A PHASE 3, MULTICENTER, RANDOMIZED, DOUBLE-BLIND, PLACEBO CONTROLLED STUDY EVALUATING THE EFFICACY AND SAFETY OF BIMEKIZUMAB IN SUBJECTS WITH ACTIVE ANKYLOSING SPONDYLITIS

axSpA epidemiology
Axial SpA is a chronic inflammatory disease that impacts a substantial
proportion of the population. Limited evidence exists regarding the global
occurrence of axSpA with a prevalence of 0.20 to 0.25% in Europe and North
America, and a wider range in Asia (0.06 to 0.20%) (Stolwijk et al, 2016);
however, recent data suggest that the prevalence is similar to that of RA in
the US (axSpA: 0.7% to 1.4%; RA: 0.5% to 1.0%) (Reveille et al, 2012;
Myasoedova et al, 2010; Helmick et al, 2008). Axial SpA comprises those
diseases with mainly axial involvement (sacroiliac joints and spine), including
AS and nr-axSpA.

Current treatments for axSpA
Nonsteroidal anti-inflammatory drugs are used as first-line treatment and are
effective for the symptoms (pain and stiffness) of axSpA (van der Heijde et al,
2017; Ward et al, 2015; Poddubnyy, 2013; Poddubnyy et al, 2012), but many
patients lose or never have clinically meaningful response and structural
damage often progresses despite their use. Conventional disease-modifying
antirheumatic drugs (DMARDs, eg, methotrexate [MTX] and sulfasalazine [SSZ])
have no proven efficacy in axial disease, but may benefit patients with
peripheral joint disease (Haibel et al, 2007; Braun et al, 2006; Haibel et al,
2005). Therefore, DMARDs are recommended only in patients with predominantly
peripheral manifestations (Braun et al, 2011).
Patients who are intolerant of or have inadequately responded to NSAIDs, or
those in whom NSAIDs are contraindicated, have approved treatment options such
as tumor necrosis factor alpha (TNF*) inhibitors (van der Heijde, 2017; Ward et
al, 2015). Recently, the interleukin (IL)-17 cytokine family has been
identified as a therapeutic target in axSpA and secukinumab, an IL-17A
monoclonal antibody, has recently been approved as a treatment option in active
AS.

Bimekizumab
Bimekizumab (UCB4940) is an engineered, humanized full-length monoclonal
antibody of IgG1 subclass of approximately 150,000 Dalton, which is expressed
in a genetically engineered Chinese Hamster Ovarian (CHO) cell line.
Bimekizumab has high affinity for human IL-17A and human IL-17F and selectively
and potently inhibits the activity of both isoforms in vitro. Interleukin-17A
and IL-17F are key proinflammatory cytokines believed to play important roles
in autoimmune and inflammatory diseases. Therefore, bimekizumab permits an
evaluation of the potential for additional efficacy, which may be conferred by
dual inhibition of both cytokines, in patients suffering from diseases in which
both cytokines are active. Bimekizumab is being developed for the treatment of
patients with inflammatory diseases such as PsA, psoriasis (PSO), axSpA and
hidradenitis suppurativa.

Objective(s):

Primary objective:
The primary objective is to demonstrate the efficacy of bimekizumab
administered subcutaneously (sc) every 4 weeks (Q4W) compared to placebo in the
treatment of subjects with active ankylosing spondylitis (AS).
Secondary objectives:
The secondary objectives of the study are as follows:
* To assess the efficacy of bimekizumab compared to placebo
* To assess the safety and tolerability of bimekizumab
* To assess the impact of bimekizumab on patient-reported quality of life
* To assess the impact of bimekizumab on spinal mobility
* To assess the impact of bimekizumab on enthesitis and on peripheral arthritis

Other objectives:
The other objectives are as follows:
* To assess the immunogenicity of bimekizumab
* To assess the pharmacokinetics (PK) of bimekizumab
* To assess the maintenance of efficacy of bimekizumab
* To assess the relationship between exploratory biomarkers, drug treatment,
and AS disease biology
* To assess the impact of bimekizumab on work productivity
* To assess the impact of bimekizumab on inflammatory changes using magnetic
resonance imaging (MRI)

Study design and methodology:

