) to determine the course of the concentration of the study
compounds in the blood over time. The use of the indwelling cannula can
sometimes lead to inflammation, swelling, hardening of the vein, blood
clotting, and/or bruising around the puncture site. In some individuals, a
blood draw can sometimes cause pallor, nausea, sweating, low heart rate, and/or
a drop in blood pressure with dizziness or fainting.

Heart tracing
To make a heart tracing, electrodes (small, plastic patches) will be placed on
the arms, chest, and legs. Prolonged use of these electrodes can cause skin
irritation (rash and itching).

Fasting
The volunteers 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 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
your throat may cause the volunteer to gag. When the sample is taken from the
back of your nose, the volunteer may experience a stinging sensation and the
eyes may become watery.