Conditions: Mucopolysaccharidosis III, Type B (MPS IIIB) Sanfilippo B
Allocation: NA | Intervention model: SINGLE_GROUP
Enrollment: 3
Healthy volunteers: no

Brief summary:
This study evaluated the safety and tolerability of intravenous (IV) administration of SBC-103 in previously studied, SBC-103 treatment naïve patients with mucopolysaccharidosis III, type B (MPS IIIB, Sanfilippo B) who participated in the NGLU-CL01 study. The NGLU-CL01 study was a non-interventional study that evaluated structural brain abnormalities and blood brain barrier (BBB) integrity by magnetic resonance imaging (MRI) and cerebrospinal fluid/serum albumin index.

Detailed description:

Arms:
arm 1: Patients were administered 1 mg/kg by IV infusion once every other week (qow) for at least 12 weeks. After evaluation of 12-week safety, tolerability, and pharmacodynamic data in individual patients, the dose was increased to 3 mg/kg qow. Infusions were to be at least 10 days apart and were administered every 14 days ±5 days.

Interventions: intervention 1: SBC-103
Intervention descriptions: intervention 1: SBC-103 is a recombinant human alpha-N-acetylglucosaminidase (rhNAGLU). Patients were started with low dose of SBC-103 for 12 weeks and then will escalate to a higher dose.

Protocol document:
ICF_000.pdf: 
Alexion Pharmaceuticals, Inc. NGLU-CL01-T Protocol Amendment 2.0  24 Feb 2016
UK PARENT/GUARDIAN INFORMATION SHEET AND CONSENT FORM Version 5.0 25Jan2017
Page 1 of 19
Site/ institution headed paper
Parent/Legally Acceptable Representative Information Sheet and Consent Form
(UK)-Part 1
NAME OF STUDY:
A Phase I/II Open Label Study in Previously Studied,
SBC-103 Treatment Naïve MPS IIIB Subjects to
Investigate the Safety, Pharmacokinetics, and
Pharmacodynamics/Efficacy of SBC-103
Administered Intravenously
Short Title:
SBC-103 Intravenously in SBC-103 Treatment Naïve
MPS IIIB (NGLU-CL01-T)
STUDY NUMBER:
NGLU-CL01-T
STUDY SPONSOR:
Alexion Pharmaceuticals, Inc.
100 College Street
New Haven, CT 06510, United States
STUDY DOCTOR (INVESTIGATOR):
[Investigator Name]
[Site Address]
[Office Hours Tel]
[Out of Hours Tel]
Why are you receiving this information?
Your child is being invited to take part in a research study because he/she has Mucopolysaccharidosis type IIIB
(“MPS IIIB”) and have previously participated in study NGLU-CL01.
Before you decide whether to give
permission for your child to participate in this research study, it is important for you to understand why the
research study is being done and what it will involve. The following information describes the study and your
child’s role as a possible participant.  Please read this information carefully and do not hesitate to ask the study
doctor any questions to ensure that you are able to make an informed decision as to whether your child may
participate. Please take as much time as you need to decide whether or not you think you would want your child
to take part; you do not have to decide today. You may take this information sheet home with you and discuss
participation with family, friends or your general practitioner (GP).
Part 1 tells you the purpose of this study and what will happen to your child if he/she takes part.
Part 2 gives you more detailed information about the conduct of the study.
Your child is under no obligation to take part in this study.
What is the purpose of this clinical research study?
The study sponsor is evaluating a drug called SBC-103. SBC-103 is an investigational drug. “Investigational”
means the drug is not approved for use in the treatment of your child’s disease by any regulatory authorities.
This study is being done to learn more about the safety and effects of SBC-103. In this document, SBC-103 will
be referred to as “study drug”.
Mucopolysaccharidosis type IIIB (MPS IIIB) also known as Sanfilippo B Syndrome is a rare disease that causes
build-up of sugars (heparan sulfate) in the brain and other parts of the body. This is due to the lack of the
enzyme called NAGLU (or N-acetylglucosaminidase). The build-up causes serious health problems that include
changes in behaviour, mental retardation and severe physical disability. There are currently no effective or
approved treatments for MPS IIIB. In studies with animals that also lack the NAGLU enzyme, SBC-103 has


Alexion Pharmaceuticals, Inc. NGLU-CL01-T ProtocolAmendment 2.0  24 Feb 2016
UKPARENT/GUARDIANINFORMATION SHEET AND CONSENT FORM Version5.025Jan2017
Page2of19
been shown to reduce the build-up of sugars in the brain and liver of these animals.The effects of the study drug
in humans are currently being studied inone other study of 11 children. Thestudywill helpprovide information
on whethersimilar reduction of sugars can be observed inparticipants with MPS IIIB.
Doesyourchildhave to take part?
No. Participation is entirely voluntary and you may refusefor your childto participate or withdrawhim/herfrom
the trial at any time without penalty or loss of benefits to whichhe/sheisotherwise entitled. If you would like
your childto participate you will need to read this information sheet and sign a declaration form to show you
would likeyour childto take part.
Depending on your child’s age and level of understanding, he/she may be given an age-specific information
sheet and assent form to sign.  Your child may decide not to take part in the study, even if you have agreed for
him/herto take part.
How manyparticipants will take part in this study?
It is expected that approximately5participants in the UnitedKingdomwill participate in this study.
How long willyour childbe in the study?
If your childtakespart in the study, yourchild’sparticipation could last for approximately3years (164 weeks).
This will include a Screening period that may last up to4 weeks,atreatment period that will last up to 156
weeks,and a follow-up phone call4weeksafterthelast dose ofstudydrug.
How many visits and what procedures are involved?
If you decide toallow your child toparticipate in this studyandyourchild isconsidered eligible, your childwill
havevisitsevery other week for up to 156 weeks (3 years).Mostvisitswill take approximately 5-7 hours. Some
visits will take approximately 10 hours. Two visitswill require an overnight stay at the clinic/hospital.At your
child’svisit at Week24 (6 month)he/shewill have a complete evaluation similar to the screening visit. The
number of days your childvisitsthe clinic may be more if the study doctor schedules procedures over several
days.
Your childwill have a follow-up telephone call within 24 hours of dosing from Week 2 through Week 6 (after
yourchild’s2nd, 3rd and 4th dose), and 4 weeks after yourchild’slast dose of the studydrug.Duringthese calls,
we will ask you how your child isfeelingand if there have been any changes in yourchild’smedications.
What will happen at your child’s firststudy doctorvisit (Screening)?
Thefollowingtests andprocedures will be performed to determine if your childqualifiestotake partin this
study.This study visit may take place over more than one day:
Informed Consent-Before any study procedures are done, you will be asked to sign theConsent Form. You
should read and understand the form before signing. Yourchild’sstudy doctor will discuss withyou any
questions you may have.
Medical History-We will ask you about your child’spast health historysince thecompletion ofthe NGLU-
CL01 study.Data on your child
's siblings(under age of16)medical history will be obtained from the
NGLU-CL01 database. Any changes in sibling’s medical history since your child’s participation in
theNGLU-CL01 study will be recorded.
Medication History-We will ask you about the medicine(s) your childtakesnow orhastaken in the past 30
days and will record this, including all current medications (use of prescription and over-the-counter
medications), any supplements your childtakessuch as herbal preparations, vitamins and mineral
supplements.
Electrocardiogram (ECG)-This test is a painless way of looking at how yourchild’sheart is working.


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Alexion Pharmaceuticals, Inc. NGLU-CL01-T ProtocolAmendment 2.0  24 Feb 2016
UKPARENT/GUARDIANINFORMATION SHEET AND CONSENT FORM Version5.025Jan2017
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What to expect at the overnight stay?
During the overnight stay, all of your child’smeals will be provided. You may bring books, magazines,
electronic devices such as laptops, tablet computers, smartphones, etc. to the clinic. You may bring comfortable
clothing and personal items, but pleaseleave any valuables, such as jewellery, at home.
The day after yourchild’sfirst infusion the study team will take blood for tests before your childgoeshome.
The amount of blood taken on the day after yourchild’sinfusion will be about 5ml (1 teaspoon). Depending on
yourchild’sageand body weight,less blood may be taken.
What will happen at the next studyvisits?
Every 2 weeks for the next156weeks (3 years) your childwill come to the hospital/clinic.We will give your
childstudy drugapproximately every 2 weeksfor a total ofapproximately79dosesadministered.Visitswill
usuallylast between 5-7 hours.
At every visit your childwill have the following:
We will ask you or your childhowhe/she isfeeling now, and since thelast visit.
We will ask you about the medicines your child istaking.
We will call you after each visit at Week 2, Week 4 and Week 6 to ask you and yourchildhowhe/she has
been feeling.
Yourchild’svital signs will be taken before the infusion andseveral times during and after the infusion.
Yourchildwill be given a dose ofstudy drugby IV infusion.
Every 4 weeks (1 month)your childwillhavethe following:
A physical exam will be completed.
Bloodand urinewill be taken for testsbefore yourchild’sinfusion.The amount of blood taken onthese
visitswill be about 27mL(a little more than 4 teaspoons). Depending on yourchild’sageand size, less
blood may be taken.
Every 12–16weeks your childwill have the following:
Anelectrocardiogram (ECG) test will be performed.
Anaesthesia/Sedation will be given for the lumbar puncture procedure.
Lumbar Puncture will be done to get some cerebrospinal fluid from yourchild’sback. A total of 10ml of
fluid (2 teaspoons) will be collected.
Blood tests to check levels of enzyme will be taken before, during and after study drug infusion at Week 12,
Week 24, Week 52, Week 78, Week 104, Week 130, and Week 156/End of Treatment. Some of these visits
will require your childto stay after the infusion is completed.
Every 6 months to 1 year your childwill havethe following:
Anesthesia/Sedation will be given for the MRI procedure.
A MRIwill be performed.
Questionnaires-We will ask you and your childsome questions and will ask youto fill out several
questionnaires that will helpto understand how MPS IIIB affects youor your child’slife. You can skip any
questions you do not want to answer.
Photo-To assesspossible changes in yourchild’sappearance during the study, we will takea picture of your
child’sface.


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4 weeks (1 month) after yourchild’slast visit your childwill have a phone call:
To discuss any changes in the medications your child istaking.
To discusshow your child isfeeling now, and since the last visit.
The studydoctorwill watch yourchild’shealth closely during the study.Thestudy doctormay askyou to allow
your childto have other tests ifhis/herhealth changes.


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The following table shows you a summary of which tests to expect at each visit during the study:
Screening
Week 0
Day 1
Every
2
Weeks
Every
4
Weeks
Week
12
Week
24
Eligibility
X
X
Medical History
X
Physical Exam
X
X
X
X
X
X
Vital Signs
X
X
X
X
X
X
X
Photograph
X
X
Blood and Urine
Samples
X
X
X
X
X
X
ECG
X
X
X
X
Questionnaires
X
X
Lumbar puncture –
Spinal Fluid
Samples
X
X
X
General
Anesthesia/Sedation
X
X
X
MRI
X
X
Questions about
how your child is
feeling
X
X
X
Questions about
medicines your
child has taken
X
X
X
Study Drug Infusion
X
X
X
X
X
Overnight Stay*
X
X
*There will be an overnight stay at week 24.


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Every
12-16
weeks
Every 12-
28 weeks
Every
6 months
–1yr
Week
156/End of
Treatment
Week
160
Physical exam/height and
weight
X
Vital signs
X
Photograph
X
X
Blood and urinesamples
X
Electrocardiogram (ECG)
X
X
Questionnaires
X
X
Lumbar puncture
X
X
Medicine to make your
childsleepy or to feel
numb
X
X
X
MRI
X
X
Questions about how your
child isfeeling
X
Questions on medications
X
Infusion of SBC-103
X
Phone call (4 weeks after
last infusion of SBC-103)
X


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child start any new treatment without first asking yourstudy doctor, not even over the counter drugs,
herbs, or supplements that you can get without a prescription.
Risk associated with the study procedures
There are possible risks due to some of the procedures to be performed:
Intravenous Infusion Risks
Intravenous Infusion (IV dosing) is where the drug solution is given through a needle into yourchild’shand, arm
or chest vein.  Medications administered into veins (intravenously) can sometimes cause pain, swelling and
redness of the vein and surroundingtissues, which may not go away quickly, even if the medication is stopped.
Infection and nerve injury can also occur.
IV Catheter
The placement of a thin tube inside the vein in yourchild’sarm, hand or chestis necessary to give your childthe
study drug and to make taking blood samples easier. Thefollowing risks may be encountered with this
procedure:
Pain during placement-Discomfort can result from the needle stick and placement of the catheter at the
time it is inserted. Doctors try to lessen thepain with a local numbing medicine (anaesthetic like novocaine).
The discomfort is usually mild and goes away once the catheter is in place.
Collapsed lung-This is called a pneumothorax. The lung is very close to the veins of the neck or chest. If
the needle passes through the vein, it could pierce the lung causing it to leak and collapse on that side. If this
happens, the doctor can place a tube between the ribs into the chest to suck out the air that is leaking from
the lungs. This complication is particularly dangerous when a patient is on a breathing machine. Rarely,
collapse of the lung can cause death. This complication can even happen when everythingis done correctly.
Infection-Any tube (catheter) entering the body can make it easier for bacteria to get in and infect the
patient. The longer a catheter remains in the body, the more likely it is to become infected. Special care in
bandaging the skinat the needle site and changing the connecting tubes and fluids help to decrease this risk.
With great care, these catheters can remain in the body for several weeks without becoming infected.
Bleeding-Bleeding around holes in the veins is usually mild and seals on its own. Since the major arteries
run alongside the major veins, the arteries can be punctured by accident. Even bleeding from an artery can
stop on its own before serious problems occur. Rarely, the chest fills with blood, which can be life-
threatening. In that situation, it may be necessary to place a tube between the ribs to drain out the blood.
Clotting around the catheter-Blood clots can commonly form in and around these catheters inside the
veins. Such clots usually do not cause problems. Once the catheter is removed, the body can often dissolve
the clot over time. Sometimes, clots can break off and travel out into the lungs. This is called a pulmonary
embolism. A blood clot in the lungs can cause breathing problems and, very rarely, death.
Air entering through the catheter-Rarely, air enters the catheter as it is being inserted. The air bubbles can
travel through the heart and cause lung injury and low blood pressure. This problem is called an air
embolism. Special care is taken to avoid air entry.
Please tell the study doctorornurse if your childfeelssomething strange is happening tohim/her. If these things
happen to your child,he/shemay need to have other testing done to decide ifhe/shecan keep getting study drug.
Blood Sampling–Your childmay feel some pain, bruising, redness or itching where the needle pierced the
skin.  Very rarely your childmight feel dizzy or faint,he/shemay get an infection intheblood, an infection on


