A Double-Blind, Placebo-Controlled, Randomized, 18-Month Phase 2a Study to Evaluate the Efficacy, Safety, Tolerability, and Pharmacokinetics of Oral UCB0599 in Study Participants With Early Parkinson*s Disease

Parkinson*s disease is a progressive neurodegenerative disorder that presents
with a spectrum of motor and non-motor signs and symptoms. The mean age at
onset is 60 years. The incidence of PD is approximately 20/100,000 persons per
year; however, it is much higher in the population aged 65 years or older
(>100/100,000 persons per year) (Twelves, 2003). Similarly, the prevalence of
PD increases with age. It is estimated to be 1.4% in the population aged 55
years or older and 4.3% in the population aged 85 years and older (de Rijk,
1995).
The clinical diagnosis of PD relies on the presence of the cardinal motor
signs: bradykinesia, rigidity, tremor, and postural instability. However,
non-motor symptoms such as loss of smell, depression, constipation, and rapid
eye movement sleep behavior disorder can occur several years before the onset
of motor symptoms.

Early PD is characterized by mild, manageable motor symptoms that may not
require
symptomatic treatment (ST), or that show a good response to levodopa, which
represents the standard of care. Other commonly used standard of care
medications include dopamine agonists, monoamine oxidase B inhibitors, and
catechol-O-methyl transferase inhibitors. As PD progresses, the motor and
non-motor symptoms become more bothersome, and patients may start experiencing
motor complications. After 2 to 5 years of treatment with levodopa, 30% to 50%
of patients develop motor fluctuations. Advanced PD is characterized by marked
motor disability with loss of independent ambulation. After 210 years since
onset, most patients suffer from difficult-to-treat motor symptoms (eg, falls,
freezing of gait, dysarthria, and dysphagia) and from non-motor symptoms for
which treatment options are limited (eg, dementia, psychosis, depression,
autonomic dysfunction, and pain). Patients are often bedridden after 10 to 14
years (Poewe, 2006). To this day, slowing disease progression remains the main
unmet medical need in PD.

Parkinson*s disease is pathologically characterized by the loss of dopaminergic
neurons in the substantia nigra, associated with ASYN pathology (neuronal
cytosolic inclusions called Lewy bodies which consist of misfolded,
pathological aggregates of ASYN). Although the majority of PD cases are
sporadic, a small proportion are caused by mutations in PD-related genes,
including copy number variations and point mutations of the ASYN-coding gene
(SNCA) (Siddiqui, 2016). The gene copy number variations are of particular
interest, as they indicate that an increased frequency of the wild-type ASYN is
sufficient to cause PD. This is further reinforced by the observations in
families with SNCA copy number variations where the pathogenic effect depends
on the gene dosage (Devine, 2011). Furthermore, single nucleotide polymorphisms
in SNCA that have been associated with PD in genome-wide association studies
have been shown to increase ASYN expression, highlighting the relevance of
genetic variation in SNCA in sporadic PD (Soldner, 2016; Nalls, 2014). The
140-amino acid ASYN protein is highly expressed in the brain but is also found
in the cerebrospinal fluid (CSF) and periphery (ie, red blood cells and
plasma). As an intrinsically disordered protein, ASYN exists in a soluble
monomeric form in the cytoplasm and in the extracellular compartment. When it
adopts a partially ordered, extended helical structure, ASYN also has a natural
affinity for membranes, such as synaptic vesicles. Under certain conditions,
ASYN can convert into oligomeric, beta-sheet rich structures where such
aggregation is driven through the central region of the molecule, rich in
hydrophobic residues (residues 61 to 95) known as the nonamyloid beta component
region. These oligomeric structures are believed to be the toxic species
responsible for the spread of pathology from neuron to neuron (Chen, 2015).
Treatments that prevent misfolding and aggregation of ASYN may slow the
neurodegeneration in PD, resulting in slower progression of motor symptoms,
thus providing a therapeutic benefit to patients with PD.

UCB0599 is an orally available inhibitor of ASYN misfolding and downstream ASYN
aggregation. Nonclinical pharmacology studies have provided evidence that
UCB0599 inhibits ASYN misfolding in the presence of lipid membranes. In vivo
pharmacology studies demonstrated that UCB0599 reduced total brain ASYN levels
as well as proteinase K-resistant (ie, aggregated) ASYN in a transgenic mouse
model overexpressing SNCA. Moreover, it reduced glial fibrillary acidic
protein, a marker of neuroinflammation, and normalized dopamine transporter
loss observed in this model, which are both considered a functional consequence
of ASYN aggregation. These data suggest UCB0599 may slow neurodegeneration in
PD, resulting in slower disease progression, thus providing a therapeutic
benefit to patients with PD. To date, slowing PD disease progression remains
the main unmet medical need in PD.