This is a multicenter, Phase 3, randomized, double-blind, placebo-controlled
study to evaluate the efficacy and safety of bimekizumab in eligible subjects
with active AS. The study will include 3 periods: a Screening Period (*14 days
to *35 days), a Treatment Period (52 weeks) consisting of a 16-week
Double-Blind Treatment Period and a 36 week Maintenance Period, and a Safety
Follow-Up (SFU) Period (20 weeks after the final dose of investigational
medicinal product [IMP]) (ie, Week 48 for subjects who completed AS0011; for
subjects not entering the extension study or who discontinue early, including
those withdrawn from study treatment). The maximum study duration per subject
will be 73 weeks.
During the Double-Blind Treatment Period, subjects will be randomized in a 2:1
fashion (stratified by region and prior TNF* inhibitor experience) to 1 of 2
treatment arms to receive blinded IMP regimens of bimekizumab 160 mg sc Q4W or
placebo sc Q4W.
The Double-Blind Treatment Period ends after Week 16 assessments. At Week 16,
subjects will transition from the double-blind, placebo-controlled treatment
into the 36-week Maintenance Period with bimekizumab treatment. The 36-week
Maintenance Period starts with the Week 16 IMP administration. All subjects
will receive bimekizumab 160 mg sc Q4W during the Maintenance Period.
Starting at Week 20, nonbiologic rescue therapy for axial spondyloarthritis
(axSpA) may be adjusted or added, at the Investigator*s discretion, while
continuing bimekizumab.

Subjects completing Week 52, who are not withdrawn from IMP, may be eligible
for enrollment in an extension study with bimekizumab. Subjects who are
ineligible for or choose not to participate in the extension study at Week 52,
will undergo a SFU Visit. Subjects withdrawing from the IMP will have an Early
Termination Visit and a SFU Visit 20 weeks after the final dose of IMP, as
applicable.
Interim analyses of all available data (including efficacy, safety, and
pharmacokinetic [PK]) will be conducted after the planned number of randomized
subjects have completed 24 weeks and 52 weeks of treatment or have withdrawn
from IMP or the study. The final analysis of all available data will be
performed after all randomized subjects have completed the SFU Visit or have
withdrawn from the IMP and/or study.

Treatment(s), dose(s), mode of administration, and duration:
During the Double-Blind Treatment Period, bimekizumab or placebo will be
administered to subjects by the unblinded study personnel at the study site as
per dosing schedule given below:
* Bimekizumab 160 mg sc at Week 0 (Baseline) followed by bimekizumab 160 mg sc
Q4W at Weeks 4, 8, and 12
* Placebo sc at Week 0 (Baseline) followed by placebo sc Q4W at Weeks 4, 8, and
12.

During the Maintenance Period, bimekizumab will be administered to subjects by
the blinded or unblinded study personnel at the study site, according to the
site-specific blinding plan, as per dosing schedule given below:
* Subjects who received bimekizumab 160 mg sc Q4W during the 16 week Double
Blind Treatment Period will continue to receive bimekizumab
160 mg sc Q4W.
* Subjects who received placebo during the 16 week Double Blind Treatment
Period will be re allocated to bimekizumab treatment. After the Week
16 assessments are performed, all subjects will receive bimekizumab 160
mg sc at the Week 16 Visit.
Unblinded study personnel will be responsible for recording the administration
information on source documents, and administration of the IMP as sc
injections. The unblinded personnel will not be involved in any other aspect of
the study.

WHAT PARTICIPATION INVOLVES
In total your participation in this study will be up to 73 weeks (approximately
1.5 year). You will have to come to the clinic for up to 18 visits (most visits
occur every 4 weeks).
The study consists of 3 periods:
* a screening
* a treatment (52 weeks) and maintenance (36 weeks: from Week 20 to Week 52)
* a final Safety Follow-Up Visit (this will be done 20 weeks after the final
dose of the study drug). A final Safety Follow-Up visit is required:
* if you complete the study up to Week 52 and do not enter the extension study.
More information about this extension study is explained under
the header *treatment*.
* if you are withdrawn from the study drug and return for all scheduled visits
up to Week 52.
* if you withdraw consent and do not return for all scheduled visits you will
still be encouraged to return for a final safety assessment.