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UK PARENT/GUARDIAN INFORMATION SHEET AND CONSENT FORM Version 5.0 25Jan2017
Page 12 of 19
the spot where the needle went into his/her arm or a blood clot may form.  In very rare cases, the needle might
damage a nerve or a blood vessel. This will be performed by very experienced staff under sterile conditions so
this is very unlikely to occur.
ECG - During the ECG test, the study staff will put sticky patches on your child’s skin.  Some people may get a
slight skin irritation from the patches or from their removal, but this is usually mild and goes away within a few
days.
MRI
During the MRI, your child will lie on a narrow table, which slides into a large tunnel-shaped scanner. An MRI
exam causes no pain, but your child may have difficulty keeping still or may become nervous in the scanner.
Your child may be given anaesthesia/sedation to help him/her to lie still.  The sound of the MRI scanner can be
quite loud; your child may be given special ear plugs to minimise the noise. If your child has metal objects in
his/her body, this can be a safety risk to your child or affect the MRI image. Metal or electronic devices in the
body can include the following: metallic joint prostheses, artificial heart valves, an implantable heart
defibrillator, a pacemaker, metal clips to prevent veins from leaking, cochlear implants, body piercing, a bullet,
shrapnel or any other type of metal fragment.
Lumbar puncture
Prior to the lumbar puncture, we will give your child some medicine that will help him/her feel sleepy and
medicine to make it not hurt, but your child may still feel some pain. The skin on your child’s back may be a
little sore for a short time at the place where the fluid was taken. To help with this, we will use a special cream.
Your child may also have a mild sore head for a short time. We will give your child medicine to help this get
better.
Anaesthesia/Sedation
During procedures such as MRI and lumbar puncture your child may be sedated, which means that your child
will be given some medicine that will help him/her go into a kind of deep sleep where he/she is unable to move
or to feel pain. Medicines are usually given intravenously (through a vein) in your child’s arm or leg or inhaled
through a mask. Monitoring devices are used to watch your child’s blood pressure, heart rhythm and breathing.
Although common and generally safe, any sedation carries some degree of risk and it is important for you to be
aware of these risks. Risks of sedation include excessive sleepiness, slow to wake up,
low blood pressure,
slowed breathing, apnea (no breathing), abnormal or irregular heartbeats, nausea, vomiting, aspiration (inhaling
stomach contents into the lungs), or very rarely death. Usually, participants will breathe by themselves during
the kind of general anaesthesia that will be used. However, the work of breathing may have to be performed
artificially with assistance of a breathing machine (ventilator). In this case, a tube would be inserted into your
child’s airway (‘breathing pipe’) in order to safely and securely manage the breathing during the anaesthesia.
The anaesthesia will be given and managed by an experienced paediatric anaesthetist. Your child will therefore
be continuously and strictly monitored during the whole procedure until fully awake. This will be done under
supervision of the anaesthesia team.
In the event that your child experiences any side effects during his/her participation in the study you should
contact the study doctor as soon as possible.


Alexion Pharmaceuticals, Inc. NGLU-CL01-T ProtocolAmendment 2.0  24 Feb 2016
UKPARENT/GUARDIANINFORMATION SHEET AND CONSENT FORM Version5.025Jan2017
Page13of19
Allergy Skin Test
The risk with skin testing is that allergy symptoms might occur during the test.  The most common side effects
of skin testing are itching and/or swelling of the skin where the test was done.  The itching and/or swelling are
usually most noticeable during the test and typically go away within a few hours, although it can last for 1 or 2
days.  In rare cases, a more serious allergic reaction can occur.
Are there any reproductive risks?
Women: It is not known if the study treatment may affect an unborn child or nursing infant.  For this reason, if
your child isbreast-feeding, pregnant or plansto become pregnant,your childmay not participate in this study.
If your child iscapable of becoming pregnant,shemust use an acceptable method of birth control throughout the
entire studyand for 30 days afterherlast dose of study drug.
Men: It is not known if the study treatment may affect yourchild’ssperm or an unborn child.  For this reason,
your childmust use an acceptable method of birth control throughout the entire studyand for 30 days after your
child’slast dose of study drug.
Birth control methods considered acceptable for this study includehormonal contraception (pills, injections,
contraceptive patch, implant), intrauterine device, and double-barrier methods (any double combination of male
or female condom with spermicidal gel, diaphragm, sponge or cervical cap with spermicidal gel) or true
abstinence.Please discuss this with yourchild’sstudy doctor.
Your childmust use birth control for the entire study and for at least 30 days after yourchild’slast dose
of study drug.
It is important that you tell the study doctor immediately if your childorhis/herpartner becomes pregnant
duringand up to 90 days afterthe study.  The doctor will talk with you about what you should do.  Yourchild’s
participation in the study may be stopped,and your childand/orhis/herpartnerwill be required to sign a
separate informed consent form prior to collection of data about the pregnancy and associated outcome for
scientific or security reasonsand genetic risks.
What are the advantages and disadvantages of participation in the study?
Since this is thesecondstudy in patients,and the results of the first study are not yet available,it is not known if
your child is likely to benefit. However, by taking part, your childwill provide new information that may
benefit otherparticipantsin the future.Potential disadvantages of participations include the risk of experiencing
side effects from treatment with SBC-103, or from study-related procedures. These side effects and risks are
described in the sections above.
What happens when the research study stops?
When the study stops the study doctor will discuss ongoing standard of care.
What if there is a problem?
Any complaint about the way you/ your childhavebeen dealt with during the study or any possible harmyour
childmight suffer will be addressed. The detailed information on this is given in Part 2.
Will taking part in the study be kept confidential?
Yes. We will follow ethical and legal practice and all information about your childwill be handled in
confidence. The details are included in Part 2.
This completes Part 1.
If the information in Part 1 has interested you and you think youmay likeyour childto take part, please read the
additional information in Part 2.


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Alexion Pharmaceuticals, Inc. NGLU-CL01-T ProtocolAmendment 2.0  24 Feb 2016
UKPARENT/GUARDIANINFORMATION SHEET AND CONSENT FORM Version5.025Jan2017
Page15of19
Alexion Pharmaceuticals, Inc.would not be bound by these guidelines toreimbursewhere:
The injury resulted from a drug or procedure outside the trial protocol.
The protocol was not followed.
Copies of these guidelines are available fromthestudy doctor on request.
If you think your child hashadan injury/illness that is related to the study, you should immediately tell <<insert
name>>,the investigator, or one of the staff members working on the study.  The investigator and the study staff
may be reached at <<insert address and telephone number>>.
How will yourchild’sconfidentiality be respected and the privacy of yourchild’spersonal informationbe
maintained?
You have the right to control the use and disclosure of your child’spersonal information.  Basic personal
information will be recorded including yourchild’sname, contact details, gender, height, weight and racial
origin(to be used only for clinical purposes), as well as information on yourchild’smedical history, and clinical
data collected about yourchild’sparticipation in the study.The following people may also access yourchild’s
medical records in addition to the study doctor and study personnel:
Study monitors and auditorswho may work forAlexion Pharmaceuticals, Inc. (the study sponsor)or its
affiliates orauthorised representatives,tocheck that thestudy is being performed correctly and that the
information collected about your childis accurate;
National and international regulatory authorities(including without limitation theMedicines and Healthcare
products Regulatory Agency MHRA) andthe UnitedStates Food and Drug Administration(FDA) involved
inensuring that the study is being performed correctly according to the study protocol and applicable laws.
All personnel accessing yourchild’srecordsor yourchild’spersonal dataare required to respect yourchild’s
confidentiality at all timesin accordance with any applicable laws.
To ensure privacy, yourchild’sname and other identifying information will not be attached tostudy dataor
samples released for research purposes.  Instead, your childwill only be identified by a code.  Only the study
doctor andauthorisedpersonnel will be able to connect this code to yourchild’sname, by a list that will be kept
securely by the study site for15years.This list will not be removed from the site by the study sponsor and its
representatives or contracted third parties.After15 yearsthe link to the coded data will be destroyed.Once the
code key is destroyed, it will not be possible to link the data collected about your childtohis/hername, your
child’sdata will become anonymous, and thestudy sponsor will only keep and use fully anonymous data.
Where allowable by local law, yourchild’sdate of birth may also be recorded to help identify yourchild’sstudy
record.
Yourchild’scodedstudydata will be forwarded tothe study sponsor and its representatives or contracted third
partiesfor activities related to the study.  The study sponsor mayprocess,access,store, transfer, and use the
coded study data collected from yourchild’smedical records and health information as explained above. Once
the code key is destroyed and yourchild’scoded data becomes anonymous, the study sponsor mayprocess,
access,store,transfer, and use it indefinitely.
Study datawill be transferredand storedinto a computer database and processed to allow the results of this
study to beprocessed,accessed,analysedand reported or published. If the results of the study are published,
yourchild’sidentity will remain confidential.
Recipients of yourchild’sinformation may be in countries that do not have data protection safeguards and
rights.Alexion Pharmaceuticals, Inc.and its authorised representatives, and regulatory authorities, shall anyway


Alexion Pharmaceuticals, Inc. NGLU-CL01-T ProtocolAmendment 2.0  24 Feb 2016
UKPARENT/GUARDIANINFORMATION SHEET AND CONSENT FORM Version5.025Jan2017
Page16of19
seek to maintain confidentiality within the limits of local laws in these countries.A list of companies to whom
yourchild’scoded information is transferred is available fromAlexion Pharmaceuticals, Inc.viathestudy
doctor.
Under data protection lawUK Data Protection Act 1998yourchild’sstudy site andAlexion Pharmaceuticals,
Inc.shall be jointly responsible as ‘controllers’ for ensuring that yourchild’sinformation is safeguarded.
Alexion Pharmaceuticals, Inc.has appointedPPD Global Ltd,Granta Park, Great Abington, Cambridge, CB21
6GQ, UKas its ‘representative’ in yourchild’scountry to fulfill its obligations under this law. You have the
right to access, throughthestudy doctor, all the information collected aboutyour childand, if applicable, ask for
corrections.
If your childshould withdraw from the study, data collected prior to yourchild’swithdrawal may still be
accessed, used, stored, transferred andprocessed along with other data collected as part of the study.  Normally
no new information will be collected for the study database unless you specifically consent to that.  However,
the law does require that any side effects your childmay suffer are documented and reported.  You have the right
to requirethat any previously retained samples are destroyed.Ifyou require that your child’s samples be
destroyed,and yourchild’ssamples have already been tested, those results will still remain and continued to be
accessed, used, stored, transferred and processedas part of the overall research data.
A description of this clinical trial will be available on http://www.clinicaltrials.gov, as required by US Law.
This web site will not include information that can identify your child.  At most, the web site willinclude a
summary of the results.  You can search this Web site at any time.
What will happen to your child’sdata?
This clinical study may only be performed by collecting and using yourchild’smedical information. Data
protection laws give you the right to control the use of yourchild’spersonal information.  Therefore, by signing
this form you specificallyauthoriseyourchild’sinformation to be checked,accessed, used, stored,transferred
and processed as follows:
Theauthorisedrepresentatives ofAlexion Pharmaceuticals, Inc.and regulatory authorities’ inspectors may
review yourchild’smedical information by direct access to yourchild’smedical records.
Study data, including yourchild’scoded medical information, may be used,processed,stored,accessed,
transferredand shared for legitimate study and scientific purposes, including(if you do not object), for
future use in medical or pharmaceutical research.
Study data may be transferred to other countriesoutside of the United Kingdomforaccess, use, storage and
processing, including countries not covered by the data protection legislation.
Involvement of the General Practitioner/Family doctor (GP)
Yourchild’sfamily doctor (general practitioner) will be notified of yourchild’sinvolvementin this study and
asked to provide details fromhis/hermedical records including any treatment received during the study if you
give permission to do so,by signing theconsent form.
What will happen to any samples given?
Your biological samples may be collected,used, stored, accessed, transferred,processed(to other countries
outside the United Kingdom)and reported as necessary for the purposes of the study.
Some of thespinal fluid samples collected during the lumbarpunctureandsome ofthe blood sampleswillbe
sent to the hospital’s local laboratory <insert address> for testing and will be destroyedwithin6 months after
official release of study data reports.Blood, urine, spinal fluid samplesand tissue samples willalsobe sent and
stored at the following locations:


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Alexion Pharmaceuticals, Inc. NGLU-CL01-T Protocol Amendment 2.0  24 Feb 2016
UK PARENT/GUARDIAN INFORMATION SHEET AND CONSENT FORM Version 5.0 25Jan2017
Page 18 of 19
Site/ institution headed paper
Consent Form
(UK)
Principal Investigator:
Site/Institution:
Participant Number:
Short Title: SBC-103 Intravenously in SBC-103 Treatment Naïve MPS IIIB (NGLU-CL01-T)
Please initial box
1. I confirm that I have read and understand the participant information sheet for the above study.
I have had the opportunity to consider the information, ask questions and have had these answered
satisfactorily.
2. I understand that my child’s participation is voluntary and that I am free to withdraw my child at any
time without giving any reason, without my/my child’s medical care or legal rights being affected
3. I understand that relevant sections of my/my child’s medical notes and data collected during the study,
may be looked at by individuals from Alexion, from regulatory authorities or from the NHS Trust
where it is relevant to their taking part in this research. I give permission for these individuals to have
access to my/my child’s records.
4. I have no objection to, and authorize my/my child’s personal information and blood samples collected
during the study being sent outside the European Economic Area (EEA) as described in this information
sheet.
5. I have no objection to, and authorize my/my child’s GP being informed of my/my child’s participation
in the study and providing information from my/my child’s medical records to the study team as described
in this information sheet.
6. I agree for my child to take part in this study
Do you additionally consent to the use of your child’s remaining samples of blood, urine or CSF for exploratory
biomarker testing in future medical or pharmaceutical research? If you check the “no” box it will not disqualify
your child from participating in this study.
Yes      No
Do you additionally consent to the use of your child’s photo for the purposes described in the information sheet
knowing that your child’s identifying features will not be hidden? If you check the “no” box it will not
disqualify your child from participating in this study.
Yes       No


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SAP_002.pdf: 
Alexion Pharmaceuticals, Inc. 
Statistical Analysis Plan 
{Protocol: NGLU-CL01-T 24 Feb 2016 (Version 2.0 Final)} 
{01 Sep 2017, Version 1.0} 
 
 
Alexion Pharmaceuticals, Inc. 
 