UCB0599 has not been approved by any health authorities worldwide as of the
date of this document. UCB has conducted five Phase 1 clinical studies to
support the development of UCB0599: 1 study, conducted with the UCB1332
racemate and a single microdose of the UCB0599 R-enantiomer (UP0023), and 4
studies with UCB0599 administration at clinically relevant doses (UP0030,
TM0017, UP0077, and UP0078).
In the UCB0599 Phase 1 clinical development program, UP0023, UP0030, TM0017,
and UP0077 demonstrated that UCB0599 has good PK properties (dose-exposure
linearity, rapid absorption, t1/2 of approximately 11 to 13 hours, and no
time-dependent PK behavior observed) and an acceptable safety and tolerability
profile for further clinical development. UP0078 demonstrated that food had a
minimal effect on the PK profile for UCB0599. Coadministration of the strong
cytochrome P450 3A4 (CYP3A4) inhibitor, itraconazole, had a significant effect
on UCB0599 disposition, demonstrating a strong drug-drug interaction effect.

The main objective of PD0053 is to provide POC for the efficacy of the ASYN
misfolding inhibitor UCB0599 in reducing disease progression in study
participants with early-stage PD, and to instruct later stage development. The
ultimate goal is to provide novel treatment options to PD patients which have
the potential to modify the progression of the disease.

PD0053 is a randomized, double-blind, placebo-controlled, 18-month Phase 2a
study to evaluate the efficacy, safety, tolerability, and PK of orally
administered UCB0599 in study participants with early-stage PD who are not
treated with symptomatic medications targeting motor symptoms of PD at the time
of inclusion. The primary objective of the study is to demonstrate the
superiority of UCB0599 over placebo with regard to clinical symptoms of disease
progression over 12 and 18 months in this patient population. The difference
between UCB0599 and placebo will be evaluated for both the low and high doses
of UCB0599 (180mg/day and 360mg/day). The comparison of the high dose of
UCB0599 with placebo will be considered as the primary evaluation. Oral UCB0599
capsules or matching placebo capsules will be administered twice per day (BID),
approximately 12 hours apart.

PD0053 includes a Screening Period (including, where available, a wearable
sensor familiarization period for those participants who consent to its use),
an 18-month Treatment Period, (including, where available, a wearable sensor
familiarization period for those
participants who consent to its use after the Screening Period), and a Safety
Follow-up (SFU) Period. Study participants who complete the Treatment Period
will have the option to transition into an open-label extension study (OLE;
PD0055). In this case, participants will not enter the SFU Period of PD0053.

The study will be conducted utilizing a decentralized model, ie, study visits
will be composed of a combination of site visits and remote visits. During
remote visits, study assessments will be conducted with the study participant
from his/her home. This is done to reduce study participant burden and
encourage greater study participation.

In a decentralized model, video communication technology will be integrated
into the clinical research process to support management of research
activities, including data collection and providing study participants with a
channel for direct feedback. Mobile healthcare personnel (ie, a qualified
nurse) may visit the study participant*s/caregiver*s home to complete certain
study assessments. Video and communication technology will be used for
interactions among the Investigator, mobile healthcare personnel, and study
participants/caregivers for remote visits. All data will be collected
electronically using purpose-built technology and will be monitored remotely by
clinical research associates while complying with all data privacy standards.

The UCB0599 doses are 180mg/day or 360 mg/day, to be taken orally in a dose
regimen of 90 mg BID or 180 mg BID, approximately 12 hours apart. UCB0599 and
placebo are formulated as capsules. Treatment duration is up to 18 months.
There is no dose modification allowed.

The study drug being tested may cause some side effects and possible
discomforts. The patient may experience none, some, or all of those given below
because medicines and their possible side effects can affect individual people
in different ways. Studies with new investigational study products generally
have the risk that you may experience side effects that are currently unknown
and unforeseeable.
Based on clinical studies conducted so far, a total of 98 study participants
were given the study drug at doses similar to the dose used in this study.
Common (occurring between 1 and 10 in 100 study participants) side effects
observed in study participants in previous studies are listed as follows:
• Headache
• Feeling sleepy or lacking energy
• Sleepiness or dizziness
• Involuntary muscle contractions
• Physical weakness or tiredness
• Low or increased blood pressure
• Allergic reaction (to drug)
• Hives or lip swelling as part of an allergic reaction to the drug
• Increased or decreased appetite
• Shingles
• Difficulty seeing clearly
• Frequent loose bowel movement or constipation
• Indigestion or stomach pain
• Frequent urination
• Change of kidney function
• Cough