Screening
Your first visit will be the screening visit. At this visit your study doctor
will explain the study and answer any questions you may have. After reading
this Patient Information Form and if you agree to participate in this study,
you will be asked to sign the Informed Consent Form at the end of this
document. You must give your written informed consent before you undergo any
study-related activities including screening procedures. During this visit,
some tests will be conducted.
The Screening Period will last for at least 2 weeks and up to 5 weeks to
perform all required assessments to determine if you can participate in the
study. This period can be repeated if some of your test results need to be
repeated, or you may be asked to stop the intake of certain drugs that are not
allowed to be taken while taking part in the study.
The following procedures will be done during the screening visit:
* The study doctor will check that you are eligible to take part in the study.
* Your study doctor will ask your personal information such as your age, sex
,complete history of lifestyle (alcohol, smoking, and drug consumption).
* Your study doctor will also ask your AS history, any other medical history,
what medicines you take now and had taken before, and your current medical
conditions.
* You will be asked about any health problems or other medical conditions that
you may have had.
* You will be asked to fill in several questionnaires at the visits. You will
be given an electronic device (tablet) to record your answers to the
questionnaires during the visits. These questionnaires will be repeated
throughout the course of the study to monitor if the study drug has any impact
on your mental health.
* You will be asked questions about symptoms of Tuberculosis and potential
exposure to Tuberculosis. Tuberculosis is also called TB and it is an
infectious disease (caused by a bacterium) mainly of the lung, but it can
affect other areas of the body. TB bacteria may be present in your body but not
yet causing an infectious disease, this is referred to as "latent" TB. If
latent TB is diagnosed, you can participate in this study only after receiving
appropriate treatment for TB infection. A chest X-ray will be taken (unless
you have had a chest X-ray in the previous 3 months and the report is
available). The chest X-ray must be clear of signs of TB infection (previous or
current) before first study drug administration.
* Your vital signs (blood pressure, pulse rate, and body temperature) will be
measured.
* Your weight and height will be measured. During this measurement, you will be
asked to remove your footwear.
* An electrocardiogram (ECG - is a painless, non-invasive test that shows how
your heart works, it takes a picture of the electrical activity of your heart)
will be performed.
* A blood sample will be obtained for routine laboratory examinations to learn
about your general health and body functions, and for pregnancy test in women
who are able to have children.
* A blood sample will be obtained to test for hepatitis B and C, the human
immunodeficiency virus (HIV), TB, and HLA-B27 (human leukocyte antigen B27, a
protein in the blood). Hepatitis B and C are viruses that can damage the liver.
HIV is the virus that can cause the acquired immune deficiency syndrome (AIDS).
Positive results for hepatitis or HIV will be reported to health authorities as
per the local requirements. In case you have a positive result, you are
encouraged to discuss with your study doctor what further medical care may be
applicable to you. If you have any questions about these tests, please ask the
study doctor or study staff.
* A urine sample will be obtained for routine laboratory examinations and
screening for drugs.
* An X-ray of the joint will be taken to confirm your eligibility for the study
(unless you have had a joint X-ray performed any time prior to Screening).
* X-ray of your spine will be taken (unless you have had spine X-ray within 6
months prior to Screening) to assess your disease progression.
* An MRI scan of the joint and spine will be performed at this visit if you
agreed to participate in the MRI sub-study by signing the MRI sub-study consent
form.
* An additional blood samples and/or stool sample will be collected if you
agreed to participate in the genetic/biomarker sub-study by signing the
genetic/biomarker sub-study consent form.

* Additionally, you will also be asked if you would like to participate in an
optional genetic/biomarker sub-study and/or an MRI sub-study that are being run
within the main study. Additional blood samples and/or stool samples will have
to be taken for the genetic/biomarker sub-study. For the MRI sub-study, you
have to undergo additional MRI scans. If you wish to take part in the sub
studies, you will be given an extra sub-study Patient Information Sheet and
Informed Consent Form to read and sign. The study doctor will discuss this with
you and will answer any questions you might have. Your refusal to participate
in any sub-study will not affect your ability to participate in the main study.
However, the knowledge gained from this research may help in the development of
new therapies for all patients with AS.

Treatment
After all the Screening procedures have been done, and it is found that you can
take part in the study, you will be entering the Treatment Period and receive
your first dose of study drug at the end of the Baseline Visit.
Duration of the Treatment Period is 52 weeks and includes 2 stages:
* Double-Blind Treatment Period of 16 weeks, and
* Maintenance Period of 36 weeks
During the Double-Blind Treatment Period, you will be randomly assigned like
drawing straws from a hat to receive either bimekizumab, or a placebo for 16
weeks. You will receive either of them in a double blind fashion. *Double-
blind* means that neither you nor the staff at the clinical site will know
which treatment you are receiving. You will have a 66% chance of receiving
bimekizumab and 33% chance of receiving placebo.
The assigned study drug will be given to you as an injection under the skin.
Each injection will last approximately 10 to 15 seconds and will be given on
either your tummy, upper arm or the outside of your upper thighs. The injection
site will be rotated between visits. Injections will not be in the areas where
skin is tender, red, bruised, and hard.
There are 4 injection days during the treatment period: Baseline (Day 1), Week
4, Week 8, , and Week 12. In case you are not able to visit the clinic on your
scheduled day, you can visit the clinic either 3 days before or 3 days later
than the scheduled visits date after discussing with your study doctor.
During these visits, the questionnaires will be completed at first and the
injection will be given after completion of all study assessments on the
specified days.