 
STATISTICAL ANALYSIS PLAN FOR 
CLINICAL STUDY REPORT (CSR) 
 
 
PROTOCOL NUMBER: NGLU-CL01-T 
 
A Phase I/II Open Label Study in Previously Studied, SBC-103 
Treatment Naïve MPS IIIB Subjects to Investigate the Safety, 
Pharmacokinetics, and Pharmacodynamics/Efficacy of SBC-103 
Administered Intravenously  
 
 
 
 
Author: 
 
Date: 01 Sep 2017 
Version: 1.0  






Alexion Pharmaceuticals, Inc. 
Statistical Analysis Plan 
{Protocol: NGLU-CL01-T 24 Feb 2016 (Version 2.0 Final)} 
{01 Sep 2017, Version 1.0} 
2. TABLE OF CONTENTS, LIST OF TABLES, AND LIST OF FIGURES  
TABLE OF CONTENTS 
2. 
TABLE OF CONTENTS, LIST OF TABLES, AND LIST OF FIGURES .................3 
3. 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS...............................7 
4. 
DESCRIPTION OF THE PROTOCOL .......................................................................9 
4.1. 
Changes from Analyses Specified in the Protocol .......................................................9 
4.1.1. 
Primary Objective .........................................................................................................9 
4.1.2. 
Secondary Objectives ...................................................................................................9 
4.1.3. 
Exploratory Objectives .................................................................................................9 
4.1.4. 
Assessments / Parameters Included in Analysis .........................................................10 
4.2. 
Changes from Analyses Specified in the Previous Version of the SAP .....................10 
5. 
DEFINITIONS ...........................................................................................................11 
5.1. 
Efficacy .......................................................................................................................11 
5.1.1. 
Primary Endpoint(s) ....................................................................................................11 
5.1.2. 
Secondary Endpoints ..................................................................................................11 
5.1.2.1. 
Pharmacokinetic (PK) Parameters ..............................................................................11 
5.1.2.2. 
Pharmacodynamic (PD) Parameters ...........................................................................11 
5.1.3. 
Tertiary Endpoints ......................................................................................................11 
5.1.4. 
Other Efficacy Endpoints ...........................................................................................11 
5.1.4.1. 
Exploratory Endpoints ................................................................................................11 
5.2. 
Safety ..........................................................................................................................11 
5.2.1. 
Adverse Events (AEs) .................................................................................................11 
5.2.2. 
Vital Signs ..................................................................................................................12 
5.2.3. 
Laboratory Assessments .............................................................................................12 
5.2.4. 
Other Safety Assessments of Special Interest ............................................................12 
5.2.4.1. 
Anti-Drug Antibodies (ADA) .....................................................................................12 
5.2.4.2. 
ECG ............................................................................................................................12 
6. 
DATA SETS ANALYZED (STUDY POPULATIONS) ...........................................13 
6.1. 
Full Analysis Set (FAS) ..............................................................................................13 
6.2. 
Per Protocol (PP) Set ..................................................................................................13 
6.3. 
Safety Set ....................................................................................................................13 
Proprietary and Confidential                                                                                                                       Page 3 of 37 
 


Alexion Pharmaceuticals, Inc. 
Statistical Analysis Plan 
{Protocol: NGLU-CL01-T 24 Feb 2016 (Version 2.0 Final)} 
{01 Sep 2017, Version 1.0} 
6.4. 
Other Sets ....................................................................................................................13 
7. 
STATISTICAL ANALYSIS ......................................................................................14 
7.1. 
Study Patients .............................................................................................................14 
7.1.1. 
Disposition of Patients ................................................................................................14 
7.1.2. 
Protocol Deviations ....................................................................................................14 
7.1.3. 
Demographics, Disease Characteristics and History ..................................................14 
7.1.3.1. 
Demographics .............................................................................................................14 
7.1.3.2. 
Disease Characteristics ...............................................................................................14 
7.1.3.3. 
Medical / Surgical History and Baseline Physical Examination ................................15 
7.1.4. 
Prior and Concomitant Medications / Therapies ........................................................15 
7.2. 
Efficacy Analyses .......................................................................................................15 
7.2.1. 
Primary Analysis ........................................................................................................15 
7.2.1.1. 
Handling of Dropouts or Missing Data ......................................................................15 
7.2.1.2. 
Subgroup Analysis ......................................................................................................15 
7.2.1.3. 
Multicenter Studies .....................................................................................................15 
7.2.1.4. 
Hypothesis Testing and Significance Level ...............................................................15 
7.2.1.5. 
Sensitivity Analyses ....................................................................................................15 
7.2.2. 
Secondary Analyses ....................................................................................................15 
7.2.2.1. 
Neurocognitive and Developmental Assessments ......................................................15 
7.2.2.2. 
MRI Findings ..............................................................................................................15 
7.2.2.3. 
Blood Brain Barrier (BBB) Integrity Assessments ....................................................16 
7.2.2.4. 
Pharmacokinetic and Pharmacodynamic Analyses ....................................................16 
7.2.3. 
Tertiary Analyses ........................................................................................................16 
7.2.4. 
Other Efficacy Analyses .............................................................................................16 
7.2.5. 
Exploratory Analyses ..................................................................................................16 
7.3. 
Safety Analyses ..........................................................................................................16 
7.3.1. 
Study Duration, Treatment Compliance, and Exposure .............................................16 
7.3.2. 
Adverse Events (AEs) .................................................................................................16 
7.3.2.1. 
Overall Summary of Adverse Events .........................................................................17 
7.3.2.2. 
AEs and SAEs by System Organ Class (SOC) and Preferred Term (PT) ..................17 
7.3.2.3. 
AEs and SAEs by SOC, PT, and Relationship ...........................................................18 
7.3.2.4. 
AEs and SAEs by SOC, PT, and Severity ..................................................................18 
7.3.2.5. 
Deaths, Other SAEs, and Other Significant Adverse Events .....................................18 
Proprietary and Confidential                                                                                                                       Page 4 of 37 
 


Alexion Pharmaceuticals, Inc. 
Statistical Analysis Plan 
{Protocol: NGLU-CL01-T 24 Feb 2016 (Version 2.0 Final)} 
{01 Sep 2017, Version 1.0} 
7.3.3. 
Other Safety ................................................................................................................18 
7.3.3.1. 
Analyses for Laboratory Tests ....................................................................................18 
7.3.3.2. 
Vital Signs ..................................................................................................................19 
7.3.3.3. 
Other Safety Parameters of Special Interest ...............................................................19 
8. 
REFERENCES ...........................................................................................................20 
9. 
APPENDICES ............................................................................................................21 
9.1. 
Schedule of Study Assessments..................................................................................21 
9.2. 
Changes from Analyses Specified in the Previous Version of the SAP .....................36 
9.3. 
Sample Size, Power, and Randomization ...................................................................36 
9.3.1. 
Sample Size and Power ..............................................................................................36 
9.3.2. 
Randomization ............................................................................................................36 
9.4. 
Technical Specifications for Derived Variables .........................................................36 
9.4.1. 
Baseline Definition .....................................................................................................36 
9.4.2. 
Visit Windows ............................................................................................................36 
9.4.3. 
Imputation of Partial Dates .........................................................................................36 
9.5. 
Additional details on Statistical Methods ...................................................................37 
 
 
 
 
 
Proprietary and Confidential                                                                                                                       Page 5 of 37 
 


Alexion Pharmaceuticals, Inc. 
Statistical Analysis Plan 
{Protocol: NGLU-CL01-T 24 Feb 2016 (Version 2.0 Final)} 
{01 Sep 2017, Version 1.0} 
LIST OF TABLES 
Table 1: 
Abbreviations and acronyms ........................................................................................7 
 
 
 
Proprietary and Confidential                                                                                                                       Page 6 of 37 
 


Alexion Pharmaceuticals, Inc. 
Statistical Analysis Plan 
{Protocol: NGLU-CL01-T 24 Feb 2016 (Version 2.0 Final)} 
{01 Sep 2017, Version 1.0} 
3. 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
The following abbreviations and acronyms are used in this SAP.  
Table 1: 
Abbreviations and acronyms 
Abbreviation or acronym 
Explanation 
ADA  
Anti-drug antibodies  
AE  
Adverse event(s)  
AESI 
Adverse event(s) of special interest 
ATC 
Anatomical therapeutic chemical 
BBB  
Blood brain barrier  
BOT-2  
Bruininks-Oseretsky Test of Motor Proficiency, Second Edition  
BSID-III  
Bayley Scales of Infant and Toddler Development, Third Edition  
CCC-2  
Children’s Communication Checklist, Second Edition  
CSF  
Cerebrospinal fluid  
CSF-AI  
Cerebrospinal fluid/serum albumin index  
CSHQ  
Children’s Sleep Habits Questionnaire  
CSP 
Clinical study protocol 
CSR 
Clinical study report 
ECG  
Electrocardiogram  
eCRF 
Electronic case report form 
FAS 
Full Analysis Set 
FDNA  
Facial Dysmorphology Novel Analysis  
HGF  
Hepatocyte growth factor  
HS  
Heparan sulfate  
IAR  
Infusion-associated reaction  
ICH  
International Conference on Harmonization  
IgG  
Immunoglobulin G  
IMP  
Investigational Medicinal Product  
IV  
Intravenous(ly)  
KABC-II  
Kaufman Assessment Battery for Children, Second Edition  
MedDRA 
Medical Dictionary for Regulatory Activities 
MPS IIIB  
Mucopolysaccharidosis III, type B  
MRI  
Magnetic resonance imaging  
NAGLU  
Alpha-N-acetylglucosaminidase  
NRE  
Non-reducing end  
PD  
Pharmacodynamic(s)  
PK  
Pharmacokinetic(s)  
PT  
Preferred Term  
QOW 
Every other week  
Rel Day 
Relative study day 
SAE  
Serious adverse event  
SAP  
Statistical analysis plan  
SBRS  
Sanfilippo Behavior Rating Scale  
SD 
Standard deviation 
SDTM 
Study Data Tabulation Model 
SF-10  
10-item Short Form Health Survey for Children  
SI 
International system of units 
SOA  
Schedule of Assessments  
SOC 
System Organ Class 
TEAE 
Treatment-emergent adverse event 
Proprietary and Confidential                                                                                                                       Page 7 of 37 
 


Alexion Pharmaceuticals, Inc. 
Statistical Analysis Plan 
{Protocol: NGLU-CL01-T 24 Feb 2016 (Version 2.0 Final)} 
{01 Sep 2017, Version 1.0} 
Abbreviation or acronym 
Explanation 
TESAE 
Treatment-emergent serious adverse event 
US  
United States (of America)  
Vineland-II  
Vineland Adaptive Behavior Scales, Second Edition  
WHO 
World Health Organization 
WHO-DD 
World Health Organization Drug Dictionary 
ZBI  
Zarit Burden Interview 12-item short form  
Proprietary and Confidential                                                                                                                       Page 8 of 37 
 


Alexion Pharmaceuticals, Inc. 
Statistical Analysis Plan 
{Protocol: NGLU-CL01-T 24 Feb 2016 (Version 2.0 Final)} 
{01 Sep 2017, Version 1.0} 
4. 
DESCRIPTION OF THE PROTOCOL 
Study NGLU-CL01-T, A Phase I/II Open Label Study in Previously Studied, SBC-103 Treatment 
Naïve MPS IIIB Subjects to Investigate the Safety, Pharmacokinetics, and 
Pharmacodynamics/Efficacy of SBC-103 Administered Intravenously, is an open label Phase I/II 
study designed to evaluate the safety and tolerability of intravenous (IV) administration of 
SBC-103 in previously studied, SBC-103 treatment naïve subjects with mucopolysaccharidosis 
III, type B (MPS IIIB, Sanfilippo B) who participated in the NGLU-CL01 study. The 
NGLU-CL01 study was a non-interventional study that evaluated structural brain abnormalities 
and blood brain barrier (BBB) integrity by magnetic resonance imaging (MRI) and cerebrospinal 
fluid/serum albumin index (CSF-AI). 
The protocol can be referenced for additional details. The schedule of events is attached in 
Appendix 9.1 of this Statistical Analysis Plan (SAP). 
On 11 Jul 2017, Alexion decided to stop the clinical development program with SBC-103.  A 
clinical study report (CSR) will detail the final demographic, disposition, exposure and safety 
data of each study. 
 