Drug hypersensitivity:
The most serious side effect(s) that have happened in study participants who
have taken the study drug in other research studies were hypersensitivity
(allergy like) reactions. These allergy like reactions typically included
itching, skin rash (redness, swollen patches or hives) and swelling of hands,
feet, lips, or tongue. Severe, allergy-like reactions may cause difficulty
breathing, low blood pressure and could be life threatening, if not treated. So
far, moderately intense but not severe allergy-like reactions have occurred in
three study participants taking the study drug. In these three cases,
moderately intense but not severe allergy-like reactions started within a month
after starting treatment with the study drug. However, it cannot be excluded
that an allergy like reaction may appear at any time during the study.

There is good scientific support to suggest that the study drug could be an
effective treatment of your disease. However, currently there is limited
knowledge about what side effects may occur. Potential side effects estimated
based on animal data and from a first study in healthy volunteers are listed
below, although other side effects may also occur.
• Blood effects: Increased chance of forming a blood clot, possibly leading to
blocked vein or artery. Increased chance of bleeding, possibly causing bruises
or bleeding.
• Heart effects: Slower heart rate, faster heart rate.
• Gastrointestinal effects: Vomiting (being sick and throwing up).
• Effects on the function of the liver.
• Effects on the function of the kidneys.
• Damage to the muscles.


Potential risks of the study procedures:

Blood sampling:
Blood samples will be taken from a vein in the patient's arm or hand during the
study. Blood maybe taken using a needle or a cannula (flexible plastic tube)
inserted in a vein in the arm. This minimizes the use of needles, though
sometimes (if the cannula becomes blocked) a new cannula may need to be
inserted or the use of a needle may be necessary. The taking of a blood sample
may cause some slight discomfort and bruising, and there is a risk of
infection. Other risks, although rare, include dizziness and fainting. In very
rare cases, nerve damage may occur.

Electrocardiogram (ECG):
When the patient has an ECG, small sticky pads will be placed on the arms,
legs, and chest and a machine will measure the electrical activity of the
heart. The study staff may need to clip/shave small patches of the hair in
these areas. These sticky pads may cause some local skin irritation and may be
uncomfortable to remove. Both female and male participants must undress from
the waist up in order to ensure correct ECG recording.

Blood pressure:
When the blood pressure is taken, an inflatable cuff will be placed on the
patient's arm and a machine will measure the blood pressure and heart rate
after the patient's has been lying down for 5 minutes and while standing up.
The patient may experience mild discomfort in his or her arm while the cuff is
inflated.

Magnetic Resonance Imaging (MRI; if not done before with an available report):
An MRI is a type of scan that uses magnetic fields and radio waves to take
pictures of the inside of the head and/or body. The procedure does not use
X-ray radiation. There have been no ill effects reported from exposure to the
magnetic or radio waves used in MRI. However, it is possible that harmful
effects could be recognized in the future. A known risk is that the magnet
could attract certain kinds of metal that may cause injury. The patient will be
asked about metal within his or her body (this includes, for example, body
piercings, or a pacemaker). In addition, the MRI scanner makes a loud, knocking
noise that in very rare and extreme cases could affect hearing ability. The
study staff will provide the patient with ear plugs or other protection for his
or her hearing while in the MRI scanner. Lying in the small confined area may
case you some discomfort or anxiety. The study doctor may choose to give the
patient medication to help him or her relax during the procedure.

DaT-SPECT:
DaT-SPECT is a tool used to confirm the diagnosis of PD. It is a specific type
of imaging technique that helps to look at cells in the brain that are
important for the action of dopamine (a brain chemical) in the brain. It
involves receiving an injection that contains a small amount of a radioactive
substance. Side effects can include headache, dizziness, increased appetite and
an unusual feeling under the skin.

Cerebrospinal fluid sample (CSF) sample by lumbar puncture:
A lumbar puncture (also known as spinal tap) will be performed for collection
of a small amount of CSF, which is the fluid that surrounds the brain and
spinal cord. CSF will be used to test for biomarkers. A lumbar puncture is done
by inserting a thin, hollow needle between two bones in the lower back. Prior
to the lumbar puncture, a local anesthetic may be applied to numb the area. The
most frequent side effect of lumbar puncture is a severe headache that may be
accompanied by nausea, vomiting, and dizziness. The needle insertion may cause
some slight discomfort and bruising, and there is a risk of infection. While
extremely rare, the procedure may also cause bleeding into the fluid
surrounding the spinal cord and brain or an abnormal movement of the patient's
brain inside the skull, either of which can be fatal.