During the Maintenance Period all study patients will receive bimekizumab
The assigned study drug will be given to you as an injection under the skin
every 4 weeks over a period of 36 weeks.
There are 9 injection days during the maintenance period. In case you are not
able to visit the clinic on your schedule day, you can visit the clinic either
4 days before or 4 days later the scheduled visits date after discussing with
your study doctor.
If you qualify and if you agree, you may be invited to participate in an
extension study if you have been treated with study drug up to Week 52. The
study doctor will let you know if you qualify for the extension study.
At the completion of the maintenance period, the study doctor will discuss with
you the treatment options for you. There will be an extension study for
patients who complete this study, in which patients can receive the study
treatment. If you complete this study and are considered eligible by the study
doctor, you will be able to take part in the extension study with written
informed consent. Study drug will be administered for the patients who agree to
take part in the extension study at Week 52 Visit.

Early Termination Visit:
An Early Termination Visit will be performed if you are leaving the study much
earlier than the study completion, either because you decided to discontinue by
yourself, or because of safety issues regarding your personal health as
determined by your study doctor.
Safety Follow-Up Visit (if applicable):
This final visit will take place 20 weeks after your last injection of study
drug. In case you are not able to visit the clinic on your scheduled day, you
can have the visit either within 3 days before or 7 days later the scheduled
visit date after discussing with your study doctor.
* You will have this visit if you have withdrawn from the study early or if you
have completed the study and are not taking part in the extension study. If you
take part in the extension study, you will not have this visit. This visit
marks the end of your study participation and serves to check on your health
status.

Unscheduled Visit:
If the study doctor considers that an Unscheduled Visit is needed for your
safety and wellbeing, you will be requested to complete it at any time during
the study but prior to the Safety Follow-Up Visit. Additional assessments may
be performed during the Unscheduled Visit(s) at the study doctor's discretion
to protect your safety and wellbeing.

Rescue therapy:
You may require add-on therapies referred to as Rescue therapy, this will be
determined by your study doctor. You may receive rescue therapy while
continuing to receive the study drug dose, anytime from Week 20 onwards. Rescue
therapy may include only the following options, no other medication changes or
additions are permitted for rescue therapy. The options are,
* Start, stop or alter the anti-inflammatory drugs, anti-rheumatic drugs and/or
joint injections that are taken at baseline or any visit.
* A decrease in the dosage of the agent taken for the treatment AS.

More information on all tests and examinations performed during the visits can
be found in Appendix C of the main PIF.

POSSIBLE SIDE EFFECTS, RISKS AND DISCOMFORTS
Like all drugs, the study drug being tested may cause side effects. In
addition, the study drug may involve risks that are currently unknown. In the
data from the completed studies, most of the side effects were mild to
moderate, easily manageable, resolved and did not require discontinuation of
the treatment. These side effects included:
* Very Common (occurring in more than 1 in 10 patients):
* Upper respiratory tract infections (such as a common cold and runny nose)
which were all mild or moderate.

* Common (occurring between 1 and 10 in 100 patients):
* Less blood cells called neutrophils which help to fight infections
* Headache
* Tiredness
* Fungal infections of the skin or mucous membranes, mostly in the mouth. If
you develop symptoms of a fungal infection, particularly in the mouth or throat
(creamy white bumps or patches on your tongue, inner cheeks, gums or throat;
bad taste in your mouth; pain or difficulty while swallowing), you must tell
your study doctor immediately so appropriate action can be discussed
* Fungal infections of the skin or nails (e.g. ringworm, athletes' foot, jock
itch, etc.)
* Ear infections
* Herpes simplex infections, a virus that may causes sores on the skin, mouth,
lips, eyes and genitals
* Intestinal infections
* Inflamed hair follicles
* Red, itchy, dry, cracked skin

In studies where patients received the study drug for a period of a year or
longer, upper respiratory tract infections, runny nose and fungal infections of
the mouth were the most frequent side effects.