4.1. 
Changes from Analyses Specified in the Protocol 
The data analyses, data summaries and data presentations specified for the NGLU-CL01-T CSR 
represent a reduced subset of the overall total data analyses, data summaries, and data 
presentations described in the NGLU-CL01-T final approved Clinical Study Protocol (CSP) 
version (Amendment 2, 24 February 2016) for the full study.  Only demographic, disposition, 
safety and exposure data will be used to create data summaries and listings for the reduced subset 
of the CSP specified full study parameters.  Only the assessments/parameters specified in Section 
4.1.4 will be included. 
4.1.1. 
Primary Objective 
The primary objective of this CSR SAP is to evaluate the safety and tolerability of IV 
administration of SBC-103 in previously studied, SBC-103 treatment naïve subjects with 
mucopolysaccharidosis III, type B (MPS IIIB, Sanfilippo B) who participated in the 
NGLU-CL01 study.  The NGLU-CL01 study was a non-interventional study that evaluated 
structural brain abnormalities and blood brain barrier (BBB) integrity by magnetic resonance 
imaging (MRI) and cerebrospinal fluid/serum albumin index (CSF-AI). 
4.1.2. 
Secondary Objectives 
No secondary objectives will be addressed in this SAP. 
4.1.3. 
Exploratory Objectives 
No exploratory objectives will be addressed in this SAP. 
Proprietary and Confidential                                                                                                                       Page 9 of 37 
 


Alexion Pharmaceuticals, Inc. 
Statistical Analysis Plan 
{Protocol: NGLU-CL01-T 24 Feb 2016 (Version 2.0 Final)} 
{01 Sep 2017, Version 1.0} 
4.1.4. 
Assessments / Parameters Included in Analysis 
• 
Demographics 
• 
Disposition 
• 
Use of Prior and Concomitant Medications (Listing only) 
• 
Treatment Exposure, Dosing Administration and Infusion Summary (Listings only) 
• 
Treatment Emergent Adverse Events (TEAEs) 
• 
Treatment Emergent Serious Adverse Events (TESAEs) 
• 
Infusion Associated Reactions (IAR) 
• 
Anti-drug Antibody (ADA) Assay and Titer Results  
• 
Laboratory Parameters: Hematology, Chemistry, Urinalysis, including Coagulation, 
Renal Function, and Liver Function (Listings only). 
• 
Lumbar Puncture:  CSF Findings and CSF-AI Ratio (listings only)  
• 
Vital Signs (listing only) 
4.2. 
Changes from Analyses Specified in the Previous Version of the SAP 
Not applicable. 
Proprietary and Confidential                                                                                                                       Page 10 of 37 
 


Alexion Pharmaceuticals, Inc. 
Statistical Analysis Plan 
{Protocol: NGLU-CL01-T 24 Feb 2016 (Version 2.0 Final)} 
{01 Sep 2017, Version 1.0} 
5. 
DEFINITIONS 
5.1. 
Efficacy  
5.1.1. 
Primary Endpoint(s) 
The primary objective is to evaluate the safety and tolerability of IV administration of SBC-103, 
and as such, there is no primary efficacy endpoint. 
5.1.2. 
Secondary Endpoints 
Analyses of secondary efficacy endpoints will not be included in the CSR.  
5.1.2.1. 
Pharmacokinetic (PK) Parameters 
Analyses of PK data will not be included in the CSR. 
5.1.2.2. 
Pharmacodynamic (PD) Parameters 
Analyses of PD or PK/PD data, including HS, will not be included in the CSR.  
5.1.3. 
Tertiary Endpoints 
Not applicable. 
5.1.4. 
Other Efficacy Endpoints 
5.1.4.1. 
Exploratory Endpoints 
Analyses of exploratory endpoints will not be included in the CSR. 
5.2. 
Safety 
The primary endpoint of this study is the safety and tolerability of SBC-103 in subjects with 
MPS IIIB.  The safety assessments will include the following: 
• 
Incidence of treatment emergent adverse events (TEAEs), treatment emergent serious 
adverse events (TESAEs), and infusion-associated reactions (IARs) which are adverse 
events of special interest (AESI). 
• 
Incidence of anti-drug antibodies (ADA) including ADA titer by time point, peak ADA 
titer, and ADA titer status (positive/negative), and the effect of ADAs on the safety of 
SBC-103, including the relationship between ADA-positive subjects and the incidence of 
IARs. 
5.2.1. 
Adverse Events (AEs) 
Adverse events are defined in Protocol Section 7.1. Also refer to Appendix 9.4.3 of this SAP for 
special handling of AE partial dates.  Any AE that occurs after the first dose of SBC-103 is 
considered a treatment emergent adverse event (TEAE) for this study. 
Proprietary and Confidential                                                                                                                       Page 11 of 37 
 


Alexion Pharmaceuticals, Inc. 
Statistical Analysis Plan 
{Protocol: NGLU-CL01-T 24 Feb 2016 (Version 2.0 Final)} 
{01 Sep 2017, Version 1.0} 
5.2.2. 
Vital Signs 
Vital signs will be provided in a listing.  The following vital signs were recorded at the times 
specified in Appendix 9.1: systolic and diastolic blood pressure (millimeters of mercury 
(mmHg)), heart rate (beats/minute), respiratory rate (breaths/minute), and temperature (degrees 
Celsius (°C) or degrees Fahrenheit (°F)). 
5.2.3. 
Laboratory Assessments 
Serum chemistry, hematology, urinalysis, including coagulation, renal function, liver function, 
CSF, and assessment of ADAs related testing will be performed as per the SOA. Details on 
specific laboratory assessments are provided in Appendix 9.1.  All laboratory results will be 
provided in listings.  
5.2.4. 
Other Safety Assessments of Special Interest 
5.2.4.1. 
Anti-Drug Antibodies (ADA) 
Patients will be monitored for the development of antibody production against SBC-103 at the 
times specified in Appendix 9.1.  Serum will be collected and analyzed for the presence of ADA, 
and if positive, further analyzed for titer, and characterization of response (e.g., 
positive/negative). 
5.2.4.2. 
ECG 
Analyses of electrocardiogram (ECG) data will not be included in the CSR. 
Proprietary and Confidential                                                                                                                       Page 12 of 37 
 


Alexion Pharmaceuticals, Inc. 
Statistical Analysis Plan 
{Protocol: NGLU-CL01-T 24 Feb 2016 (Version 2.0 Final)} 
{01 Sep 2017, Version 1.0} 
6. 
DATA SETS ANALYZED (STUDY POPULATIONS) 
The following analysis sets will be used for the presentation and analysis of the data for the CSR.  
For further information on the processing of patient data utilized in creating the following study 
population analysis dataset(s)/subset(s) and baselines, please see Appendix 9.4.1. 
 
6.1. 
Full Analysis Set (FAS) 
Not applicable. 
6.2. 
Per Protocol (PP) Set 
Not applicable. 
6.3. 
Safety Set 
The Safety Analysis Set, defined as all patients for whom informed consent has been obtained, 
who have a confirmed diagnosis of MPS IIIB, and who have received any amount of SBC-103, 
will be used to summarize all safety and tolerability data.  
6.4. 
Other Sets 
Not applicable. 
 
Proprietary and Confidential                                                                                                                       Page 13 of 37 
 


Alexion Pharmaceuticals, Inc. 
Statistical Analysis Plan 
{Protocol: NGLU-CL01-T 24 Feb 2016 (Version 2.0 Final)} 
{01 Sep 2017, Version 1.0} 
7. 
STATISTICAL ANALYSIS 
All output will be sorted and labeled according to the International Conference on 
Harmonization (ICH) recommendations, and formatted to the appropriate page size(s).  
For the analyses covered by this SAP, data analysis and presentation for this study is primarily 
descriptive in nature; therefore, no inferential analyses are planned. Selected data will be 
presented in by-patient data listings and summarized in tables across patients if appropriate.  
SBC-103 1 mg/kg was administered qow for the first 12 weeks of study; the dose was then 
escalated to 3 mg/kg for all subjects.  Descriptive summaries of data will be presented by the 
SBC-103 3 mg/kg qow dose group without regard to the initial treatment at the 1 mg/kg qow 
dose or any dose reductions. Continuous data will be summarized using descriptive statistics 
including number of patients, mean, standard deviation (SD), median, minimum, maximum, 
Lower quartile (25th percentile) Q1, and Upper quartile (75th percentile) Q3; categorical data will 
be summarized by counts and proportions. No formal statistical hypothesis testing will be 
performed. 
For this analysis, information will be displayed as the SBC-103 3 mg/kg qow dose only except in 
treatment exposure and infusion listings.  All data listings that contain an evaluation date will 
contain a relative study day (Rel Day).  Pre-treatment and on-treatment study days are numbered 
relative to the day of the first dose of study drug which is designated as Relative Day 1. The 
preceding day is Day -1, the day before that is Day -2, etc. The last day of study drug is 
designated with an “L” (e.g., Day 14L). 
7.1. 
Study Patients 
7.1.1. 
Disposition of Patients 
Patient enrollment and disposition including number of patients screened, enrolled, dosed, and 
percentage of patients who discontinued from the study, along with reasons for discontinuations 
will be tabulated and described in listings. 
7.1.2. 
Protocol Deviations 
Analyses of protocol deviations will not be included in the CSR.  
7.1.3. 
Demographics, Disease Characteristics and History 
7.1.3.1. 
Demographics 
Demographic and baseline characteristics will be summarized descriptively.  Age at study entry 
(years), gender, race, ethnicity, baseline weight, baseline height and baseline Body Mass Index 
(BMI) will be summarized.  Listings will also be provided. 
7.1.3.2. 
Disease Characteristics 
 
Disease characteristics will not be included in the CSR.  
 
Proprietary and Confidential                                                                                                                       Page 14 of 37 
 


Alexion Pharmaceuticals, Inc. 
Statistical Analysis Plan 
{Protocol: NGLU-CL01-T 24 Feb 2016 (Version 2.0 Final)} 
{01 Sep 2017, Version 1.0} 
7.1.3.3. 
Medical / Surgical History and Baseline Physical Examination 
Medical/surgical history and physical examination data will not be included in the CSR. 
7.1.4. 
Prior and Concomitant Medications / Therapies 
All medications and treatments received by the patient during the study or within the preceding 4 
weeks will be collected.  Any medication or treatment received after the first dose of SBC-103 
will be considered concomitant.  Medications will be mapped to a generic term using the current 
Alexion version of World Health Organization (WHO) Drug Dictionary (WHO-DD). 
Medications will be classified using the Anatomical Therapeutic Chemical (ATC) classification 
system.  All prior and concomitant medications/therapies will be provided in listings.   
7.2. 
Efficacy Analyses 
7.2.1. 
Primary Analysis 
As stated above, the primary objective of this study is to evaluate the safety and tolerability of IV 
administration of SBC-103, and as such, there is no primary efficacy endpoint or analysis. 
7.2.1.1. 
Handling of Dropouts or Missing Data 
Partial dates will be handled as detailed in Appendix 9.4.3 including details for calculating 
calendar or chronological age, as necessary. Missing data will be handled as detailed below for 
each measure. 
7.2.1.2. 
Subgroup Analysis 
Not applicable. 
7.2.1.3. 
Multicenter Studies 
Only 1 center participated in this study and therefore, analyses by center will not be performed.   
7.2.1.4. 
Hypothesis Testing and Significance Level 
Data analysis and/or presentation for this study are primarily descriptive in nature; therefore, no 
inferential analyses are planned and p-values will not be provided.   
7.2.1.5. 
Sensitivity Analyses 
Not applicable. 
7.2.2. 
Secondary Analyses 
Analyses of secondary efficacy endpoints will not be included in the CSR. 
7.2.2.1. 
Neurocognitive and Developmental Assessments 
Analyses of neurocognitive and developmental assessments will not be included in the CSR. 
7.2.2.2. 
MRI Findings 
Analyses of MRI findings will not be included in the CSR. 
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Alexion Pharmaceuticals, Inc. 
Statistical Analysis Plan 
{Protocol: NGLU-CL01-T 24 Feb 2016 (Version 2.0 Final)} 
{01 Sep 2017, Version 1.0} 
7.2.2.3. 
Blood Brain Barrier (BBB) Integrity Assessments 
CSF/serum albumin index (CSF-AI) assessments of BBB integrity will be provided in listings. 
7.2.2.4. 
Pharmacokinetic and Pharmacodynamic Analyses 
7.2.2.4.1. Pharmacokinetic Analyses 
Analyses of pharmacokinetic (PK) data will not be included in the CSR. 
7.2.2.4.2. Pharmacodynamic Analyses 
Analyses of pharmacodynamic (PD) data will not be included in the CSR. 
7.2.3. 
Tertiary Analyses 
Not applicable. 
7.2.4. 
Other Efficacy Analyses 
Not applicable. 
7.2.5. 
Exploratory Analyses  
No exploratory analyses will be included in the CSR. 
7.3. 
Safety Analyses 
As stated above in Section 5.2, the primary objective of this study is the safety and tolerability of 
SBC-103 in subjects with MPS IIIB. Descriptive statistics will be computed for specified safety 
parameters using the Safety Analysis Set, as appropriate, including treatment emergent adverse 
events (TEAEs), treatment emergent serious adverse events (TESAEs), and infusion-associated 
reactions (IARs) which are adverse events of special interest (AESI). The incidence of anti-drug 
antibodies (ADA) including ADA titer by time point, peak ADA titer, ADA titer status 
(positive/negative), neutralizing antibodies, and the relationship between ADA-positivity and the 
incidence of IARs will be presented. 
7.3.1. 
Study Duration, Treatment Compliance, and Exposure 
Dosing administration information will be listed by patient number and visit and will present 
details on confirmation of SBC-103 administration, reasons SBC-103 was not administered, total 
# of vials used, target dose (mg/kg), and dose concentration (mg/mL).  Exposure to study drug 
(SBC-103) related information will be listed by patient number and visit. The stop/start 
dates/times, total actual volume of drug infused (mL), infusion rate (mL/hr), type of infusion 
(dosing or saline flush), rate reduction percentage compared to previous infusion rate, and 
information on any modification to the infusion including reason for modification will be 
presented in the listings.   
7.3.2. 
Adverse Events (AEs) 
Information will be summarized on all AEs that began at any time from the date of first study 
procedure performed through the last procedure at the last study visit. Adverse events will be 
Proprietary and Confidential                                                                                                                       Page 16 of 37 
 