You may have an allergic reaction to the study drug. Although serious allergic
reactions have not yet been seen in the patients receiving this study drug,
signs may include a skin rash, swelling of the face, tongue, lips, or throat,
or having trouble breathing. If you have any of these signs, you must go to an
Emergency department immediately and make sure that your study doctor is
informed.

In rare instances, study participants taking the study drug have developed
inflammatory bowel disease or have had a worsening (flare) of existing
underlying disease. Symptoms such as persistent bloody diarrhea with urgency or
crampy abdominal pain may indicate the development or worsening of inflammatory
bowel disease. If you develop these symptoms you must tell your study doctor
immediately so appropriate action can be discussed.

Less common side effects and the risk and discomforts of the tests and
procedures
Uncommon Side effects (occurring in more than 1 in 1000 to less than 1 in 100
patients):
- Injection site reactions (such as redness, pain and swelling)
- Liver problems. If this happens to you during the study, extra testing of
blood and urine will be done to try and understand the cause and best treatment
for this
- Acne

Risk and discomforts of the tests and procedures:
* Vital signs recording: An inflatable cuff will be placed on your arm and a
machine will measure your blood pressure and pulse rate, after you
have been sitting down for 5 minutes. You may experience mild
discomfort in your arm while the cuff is inflated.
* Blood samples: Throughout the study, approximately 24 mL of blood will be
taken per visit. A total of approximately 238 mL (about half of what you give
during blood donation) will be taken throughout the study for regular study
visits. In case you are participating in genetic/biomarker sub study the total
volume would increase to 297 mL (about half of what you give during blood
donation). If necessary, additional blood samples may be collected during the
study at the study doctor's discretion to protect your safety and wellbeing.
* During the collection of blood samples, you may experience slight discomfort
and a small amount of bleeding, discoloration or bruising at the
site where the needle was inserted. Clot formation and infections may
occur at the puncture site, but this is extremely rare. Fainting may occur
during or shortly after having blood drawn. If faintness is experienced, you
should lie down immediately to avoid possible injury caused by falling, and
notify the site research staff. In very rare cases nerve damages may occur.
* Under the skin injection and injection site reactions: For most people,
needle punctures for injections do not cause any serious problems.
Sometimes they may cause bleeding or bruising where the injection is
given. Sometimes people complain of discomfort and/or pain at the site
of the injection. Rarely, injections may cause skin and/or soft tissue
infections. Additionally, if a blood vessel is entered by the needle, the risk
of infection could include germs entering into the blood system, which
can be very serious. The risk of this happening is low.
* Electrocardiogram (ECG): You will be requested to disrobe from the waist up
in order to ensure correct ECG recording. You may experience
slight skin irritation from the adhesive on the ECG electrodes, but
this is generally mild and clears up within a few days.
* Mental health problems and/or depression: Some patients who have psoriasis,
psoriatic arthritis, AS and hidradenitis suppurativa suffer from psychological
problems like depression. You will be asked to
complete questionnaires at all visits about how you are feeling
mentally and if you have had any thoughts of hurting yourself at each
visit/during the study to monitor your mental health status. Tell the
study doctor if you feel important changes in your mood or if you experience
psychological problems.
* Vaccines: Please tell your study doctor if you are planning to get
vaccinated, as some types of vaccinations are not allowed prior to dosing,
during the study and for up to 20 weeks after the last dose of the
study drug.
* Private medical insurance: If you hold private medical insurance, you are
advised to check with the company who provides this insurance
before agreeing to take part. This is to make sure that your medical
insurance will not be affected by being in a clinical study.

Exposure to radiation
X-ray * Chest, sacroiliac joint and spine: You will be exposed to a low level
of radiation. The total amount of radiation you will be exposed to in this
study is approximately 1.5 mSv. To compare: the background radiation in the
Netherlands is ~2.5 mSv per year. If you participate in scientific research
involving exposure to radiation more often, you should discuss with the
investigator whether participation at this moment would be safe. The radiation
used during the study may lead to damage to your health. However, this risk is
small. We nevertheless advise you not to participate in another scientific
study involving exposure to radiation in the near future. Examinations or
procedures involving radiation for medical reasons are not a problem. You must
not have an X-ray if you think you could be pregnant. Please inform your study
doctor accordingly.
The risk associated with having an MRI of the spine and joints is very minimal.
However, if you are claustrophobic (have a fear of closed spaces) or have had
any metal placed in your body (for example, during a surgery), you should tell
your doctor.