Alexion Pharmaceuticals, Inc. 
Statistical Analysis Plan 
{Protocol: NGLU-CL01-T 24 Feb 2016 (Version 2.0 Final)} 
{01 Sep 2017, Version 1.0} 
classified by the study Investigator into one of the following relations to study drug: not related, 
unlikely related, possibly related or related to study drug. For reporting purposes, “related” 
events will include all AEs assessed by the Investigator as: possibly related or related to study 
drug. 
All AEs captured in the eCRF will be coded using the Medical Dictionary for Regulatory 
Activities (MedDRA) coding system and displayed in tables and data listings using System 
Organ Class (SOC) and Preferred Term (PT).  All AEs will be coded using the MedDRA, 
version 13.1 or higher. 
Severity of AEs will be graded on a 3-point scale (mild, moderate and severe) based on the 
definitions, developed from Clinical Data Interchange Standards Consortium (CDISC) Study 
Data Tabulation Model (SDTM) standard terminology v3.1.1 (see Protocol Section 7.1.1).  
Adverse event incidence will be reported based on the concept of treatment emergence for the 
purposes of this analysis. Any AE that occurs after the first dose of SBC-103 is considered a 
treatment emergent adverse event (TEAE) for this study.  
Adverse events are summarized by patient incidence rates; therefore, in any tabulation, a patient 
contributes only once to the count for a given AE.   
The number and percentage of patients with a TEAE will be summarized. 
7.3.2.1. 
Overall Summary of Adverse Events 
An overall summary of TEAEs and treatment-emergent SAEs (TESAEs) will include summaries 
of events (n) and number of patients with events (n, %). 
Within each summary category (TEAEs, TESAEs) the following subcategories will also be 
summarized, as appropriate: 
• At Least 1 TEAE 
• At Least 1 Severe TEAE 
• At Least 1 Related TEAE (possibly related or related to study drug) 
• At Least 1 TEAE Leading to Withdrawal / Discontinuation from the Study 
• At Least 1 IAR 
• At Least 1 Serious TEAE 
  Additionally, the number and percentage of patients who died on study will be presented. 
7.3.2.2. 
AEs and SAEs by System Organ Class (SOC) and Preferred Term (PT) 
The number of TEAEs and the number and percentage of patients with events will be 
descriptively summarized and presented by SOC and PT.  Patients are counted once in each SOC 
and PT. Percentages will be based on the total number of treated patients. 
The number of Serious TEAEs and the number and percentage of patients with events will be 
descriptively summarized and presented by PT.  Patients are counted once in each PT.  
Percentages will be based on the total number of treated patients. 
All AEs will be presented in by-patient listings. 
Proprietary and Confidential                                                                                                                       Page 17 of 37 
 


Alexion Pharmaceuticals, Inc. 
Statistical Analysis Plan 
{Protocol: NGLU-CL01-T 24 Feb 2016 (Version 2.0 Final)} 
{01 Sep 2017, Version 1.0} 
7.3.2.3. 
AEs and SAEs by SOC, PT, and Relationship 
Individual patient AE/SAE data for Relationship to Study Drug and Relationship to Study 
Procedures is presented in the by-patient AE listings. 
7.3.2.4. 
AEs and SAEs by SOC, PT, and Severity 
 
Individual patient AE/SAE data for severity is presented by-patient AE listings. 
 
7.3.2.5. 
Deaths, Other SAEs, and Other Significant Adverse Events 
Deaths and other SAEs will be identified by the data presented in the by-patient listings of AEs. 
7.3.2.5.1    Other Significant Adverse Events 
Procedure-related AEs will be identified by the relationship to study procedures data presented in 
the by-patient listings of AEs.  
7.3.2.5.2.   Infusion-Associated Reactions 
 
Infusion-associated reactions (IARs) will be considered AEs of special interest (AESIs). An AE 
will be considered an IAR if it meets either of the following criteria: 
• 
The Investigator checks “Yes” to the question “Is AE an IAR?” on the AE eCRF. 
• 
The AE (diagnosis and/or symptom) occurs between the start of the infusion up to 4 
hours after the infusion and is assessed by the Investigator as at least possibly related to 
Investigational Medicinal Product (IMP). 
Note that several AEs may be associated with 1 IAR observed with SBC-103 administration; 
each AE is captured as a separate event. The number and percentage of patients who experience 
any IAR and the number of IARs reported over the course of the study will be summarized. Any 
patient who experiences an IAR is only counted once regardless of the number of associated 
events. Patients may be counted more than once if IARs occur on more than 1 dosing day. 
Summaries of AEs that comprise an IAR will be displayed by MedDRA PT. Each patient will be 
counted only once within each PT. 
A by-patient data listing of all AEs will be presented. 
7.3.3. 
Other Safety 
7.3.3.1. 
Analyses for Laboratory Tests 
The clinical laboratory data to be presented include hematology, chemistry, urinalysis, 
coagulation, renal function, liver function, CSF findings and CSF-AI ratio.  All clinical 
laboratory data will be listed.   
Clinical laboratory values by time of assessment will be expressed in International System of 
units (SI units) in data listings. Unscheduled lab test results will also be presented in the data 
listings. Abnormal lab values will be flagged with “H”/“L” or “HIGH”/“LOW” for out of range 
values, and an asterisk for clinical significance in the data listings. 
Patient data for clinical laboratory data will be presented in listings by patient number and visit.   
Proprietary and Confidential                                                                                                                       Page 18 of 37 
 


Alexion Pharmaceuticals, Inc. 
Statistical Analysis Plan 
{Protocol: NGLU-CL01-T 24 Feb 2016 (Version 2.0 Final)} 
{01 Sep 2017, Version 1.0} 
7.3.3.2. 
Vital Signs 
Vital signs include systolic blood pressure, diastolic blood pressure, heart rate, respiratory rate, 
and body temperature. A listing of vital signs will be presented by patient number, vital sign 
parameter, vital sign value, and visit. 
7.3.3.3. 
Other Safety Parameters of Special Interest 
7.3.3.3.1. Antidrug Antibody (ADA) 
Assays testing for screening, confirmed, neutralizing ADA will be performed and ADA titers 
will be measured for neutralizing antibodies. For this analysis, confirmed ADA assay results will 
be descriptively presented by ADA status (Positive, Negative) as the proportion of patients, n 
(%), with measurable confirmed antibodies to SBC-103 for each visit.  Neutralizing antibodies 
for confirmed positive cases will also be presented.   
ADA titer result statistics will be descriptively presented by ADA status and visit. 
The number and percentage of patients with Infusion-Association Reactions (IARs) adverse 
events by MedDRA System Organ Class, Preferred Term, and ADA positivity will be presented 
along with the number of IAR events.  If a patient experienced more than one event in a given 
SOC, that patient is counted once for that SOC.  If a patient experienced more than one event 
with a given PT, that patient is counted only once for that PT. 
7.3.3.3.2. ECG 
Analyses of ECG data will not be included in the CSR. 
Proprietary and Confidential                                                                                                                       Page 19 of 37 
 


Alexion Pharmaceuticals, Inc. 
Statistical Analysis Plan 
{Protocol: NGLU-CL01-T 24 Feb 2016 (Version 2.0 Final)} 
{01 Sep 2017, Version 1.0} 
8. 
REFERENCES 
 
 
Proprietary and Confidential                                                                                                                       Page 20 of 37 
 


Alexion Pharmaceuticals, Inc. 
Statistical Analysis Plan 
{Protocol: NGLU-CL01-T 24 Feb 2016 (Version 2.0 Final)} 
{01 Sep 2017, Version 1.0} 
9. 
APPENDICES 
9.1. 
Schedule of Study Assessments 
Assessments 
Screening 
Day 
0 
Day 
1 
 
Week 
2 
Week 
4 
Week 
6 
Week 
8 
Week 
10 
Week 
12 
Week 
14 
Week 
16 
Week 
18 
Week 
20 
Week 
22 
Week 
24 
Week 
26 
Visit Window (Days) 
-28 to 0 
-5 to 
0 
days 
±5 
days 
±5 
days 
±5 
days 
±5 
days 
±5 
days 
±5 
days 
±5 
days 
±5 
days 
±5 
days 
±5 
days 
±5 
days 
±5 
days 
±5 
days 
Informed 
Consent/Assent* 
X 
Inclusion/Exclusion 
Criteria 
X 
Medical History 
(review of changes 
from NGLU-CL01) 
X 
Physical Examination 
X 
XP 
X 
XP 
XP 
XP 
XP 
XP 
XP 
Height and Weight 
X 
XP 
XP 
XP 
XP 
XP 
XP 
XP 
Vital Signs 
X 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
12-lead ECG 
(Triplicate) 
X 
XP 
XP 
XP 
FDNA 
X 
X 
Vineland-II, BSID-III, 
KABC-II, BOT-2 
Brief Form, CCC-2, 
SBRS,CSHQ, ZBI, SF-
102 
X 
XP 
Haematology, Serum 
Chemistry (including 
Coagulation), 
Urinalysis3 
X 
XP 
X 
XP 
XP 
XP 
XP 
XP 
XP 
Pregnancy Test 
(Urine)4 
X 
XP 
XP 
XP 
XP 
XP 
XP 
XP 
 
 
 
Proprietary and Confidential                                                                                                                       Page 21 of 37 
 


Alexion Pharmaceuticals, Inc. 
Statistical Analysis Plan 
{Protocol: NGLU-CL01-T 24 Feb 2016 (Version 2.0 Final)} 
{01 Sep 2017, Version 1.0} 
 
Assessments 
Screening 
Day 
0 
Day 
1 
Week 
2 
Week 
4 
Week 
6 
Week 
8 
Week 
10 
Week 
12 
Week 
14 
Week 
16 
Week 
18 
Week 
20 
Week 
22 
Week 
24 
Week 
26 
Visit Window (Days) 
-28 to 0 
-5 to 
0 
days 
±5 
days 
±5 
days 
±5 
days 
±5 
days 
±5 
days 
±5 
days 
±5 
days 
±5 
days 
±5 
days 
±5 
days 
±5 
days 
±5 
days 
±5 
days 
Serum and Urine 
Heparan Sulphate 
(Total and NRE) 
X 
XP 
XP 
XP 
XP 
XP 
XP 
XP 
Serum Ferritin and 
Chitotriosidase 
X 
XP 
XP 
XP 
XP 
XP 
XP 
XP 
Plasma Glutamic Acid 
and Glycine 
X 
XP 
XP 
XP 
XP 
XP 
XP 
XP 
NAGLU enzyme 
activity 
X 
Serum Biomarkers 
(Exploratory including 
IgG, inflammatory 
markers) 
XP 
XP 
XP 
XP 
XP 
XP 
XP 
Serum 
Pharmacokinetic 
Profile5 
X 
X 
X 
SBC-103 ADA6 
XP 
XP 
XP 
XP 
XP 
XP 
XP 
General 
Anaesthesia/Sedation7 
XP 
XP 
XP 
Lumbar Puncture7,8 
XP 
XP 
XP 
Heparan Sulphate 
(Total and NRE) in 
CSF 
XP 
XP 
XP 
Calbindin D, HGF, Tau, 
pTau, Amyloid β, 
Albumin, IgG in CSF 
XP 
XP 
XP 
Glutamic Acids and 
Glycine in CSF 
XP 
XP 
XP 
 
 
 
 
Proprietary and Confidential                                                                                                                       Page 22 of 37 
 


Alexion Pharmaceuticals, Inc. 
Statistical Analysis Plan 
{Protocol: NGLU-CL01-T 24 Feb 2016 (Version 2.0 Final)} 
{01 Sep 2017, Version 1.0} 
 
 
Assessments 
Screening 
Day 
0 
Day 
1 
Week 
2 
Week 
4 
Week 
6 
Week 
8 
Week 
10 
Week 
12 
Week 
14 
Week 
16 
Week 
18 
Week 
20 
Week 
22 
Week 
24 
Week 
26 
Visit Window (Days) 
-28 to 0 
-5 to 
0 
days 
±5 
days 
±5 
days 
±5 
days 
±5 
days 
±5 
days 
±5 
days 
±5 
days 
±5 
days 
±5 
days 
±5 
days 
±5 
days 
±5 
days 
±5 
days 
Routine Findings 
(Cell Counts, Glucose, 
Protein) in CSF3 
XP 
XP 
XP 
SBC-103 in CSF 
XP 
XP 
XP 
Structural and 
Diffusion MRI7 
XP 
XP 
Telephone call 
X 
X 
X 
SBC-103 Dosing 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Adverse Events10 
CONTINUOUS 
Concomitant 
Medications11 
CONTINUOUS 
Proprietary and Confidential                                                                                                                       Page 23 of 37 
 


Alexion Pharmaceuticals, Inc. 
Statistical Analysis Plan 
{Protocol: NGLU-CL01-T 24 Feb 2016 (Version 2.0 Final)} 
{01 Sep 2017, Version 1.0} 
 
 
 
 
Assessments 
Week 
28 
Week 
30 
Week 
32 
Week 
34 
Week 
36 
Week 
38 
Week 
40 
Week 
42 
Week 
44 
Week 
46 
Week 
48 
Week 
50 
Week 
52 
Visit Window (Days) 
±5 
days 
±5 
days 
±5 
days 
±5 
days 
±5 
days 
±5 
days 
±5 
days 
±5 
days 
±5 
days 
±5 
days 
±5 
days 
±5 
days 
±5 
days 
Physical Examination 
XP 
XP 
XP 
XP 
XP 
XP 
XP 
Height and Weight 
XP 
XP 
XP 
XP 
XP 
XP 
XP 
Vital Signs 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
12-lead ECG1 
XP 
FDNA 
X 
Vineland-II, BSID-III, 
KABC-II, BOT-2 Brief 
Form, CSHQ, CCC-2, 
SBRS, ZBI, SF-102 
XP 
Haematology, Serum 
Chemistry (incl. 
Coagulation), Urinalysis3 
XP 
XP 
XP 
XP 
Pregnancy Test (Urine) 4 
XP 
XP 
XP 
XP 
XP 
XP 
XP 
Serum and Urine Heparan 
Sulphate (Total and NRE) 
XP 
XP 
XP 
XP 
Serum Ferritin and 
Chitotriosidase 
XP 
XP 
XP 
XP 
Plasma Glutamic Acid and 
Glycine 
XP 
XP 
XP 
XP 
Serum Biomarkers 
(Exploratory including IgG, 
inflammatory markers) 
XP 
XP 
XP 
XP 
Serum Pharmacokinetic 
Profile5 
X 
SBC-103 ADA6 
XP 
XP 
XP 
XP 
XP 
XP 
XP 
General 
Anaesthesia/Sedation7 
XP 
XP 
Proprietary and Confidential                                                                                                                       Page 24 of 37 
 


Alexion Pharmaceuticals, Inc. 
Statistical Analysis Plan 
{Protocol: NGLU-CL01-T 24 Feb 2016 (Version 2.0 Final)} 
{01 Sep 2017, Version 1.0} 
 
 
 
 
 
 
Assessments 
Week 
28 
Week 
30 
Week 
32 
Week 
34 
Week 
36 
Week 
38 
Week 
40 
Week 
42 
Week 
44 
Week 
46 
Week 
48 
Week 
50 
Week 
52 
Visit Window (Days) 
±5 
days 
±5 
days 
±5 
days 
±5 
days 
±5 
days 
±5 
days 
±5 
days 
±5 
days 
±5 
days 
±5 
days 
±5 
days 
±5 
days 
±5 
days 
Lumbar Puncture7,8 
XP 
XP 
Heparan Sulphate (Total and 
NRE) in CSF 
XP 
XP 
Calbindin D, HGF, Tau, 
pTau, Amyloid β, Albumin, 
IgG in CSF 
XP 
XP 
Glutamic Acids and Glycine 
in CSF 
XP 
XP 
Routine Findings (Cell 
Counts, Glucose, Protein) in 
CSF3 
XP 
XP 
SBC-103 in CSF 
XP 
XP 
Structural and Diffusion 
MRI7 
XP 
SBC-103 Dosing 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Adverse Events10 
CONTINUOUS 
Concomitant Medications11 
CONTINUOUS 
Proprietary and Confidential                                                                                                                       Page 25 of 37 
 


Alexion Pharmaceuticals, Inc. 
Statistical Analysis Plan 
{Protocol: NGLU-CL01-T 24 Feb 2016 (Version 2.0 Final)} 
{01 Sep 2017, Version 1.0} 
 
 
 
 
 
 
Assessments 
Week 
54 
Week 
56 
Week 
58 
Week 
60 
Week 
62 
Week 
64 
Week 
66 
Week 
68 
Week 
70 
Week 
72 
Week 
74 
Week 
76 
Week 
78 
Visit Window (Days) 
±5 
days 
±5 
days 
±5 
days 
±5 
days 
±5 
days 
±5 
days 
±5 
days 
±5 
days 
±5 
days 
±5 
days 
±5 
days 
±5 
days 
±5 
days 
Physical Examination 
XP 
XP 
XP 
XP 
XP 
XP 
Height and Weight 
XP 
XP 
XP 
XP 
XP 
XP 
Vital Signs12 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
12-lead ECG1 
XP 
FDNA 
X 
Vineland-II, BSID-III, 
KABC-II, BOT-2 Brief 
Form, CSHQ, CCC-2, 
SBRS, ZBI, SF-102 
XP 
Haematology, Serum 
Chemistry (including 
Coagulation), 
Urinalysis3 
XP 
XP 
XP 
Pregnancy Test 
(Urine)4 
P 
X 
P 
X 
P 
X 
P 
X 
P 
X 
XP 
Serum and Urine 
Heparan Sulphate 
(Total and NRE) 
XP 
XP 
XP 
Serum Ferritin and 
Chitotriosidase 
XP 
XP 
XP 
Plasma Glutamic 
Acid and Glycine 
XP 
XP 
XP 
Serum Biomarkers 
(Exploratory 
including IgG, 
inflammatory 
markers) 
XP 
XP 
XP 
Proprietary and Confidential                                                                                                                       Page 26 of 37 
 


Alexion Pharmaceuticals, Inc. 
Statistical Analysis Plan 
{Protocol: NGLU-CL01-T 24 Feb 2016 (Version 2.0 Final)} 
{01 Sep 2017, Version 1.0} 
 
 
 
 
 
 
Assessments 
Week 
54 
Week 
56 
Week 
58 
Week 
60 
Week 
62 
Week 
64 
Week 
66 
Week 
68 
Week 
70 
Week 
72 
Week 
74 
Week 
76 
Week 
78 
Visit Window (Days) 
±5 
days 
±5 
days 
±5 
days 
±5 
days 
±5 
days 
±5 
days 
±5 
days 
±5 
days 
±5 
days 
±5 
days 
±5 
days 
±5 
days 
±5 
days 
Serum 
Pharmacokinetic 
Profile5 
X 
SBC-103 ADA6 
XP 
XP 
XP 
XP 
XP 
XP 
General 
Anaesthesia/Sedation7 
P 
X 
XP 
Lumbar Puncture7,8 
XP 
XP 
Heparan Sulphate 
(Total and NRE) in 
CSF 
XP 
XP 
Calbindin D, HGF, 
Tau, pTau, Amyloid 
β, Albumin, IgG in 
CSF 
P 
X 
XP 
Glutamic Acids and 
Glycine in CSF 
XP 
XP 
Routine Findings 
(Cell Counts, 
Glucose, Protein) in 
CSF3 
XP 
XP 
SBC-103 in CSF 
XP 
XP 
SBC-103 Dosing 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Adverse Events10 
CONTINUOUS 
Concomitant 
Medications11 
CONTINUOUS 
Proprietary and Confidential                                                                                                                       Page 27 of 37 
 


Alexion Pharmaceuticals, Inc. 
Statistical Analysis Plan 
{Protocol: NGLU-CL01-T 24 Feb 2016 (Version 2.0 Final)} 
{01 Sep 2017, Version 1.0} 
 
 
 
 
 
 
Assessments 
Week 
80 
Week 
82 
Week 
84 
Week 
86 
Week 
88 
Week 
90 
Week 
92 
Week 
94 
Week 
96 
Week 
98 
Week 
100 
Week 
102 
Week 
104 
Visit Window (Days) 
±5 
days 
±5 
days 
±5 
days 
±5 
days 
±5 
days 
±5 
days 
±5 
days 
±5 
days 
±5 
days 
±5 
days 
±5 
days 
±5 
days 
±5 
days 
Physical Examination 
XP 
XP 
XP 
XP 
XP 
XP 
XP 
Height and Weight 
XP 
XP 
XP 
XP 
XP 
XP 
XP 
Vital Signs12 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
12-lead ECG1 
XP 
FDNA 
X 
Vineland-II, BSID-III, 
KABC-II, BOT-2 Brief 
Form, CSHQ, CCC-2, 
SBRS, ZBI, SF-102 
XP 
Haematology, Serum 
Chemistry (including 
Coagulation), 
Urinalysis3 
XP 
XP 
XP 
Serum albumin sample 
XP 
Pregnancy Test 
(Urine)4 
XP 
XP 
XP 
XP 
XP 
XP 
XP 
Serum and Urine 
Heparan Sulphate 
(Total and NRE) 
XP 
XP 
XP 
XP 
Serum Ferritin and 
Chitotriosidase 
XP 
XP 
XP 
Plasma Glutamic Acid 
and Glycine 
XP 
XP 
XP 
Serum Biomarkers 
(Exploratory including 
IgG, inflammatory 
markers) 
XP 
XP 
XP 
Proprietary and Confidential                                                                                                                       Page 28 of 37 
 


Alexion Pharmaceuticals, Inc. 
Statistical Analysis Plan 
{Protocol: NGLU-CL01-T 24 Feb 2016 (Version 2.0 Final)} 
{01 Sep 2017, Version 1.0} 
 
 
 
 
 
 
Assessments 
Week 
80 
Week 
82 
Week 
84 
Week 
86 
Week 
88 
Week 
90 
Week 
92 
Week 
94 
Week 
96 
Week 
98 
Week 
100 
Week 
102 
Week 
104 
Visit Window (Days) 
±5 
days 
±5 
days 
±5 
days 
±5 
days 
±5 
days 
±5 
days 
±5 
days 
±5 
days 
±5 
days 
±5 
days 
±5 
days 
±5 
days 
±5 
days 
Serum Pharmacokinetic 
Profile5 
X 
SBC-103 ADA6 
XP 
XP 
XP 
XP 
XP 
XP 
XP 
General 
Anaesthesia/Sedation7 
XP 
XP 
Lumbar Puncture7,8 
XP 
XP 
Heparan Sulphate 
(Total and NRE) in 
CSF 
XP 
XP 
Calbindin D, HGF, Tau, 
pTau, Amyloid β, 
Albumin, IgG in CSF 
XP 
XP 
Glutamic Acids and 
Glycine in CSF 
XP 
XP 
Routine Findings (Cell 
Counts, Glucose, 
Protein) in CSF3 
XP 
XP 
SBC-103 in CSF 
XP 
XP 
Structural and Diffusion 
MRI7 
XP 
SBC-103 Dosing 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Adverse Events10 
CONTINUOUS 
Concomitant 
Medications11 
CONTINUOUS 
Proprietary and Confidential                                                                                                                       Page 29 of 37 
 


Alexion Pharmaceuticals, Inc. 
Statistical Analysis Plan 
{Protocol: NGLU-CL01-T 24 Feb 2016 (Version 2.0 Final)} 
{01 Sep 2017, Version 1.0} 
 
 
 
 
 
 
Assessments 
Week 
106 
Week 
108 
Week 
110 
Week 
112 
Week 
114 
Week 
116 
Week 
118 
Week 
120 
Week 
122 
Week 
124 
Week 
126 
Week 
128 
Week 
130 
Week 
132 
Visit Window (Days) 
±5 
days 
±5 
days 
±5 
days 
±5 
days 
±5 
days 
±5 
days 
±5 
days 
±5 
days 
±5 
days 
±5 
days 
±5 
days 
±5 
days 
±5 
days 
±5 
days 
Physical Examination 
XP 
XP 
XP 
XP 
XP 
XP 
XP 
Height and Weight 
XP 
XP 
XP 
XP 
XP 
XP 
XP 
Vital Signs12 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
12-lead ECG1 
XP 
FDNA 
X 
Vineland-II, BSID-III, 
KABC-II, BOT-2 Brief 
Form, CSHQ, CCC-2, 
SBRS, ZBI, SF-102 
XP 
Haematology, Serum 
Chemistry (including 
Coagulation), Urinalysis3 
XP 
XP 
XP 
Pregnancy Test (Urine) 4 
XP 
XP 
XP 
XP 
XP 
XP 
XP 
Serum and Urine Heparan 
Sulphate (Total and NRE) 
XP 
XP 
XP 
Serum Ferritin and 
Chitotriosidase 
XP 
XP 
XP 
Plasma Glutamic Acid and 
Glycine 
XP 
XP 
XP 
Serum Biomarkers 
(Exploratory including 
IgG, inflammatory 
markers) 
XP 
XP 
XP 
Serum Pharmacokinetic 
Profile5 
X 
SBC-103 ADA6 
XP 
XP 
XP 
XP 
XP 
XP 
XP 
Proprietary and Confidential                                                                                                                       Page 30 of 37 
 


Alexion Pharmaceuticals, Inc. 
Statistical Analysis Plan 
{Protocol: NGLU-CL01-T 24 Feb 2016 (Version 2.0 Final)} 
{01 Sep 2017, Version 1.0} 
 
 
 
 
 
 
Assessments 
Week 
106 
Week 
108 
Week 
110 
Week 
112 
Week 
114 
Week 
116 
Week 
118 
Week 
120 
Week 
122 
Week 
124 
Week 
126 
Week 
128 
Week 
130 
Week 
132 
Visit Window (Days) 
±5 
days 
±5 
days 
±5 
days 
±5 
days 
±5 
days 
±5 
days 
±5 
days 
±5 
days 
±5 
days 
±5 
days 
±5 
days 
±5 
days 
±5 
days 
±5 
days 
General 
Anaesthesia/Sedation7 
P 
X 
XP 
Lumbar Puncture7,8 
XP 
XP 
Heparan Sulphate (Total 
and NRE) in CSF 
XP 
XP 
Calbindin D, HGF, Tau, 
pTau, Amyloid β, 
Albumin, IgG in CSF 
XP 
XP 
Glutamic Acids and 
Glycine in CSF 
XP 
XP 
Routine Findings (Cell 
Counts, Glucose, Protein) 
in CSF3 
XP 
XP 
SBC-103 in CSF 
XP 
XP 
SBC-103 Dosing 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Adverse Events10 
CONTINUOUS 
Concomitant Medications11 
CONTINUOUS 
Proprietary and Confidential                                                                                                                       Page 31 of 37 
 


Alexion Pharmaceuticals, Inc. 
Statistical Analysis Plan 
{Protocol: NGLU-CL01-T 24 Feb 2016 (Version 2.0 Final)} 
{01 Sep 2017, Version 1.0} 
 
 
 
 
 
Assessments 
 
 
 
Week 
134 
Week 
136 
Week 
138 
Week 
140 
Week 
142 
Week 
144 
Week 
146 
Week 
148 
Week 
150 
Week 
152 
Week 
154 
Week 156/ 
End of 
Treatment/ 
Early 
Termination 
Week 
160 
Visit Window (Days) 
±5 
days 
±5 
days 
±5 
days 
±5 
days 
±5 
days 
±5 
days 
±5 
days 
±5 
days 
±5 
days 
±5 
days 
±5 
days 
±5 
days 
±5 
days 
Physical Examination 
XP 
XP 
XP 
XP 
XP 
XP 
Height and Weight 
XP 
XP 
XP 
XP 
XP 
XP 
Vital Signs12 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
12-lead ECG1 
XP 
FDNA 
X 
Vineland-II, BSID-III, 
KABC-II, BOT-2 Brief Form, 
CSHQ, CCC-2, SBRS, ZBI, SF-
102 
XP 
Haematology, Serum 
Chemistry (including 
Coagulation), Urinalysis3 
XP 
XP 
XP 
Serum Albumin sample 
X 
Pregnancy Test (Urine) 4 
XP 
XP 
XP 
XP 
XP 
XP 
Serum and Urine Heparan 
Sulphate (Total and NRE) 
XP 
XP 
XP 
XP 
Serum Ferritin and 
Chitotriosidase 
XP 
XP 
XP 
Plasma Glutamic Acid and 
Glycine 
XP 
XP 
XP 
Serum Biomarkers 
(Exploratory including IgG, 
inflammatory markers) 
XP 
XP 
XP 
Serum Pharmacokinetic 
Profile5 
X 
Proprietary and Confidential                                                                                                                       Page 32 of 37 
 


Alexion Pharmaceuticals, Inc. 
Statistical Analysis Plan 
{Protocol: NGLU-CL01-T 24 Feb 2016 (Version 2.0 Final)} 
{01 Sep 2017, Version 1.0} 
 
 
 
Assessments 
 
 
 
Week 
134 
Week 
136 
Week 
138 
Week 
140 
Week 
142 
Week 
144 
Week 
146 
Week 
148 
Week 
150 
Week 
152 
Week 
154 
Week 156/ 
End of 
Treatment/ 
Early 
Termination 
Week 
160 
Visit Window (Days) 
±5 
days 
±5 
days 
±5 
days 
±5 
days 
±5 
days 
±5 
days 
±5 
days 
±5 
days 
±5 
days 
±5 
days 
±5 
days 
±5 
days 
±5 
days 
SBC-103 ADA6 
XP 
XP 
XP 
XP 
XP 
XP 
General 
Anaesthesia/Sedation7 
P 
X 
XP 
Lumbar Puncture7,8 
XP 
XP 
Heparan Sulphate (Total and 
NRE) in CSF 
XP 
XP 
Calbindin D, HGF, Tau, 
pTau, Amyloid β, Albumin, 
IgG in CSF 
XP 
XP 
Glutamic Acids and Glycine 
in CSF 
XP 
XP 
Routine Findings (Cell 
Counts, Glucose, Protein) in 
CSF3 
XP 
XP 
SBC-103 in CSF 
XP 
XP 
Structural and Diffusion MRI7 
XP 
Telephone call9 
X 
SBC-103 Dosing 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Adverse Events10 
CONTINUOUS 
Concomitant Medications11 
CONTINUOUS 
Proprietary and Confidential                                                                                                                       Page 33 of 37 
 


Alexion Pharmaceuticals, Inc. 
Statistical Analysis Plan 
{Protocol: NGLU-CL01-T 24 Feb 2016 (Version 2.0 Final)} 
{01 Sep 2017, Version 1.0} 
 
 
 
Key: ADA = anti-drug antibodies; BOT-2 Brief Form = Bruininks-Oseretsky Test of Motor Proficiency, Second Edition, Brief Form; BSID-III = Bayley Scales of 
Infant and Toddler Development, Third Edition; CCC-2 = Children’s Communication Checklist, Second Edition; CSF = cerebrospinal fluid; CSHQ = Children’s Sleep Habits 
Questionnaire; D = day; ECG = electrocardiogram; FDNA = Facial Dysmorphology Novel Analysis; HGF = hepatocyte growth factor; IgG = immunoglobulin G; KABC-II = 
Kaufman Assessment Battery for Children, Second Edition; NAGLU = alpha-N-acetylglucosaminidase; MRI = magnetic resonance imaging; NRE = non- reducing end; SBRS 
= Sanfilippo Behavior Rating Scale; SF-10 = Short Form Health Survey for Children; Vineland-II = Vineland Adaptive Behavior Scales, Second Edition; Wk = week; ZBI = 
Zarit Burden Interview, 12-item. 
*All study visits will be scheduled relative to Day 0. Infusions will be administered every 14 days ± 5 days and must be administered at least 10 days apart. Informed 
consent may be granted before the beginning of the screening period. All screening assessments other than informed consent should be completed within a 28-day 
window. 
XP Assessments to be performed pre-dose 
1  ECG assessments after 6 months do not need to be performed in triplicate. 
2   The Vineland-II, BSID-III or KABC-II, BOT-2 Brief Form, and CCC-2 should be administered in-person by an appropriately qualified professional. 
3   Local lab ranges will be used for those labs analysed locally. If samples are taken within 3 days of Day 0, samples do not need to be repeated on Day 0. However, a 
Day 0 serum sample for albumin should be collected at the same time as the CSF collection, to enable calculation of CSF-AI. Central laboratory parameter reference 
ranges will be used throughout the study, including in the event that laboratory parameters are analysed locally. All attempts should be made to draw laboratory 
samples for central laboratory analysis when samples are needed for local analysis. Day 1 samples will be analysed locally, all other samples may be analysed 
centrally. 
4   If a urine sample is not able to be provided, a serum pregnancy test will be performed by a local laboratory. 
5   Refer to Protocol Section 5.2.1.2 for directions and timing of PK sampling. 
6   In addition to time points indicated, obtain a sample for ADA determination anytime subject experiences a moderate-to-severe IAR during the next study visit (≥ 4 days 
after the IAR) and prior to the infusion. 
7   Lumbar puncture and MRI procedures may be performed under general anaesthesia or light sedation, as clinically appropriate in accordance with local 
institutional procedures. If clinically indicated, subjects may also receive general anaesthesia or sedation for central line placement for long-term 
vascular 
access, in accordance with institutional guidelines. When possible, the procedure to place the central line should be performed while the subject is 
already anaesthetised or sedated for another study procedure. After the lumbar puncture is completed, the subject should be observed as per 
institution standard practice. Vital signs, adverse events, and concomitant medications should be assessed before the subject is discharged from the site. 
8    During study visits where CSF is collected, and no serum chemistry sample is indicated per the SOA, a serum albumin sample should be collected to assess CSF-AI. 
After the lumbar puncture is completed, the subject should be observed as per institution standard practice. 
 
9    A telephone follow-up call will be made 4 weeks after the last dose received of SBC-103 after Week 156 End of Treatment or after the Early Termination visit. 
10   All AEs should be followed until they have returned to baseline values or stabilised or until the Investigator and Sponsor or designee agree that follow-up is no longer 
necessary. 
11   Information on all medications and treatments received by the subject within the 4 weeks preceding the Screening visit through the final visit will be recorded in  
     the CRF. 
Proprietary and Confidential                                                                                                                       Page 34 of 37 
 


Alexion Pharmaceuticals, Inc. 
Statistical Analysis Plan 
{Protocol: NGLU-CL01-T 24 Feb 2016 (Version 2.0 Final)} 
{01 Sep 2017, Version 1.0} 
12  Starting at Week 54, vital signs may be taken pre-dose (within approximately 30 minutes), approximately every 15 minutes during infusion and approximately  
      every 15 minutes for 1 hour after completion of the infusion, provided there is no occurrence of IARs during the infusion. Vital signs will be obtained after any  
    lumbar puncture as per site standard of care. 
 
Proprietary and Confidential                                                                                                                       Page 35 of 37 
 


Alexion Pharmaceuticals, Inc. 
Statistical Analysis Plan 
{Protocol: NGLU-CL01-T 24 Feb 2016 (Version 2.0 Final)} 
{01 Sep 2017, Version 1.0} 
 
9.2. 
Changes from Analyses Specified in the Previous Version of the SAP 
Not applicable. 
9.3. 
Sample Size, Power, and Randomization 
9.3.1. 
Sample Size and Power 
The sample size of up to 5 subjects was determined by the number of subjects enrolled in the 
prior NGLU-CL01 study, based on clinical and not statistical considerations and is considered 
sufficient to provide PK, safety, and PD/efficacy data, which in combination with data from 
other NGLU studies could be used to inform dose selection, regimen, and study design for future 
studies. 
9.3.2. 
Randomization 
This is an open label, non-randomized study with no requirement for blinding. 
9.4. 
Technical Specifications for Derived Variables  
9.4.1. 
Baseline Definition 
Baseline is defined as the value closest and prior to the first administration of SBC-103 on the 
first day of dosing. The first day of dosing is Day 0 in the Schedule of Assessments (SOA) and 
will be considered Relative Study Day 1 in order to construct CDISC compliant datasets.  
Analyses will use the assessments based on the Day 0 visit per the eCRF.   
9.4.2. 
Visit Windows 
It is expected that all visits will occur according to the protocol schedule. All data will be 
tabulated per the evaluation visit as recorded on the eCRF even if the assessment is outside of the 
visit window. In data listings, the relative day of all visits will also be presented. 
9.4.3. 
Imputation of Partial Dates 
For descriptive analysis purposes, partial dates will be imputed for some calculations (e.g. time 
to, and duration of, etc.). For calculation of time of laboratory test from diagnosis, partial dates 
will be handled as follows.  Date of diagnosis must be imputed from age at diagnosis and date of 
birth (DOB).  Date of diagnosis will be defined as DOB + age at diagnosis.  If DOB contains 
partial dates, date of diagnosis will be defined as imputed DOB + age at diagnosis. Time from 
diagnosis will be calculated from imputed date of diagnosis.  
For other analyses, partial dates will be handled by the following imputation methods: 
• Imputations for ages (in months): If birthdate is not missing, Age = (Assessment date - birth 
date)/30.4375. If only birth year and month are available, Age = (Assessment year- birth 
year)*12 + (assessment month-birth month). If only birth year is available then a “midpoint 
date” of July 1 will be used for an imputed birth date; using July 1 of the birth year, Age = 
(Assessment date – imputed birth date)/30.4375.  If the birth date is completely missing, Age 
= (age in years from eCRF*12) for Baseline (add the appropriate number of months for any 
follow-up assessments). 


Alexion Pharmaceuticals, Inc. 
Statistical Analysis Plan 
{Protocol: NGLU-CL01-T 24 Feb 2016 (Version 2.0 Final)} 
{01 Sep 2017, Version 1.0} 
• AE Start Date Imputation: The earliest possible date will be imputed for start date of AEs. If 
the day of the month is missing, the day will be set to the first day of the month. If the day 
and month are both missing, the day and month will be assumed to be January 1. 
• AE End Date Imputation: The latest possible date will be imputed for end date of AEs. If the 
day of the month is missing, the day will be set to the last day of the month. If the day and 
month are both missing, the day and month will be assumed to be December 31. 
• Midpoint Imputation:  For all other partial dates, a “midpoint date” will be imputed.  If the 
day of the month is missing, the day will be set to the fifteenth (15th) day of the month.  If 
the day and month are both missing, the day and month will be assumed to be July 1. 
• Should the date created with these imputation rules place it outside the possible range of 
values established by complete, known dates (such as the birth date, death date, ICF date for 
study procedures), the closest known date will be used.  In the case of date imputations for 
age calculations, the age as reported on the eCRF will be used as a reference to ensure the 
calculated age is appropriate. 
For reporting purposes, a month will be defined as 30.4375 days (rounded and displayed to 1 
decimal place) and a year defined as 365.25 days (rounded and displayed to 2 decimal places). 
9.5. 
Additional details on Statistical Methods 
Not applicable. 
Proprietary and Confidential                                                                                                                       Page 37 of 37 
 

Prot_001.pdf: 
NGLU-CL01-T Protocol 
24 February 2016 
A PHASE I/II OPEN LABEL STUDY IN PREVIOUSLY STUDIED, 
SBC-103 TREATMENT NAÏVE MPS IIIB SUBJECTS TO 
INVESTIGATE THE SAFETY, PHARMACOKINETICS, AND 
PHARMACODYNAMICS/EFFICACY OF SBC-103 ADMINISTERED 
INTRAVENOUSLY  
Protocol Number: 
NGLU-CL01-T 
Amendment Number: 
2.0 
Date of Protocol: 
24 February 2016 
EudraCT Number: 
2015-001983-20 
IND Number: 
IND 118402 
Product: 
SBC-103 
Sponsor: 
Alexion Pharmaceuticals, Inc. 
 
 
 
This study will be conducted according to the protocol and in compliance with  
Good Clinical Practice, the ethical principles stated in the Declaration of Helsinki,  
and other applicable regulatory requirements. 
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,.-------------
i 
I 
NGLU-CL01-T Protocol 
24 February 2016 
APPROVAL SIGNATURE PAGE 
Protocol Title: 
A Phase 1/II Open Label Study in Previously Studied, 
SBC-1 03 Treatment Naive MPS IIIB Subjects to Investigate 
the Safety, Pharmacokinetics, and 
Pharmacodynamics/Efficacy of SBC-1 03 Administered 
Intravenous! y 
Protocol Number: 
NGLU-CL01-T 
Amendment Number: 
2.0 
Date of Protocol: 
24 February 2016 
REVIEWED/APPROVED BY: 
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NGLU-CL01-T Protocol  
24 February 2016 
INVESTIGATOR STATEMENT 
I agree to conduct this clinical study in accordance with the design and specific 
provisions of this protocol. 
I understand that I may terminate or suspend enrolment of the study at any time if it 
becomes necessary to protect the best interests of the study subjects.  This study may be 
terminated at any time by the Sponsor, with or without cause. 
I agree to personally conduct and supervise this investigation at my institution and to 
ensure that all associates, colleagues, and employees assisting in the conduct of this study 
are informed about their obligations in meeting these commitments. 
I will conduct the study in accordance with Good Clinical Practice, the Declaration of 
Helsinki, and the moral, ethical, and scientific principles that justify medical research.  
The study will be conducted in accordance with all relevant laws and regulations relating 
to clinical studies and the protection of subjects.   
I will ensure that the requirements relating to Institutional Review Board/Independent 
Ethics Committee (IRB/IEC) review and approval are met.  I will provide the Sponsor 
with any material that is provided to the IRB/IEC for ethical approval. 
I agree to maintain adequate and accurate records and to make those records available for 
audit and inspection in accordance with relevant regulatory requirements. 
I agree to promptly report to the IRB/IEC any changes in the research activity and all 
unanticipated problems involving risks to human subjects or others.  Additionally, I will 
not make any changes in the research without IRB/IEC and Sponsor approval, except 
where necessary to ensure the safety of study subjects. 
 
 
 
Investigator Name 
 Investigator Signature 
 Date 
 
 
Investigational Site or Name of Institution  
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NGLU-CL01-T Protocol  
24 February 2016 
CLINICAL STUDY SYNOPSIS 
Protocol Title 
A Phase I/II Open Label Study in Previously Studied, SBC-103 
Treatment Naïve MPS IIIB Subjects to Investigate the Safety, 
Pharmacokinetics, and Pharmacodynamics/Efficacy of SBC-103 
Administered Intravenously 
Protocol Number 
NGLU-CL01-T 
EudraCT Number 
2015-001983-20 
IND Number 
IND 118402 
Objectives 
Primary Objective 
To evaluate the safety and tolerability of intravenous (IV) 
administration of SBC-103 in previously studied, SBC-103 treatment 
naïve subjects with mucopolysaccharidosis III, type B (MPS IIIB, 
Sanfilippo B) who participated in the NGLU-CL01 study.  The 
NGLU-CL01 study was a non-interventional study that evaluated 
structural brain abnormalities and blood brain barrier (BBB) integrity 
by magnetic resonance imaging (MRI) and cerebrospinal fluid/serum 
albumin index (CSF-AI). 
Secondary Objectives 
• 
To characterise the pharmacokinetic (PK) profile of SBC-103 
administered IV. 
• 
To determine the effects of dosing with SBC-103 administered 
IV on the levels, onset, and magnitude of changes in levels of 
total heparan sulphate (HS) in cerebrospinal fluid (CSF), serum, 
and urine. 
• 
To evaluate the pharmacodynamics (PD)/efficacy of treatment 
with SBC-103 administered IV as measured by neurocognitive 
and developmental function, changes in brain structure, and BBB 
integrity. 
• 
To evaluate change from the NGLU-CL01 study visit to baseline 
of the NGLU-CL01-T study (observational period) in the 
following where available: clinical laboratory tests including HS 
in CSF, in serum, and in urine, electrocardiograms (ECGs), 
physical examination, vital signs, concomitant medications, 
neurocognitive and developmental function, brain structure, 
microstructural integrity, and BBB integrity.   
Exploratory Objectives 
• 
To examine the onset and magnitude of changes in biomarkers, 
SBC-103 concentration in CSF, MPS IIIB disease characteristics 
and symptoms, and quality of life (QOL) after IV administration 
of SBC-103. 
• 
To evaluate change in biomarkers and MPS IIIB disease 
characteristics and symptoms from the NGLU-CL01 study visit 
to baseline of the NGLU-CL01-T study (observational period). 
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NGLU-CL01-T Protocol  
24 February 2016 
Methodology 
This study (NGLU-CL01-T) will be conducted in MPS IIIB patients 
who participated in the NGLU-CL01 study, a non-interventional study 
that evaluated structural brain abnormalities and BBB integrity by MRI 
and CSF-AI.  All subjects enrolled in the NGLU-CL01 study were 
≥ 5 years of age and had a definitive diagnosis of MPS IIIB, as 
determined by documented deficiency in alpha-N-acetylglucosaminidase 
(NAGLU) enzyme activity of < 10% of the lower limit of normal based 
on a historical test result from a local laboratory, or from a qualified 
laboratory at screening, or documented functionally-relevant mutations in 
both alleles of the NAGLU gene. 
This study is designed to evaluate the safety and tolerability of IV 
administration of recombinant human alpha-N-acetylglucosaminidase 
(rhNAGLU), referred to here as SBC-103, for the treatment of MPS IIIB.   
Following completion of screening assessments to confirm study 
eligibility, up to 5 subjects will be treated with 1 mg/kg IV for a 
minimum of 12 weeks.  After 12 weeks of treatment, review of safety and 
PD data will be conducted to determine whether it is appropriate to 
escalate the dose to 3 mg/kg.  The dose escalation decision will be made 
individually for each subject based on data from that subject and with 
consideration of any other available data on SBC-103. 
Each subject will be administered SBC-103 by IV infusion once every 
other week (qow) for a total duration of up to 3 years (156 weeks).  
Safety, PK and PD/efficacy assessments will be performed in all subjects.  
All subjects will be monitored in an in-patient setting for safety and 
tolerability for 24 hours following the first dose of SBC-103. 
Criteria for continued dosing after the first dose and for dose 
escalation after 12 weeks of treatment 
The decision to continue dosing in each subject will be made by the 
Sponsor in consultation with the Principal Investigator (PI) after review 
of 24-hour safety data from that subject and available safety data from all 
other treated subjects in the SBC-103 program. 
The decision to escalate to the 3 mg/kg dose in each subject will be 
made by the Sponsor in consultation with the PI based on safety, 
tolerability and PD data after 12 weeks of treatment on 1 mg/kg and with 
consideration of any other available data on SBC-103.  
Additional dose modifications (including reductions in dose) may be 
considered by the Sponsor after consultation with the PI, based on review 
of safety, tolerability, and response to treatment data.  
Dose frequency (e.g., weekly) modifications may be considered by the 
Sponsor after consultation with the Safety Review Committee (SRC) and 
PI, based on a review of safety, tolerability, and response to treatment 
data.  
 
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NGLU-CL01-T Protocol  
24 February 2016 
With the intent of treating subjects with the lowest dose that is safe and 
tolerable and which has potential for efficacy, dose modification (either 
an increase to 3 mg/kg or a decrease to 0.3 or 1 mg/kg) may be proposed 
for individual subject(s) during the study following ongoing evaluation of 
safety and tolerability data as well as biomarker and response to treatment 
data.  
Safety and efficacy assessments will be conducted at regular intervals 
throughout the study and will include, but not be limited to, blood 
samples for PK analysis and blood and CSF samples for biomarkers. 
At least 4 weeks after a subject’s last dose of SBC-103 is administered in 
this protocol, the subject (or the subject’s parent or caregiver) will receive 
a follow-up phone call to assess adverse events (AEs) and concomitant 
medications unless the subject has a scheduled follow-up study visit.  
During the study the SRC or Sponsor may request a pause in dosing in 
individual, multiple, or all subjects based on review of reported events 
and available data.  Dosing will resume only after the review of data and 
agreement to do so by the PI, Sponsor, and SRC. 
Study Duration 
The total duration of the study is approximately 164 weeks.  This will 
include a Screening period that may last up to 4 weeks, treatment period 
that will last up to 156 weeks, and a 4-week follow-up period after the 
last dose is administered. 
Study Centres 
One centre is expected to participate in this study. 
Number of Subjects 
Planned 
Up to 5 subjects are expected to participate in this study.  
Inclusion and 
Exclusion Criteria 
Inclusion Criteria 
A subject who meets all of the following inclusion criteria will be eligible 
to participate in this study: 
1. Previous participation in the NGLU-CL01 study. 
2. Subject consents or subject’s parent or legal guardian (if 
applicable) grants consent for the subject to participate in the 
study and provides informed consent prior to any study 
procedures being performed.  If the subject is of minor age; 
he/she is willing to provide assent where required per local 
regulations, and if deemed able to do so. 
3. Female subjects who are of childbearing potential at the time of 
consent or who become of childbearing potential during 
participation on study (a) must have a negative urine pregnancy 
test at Screening, (b) cannot be breast feeding, and (c) must use a 
highly reliable method of birth control (expected failure rate less 
than 5% per year) for the duration of the study and for 30 days 
after last dose of SBC-103.  Women may be considered of 
non-childbearing potential if they have not started their menses or 
are surgically sterile (i.e. hysterectomy, bilateral salpingectomy or 
bilateral oophorectomy). 
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NGLU-CL01-T Protocol  
24 February 2016 
4. Male subjects must use a highly reliable method of birth control 
(expected failure rate less than 5% per year) during any sexual 
contact with females of childbearing potential while participating 
in the study and for 30 days following discontinuation from this 
study even if he has undergone a successful vasectomy.  
5. Willingness and ability to comply with protocol requirements to 
the extent that may be expected of a subject with cognitive 
impairment. 
 
Exclusion Criteria: 
A subject who meets any of the following exclusion criteria will be 
ineligible to participate in this study: 
1. Received treatment with gene therapy at any time, or any 
investigational drug (including high dose genistein 
> 150 mg/kg/day) or device intended as a treatment for MPS IIIB 
within 30 days prior to Screening, or is currently being treated in 
another study that involves an investigational drug or device.  
2. Has any internal or non-removable external metal items that may 
present a safety risk for study assessments that utilise magnetic 
fields, or any other medical condition or circumstance in which 
an MRI is contraindicated according to local institutional policy.  
3. Previous hematopoietic stem cell or bone marrow transplant. 
4. Known or suspected hypersensitivity to anaesthesia or the use of 
a sedative is contraindicated for any other reason. 
5. History of poorly controlled seizure disorder. 
6. A bleeding disorder, or any other medical condition or 
circumstance in which a lumbar puncture (for collection of CSF) 
is contraindicated according to local institutional policy. 
7. Known hypersensitivity to eggs.  Subjects at high risk for food 
allergy that may include eggs should be tested according to local 
guidelines.  
8. Other medical conditions or comorbidities (e.g., alanine 
aminotransferase or aspartate aminotransferase > 3x the upper 
limit of normal, confirmed by repeat testing, analysed locally and 
based on the standardised reference range provided in the 
laboratory manual), or other markers of clinically significant liver 
dysfunction (e.g. elevated bilirubin, [with the exception of 
subjects with confirmed Gilberts Disease] confirmed by repeat 
testing, or elevated prothrombin time/international normalised 
ratio confirmed by repeat testing analysed locally and based on 
the standardised reference range provided in the laboratory 
manual) which in the opinion of the Investigator, in consultation 
with the Sponsor, would interfere with study compliance, or 
confound data interpretation. 
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NGLU-CL01-T Protocol  
24 February 2016 
Investigational 
Product, Dose, 
Route, Regimen 
SBC-103 is rhNAGLU manufactured using transgenic Gallus, which 
produce rhNAGLU in egg white.  
Dosing Schedule 
The study will consist of open-label dosing of 1 mg/kg administered by 
IV infusion once qow for at least 12 weeks.  After evaluation of 12 week 
safety, tolerability and PD data in individual subjects a dose increase to 
3 mg/kg may be implemented.  
Subsequent modifications to the dosing schedule, or dose increases or 
decreases, may be considered by the Sponsor, after consultation with the 
PI, for each subject throughout the study based on a review of safety, 
tolerability, and PD data for that subject and other available safety data 
from the SBC-103 program.  
Infusions will be administered every 14 days ± 5 days and must be 
administered at least 10 days apart. 
Reference Therapy 
There is no standard reference therapy against which the investigational 
product is being compared. 
Criteria for 
Evaluation –  
Primary Endpoint  
Primary Endpoint 
The primary endpoint of this study is safety and tolerability of SBC-103 
in subjects with MPS IIIB.  The safety assessments will include the 
following: 
• 
Incidence of AEs, serious adverse events (SAEs), and 
infusion-associated reactions (IARs). 
• 
Changes from baseline in clinical laboratory tests (haematology, 
serum chemistry, and urinalysis) and CSF findings (cell counts, 
glucose, and protein). 
• 
Changes from baseline in 12-lead ECGs. 
• 
Changes in vital signs during and post-infusion, relative to 
pre-infusion values. 
• 
Physical examination findings. 
• 
Use of concomitant medications/therapies. 
• 
Incidence of anti-drug antibodies (ADAs), including 
seroconversion rate, time to seroconversion, and ADA titre by 
time point, peak ADA titre, and ADA titre status 
(positive/negative), and the effect of ADAs on the safety of 
SBC-103, including the relationship between ADA-positive 
subjects and the incidence of IARs. 
Criteria for 
Evaluation –  
Secondary and 
Exploratory 
Endpoints  
Secondary Endpoints 
The secondary endpoints of this study are: 
• 
PK profile of SBC-103 after single and multiple doses as 
measured by: 
• 
Serum maximum concentration (Cmax). 
• 
Time to maximum concentration (Tmax). 
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• 
Area-under-the-concentration-time curve extrapolated to 
infinity (AUC∞). 
• 
Half-life (T1/2). 
• 
Clearance (Cl). 
• 
Apparent volume of distribution at steady state (Vss). 
• 
Onset and magnitude of changes in levels of total HS in CSF, 
serum, and urine following dosing with SBC-103 administered 
IV.  
• 
Change from the NGLU-CL01 study visit to baseline of the 
NGLU-CL01-T study (observational period) in CSF, serum, and 
urine HS in the absence of treatment. 
• 
Changes from the NGLU-CL01 study visit to baseline of the 
NGLU-CL01-T study (observational period) in the following: 
• 
Clinical laboratory tests (haematology, serum chemistry, 
and urinalysis) and CSF findings (cell counts, glucose, 
and protein). 
• 
12-lead ECGs. 
• 
Vital signs. 
• 
Physical examination. 
• 
Use of concomitant medications/therapies. 
• 
Change in neurocognitive and developmental function during the 
NGLU-CL01-T study (on treatment), as determined by Vineland 
Adaptive Behavior Scales, Second Edition (Vineland-II). 
• 
Change in neurocognitive and developmental function from the 
NGLU-CL01 study visit to baseline of the NGLU-CL01-T study 
(observational period), as determined by Vineland-II.  
• 
Change in neurocognitive and developmental function during the 
NGLU-CL01-T study (on treatment) as determined by the 
subject's age-appropriate scores, the Bayley Scales of Infant and 
Toddler Development, Third Edition (BSID-III) or Kaufman 
Assessment Battery for Children, Second Edition (KABC-II), 
Bruininks-Oseretsky Test of Motor Proficiency, Second Edition, 
Brief Form (BOT-2 Brief Form), and Children’s Communication 
Checklist, Second Edition (CCC-2).  
• 
Changes in brain structure, as measured by the relative proportion 
of grey and white matter volume, and indices of microstructural 
integrity, as assessed by MRI of the brain, during the 
NGLU-CL01-T study (on treatment). 
• 
Changes in brain structure, as measured by the relative proportion 
of grey and white matter volume, and indices of microstructural 
integrity, as assessed by MRI of the brain, from the NGLU-CL01 
study visit to baseline of the NGLU-CL01-T study (observational 
period). 
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• 
Changes in BBB integrity during the NGLU-CL01-T study (on 
treatment), as determined by CSF-AI. 
• 
Changes in BBB integrity from the NGLU-CL01 study visit to 
baseline of the NGLU-CL01-T study (observational period), as 
determined by CSF-AI.  
Exploratory Endpoints 
Onset and magnitude of changes in biomarkers, SBC-103 concentration 
in CSF, MPS IIIB disease characteristics and symptoms, and QOL after 
administration of SBC-103:  
• 
Biomarkers: 
• 
Change in non-reducing end (NRE) HS derivatives in 
CSF, serum, and urine. 
• 
Changes in serum ferritin and chitotriosidase. 
• 
Changes in CSF disease-related biomarkers including, 
but not limited to, hepatocyte growth factor, calbindin D, 
Tau, pTau, amyloid β, albumin, immunoglobulin G 
(IgG), glutamic acid, and glycine. 
• 
Changes in glutamic acid and glycine in relation to 
plasma (carrier-mediated excitatory amino acids that are 
markers of transport function). 
• 
Changes in CSF IgG Index ([CSF/serum IgG ratio] 
/ [CSF-AI]).  CSF IgG Index is a measure of IgG 
synthesis within the central nervous system.  
• 
Changes in inflammatory markers in serum. 
• 
Changes in other blood or urine biomarkers of interest 
that are identified during the course of this study based 
on emerging data from the scientific literature or the 
Sponsor’s MPS IIIB development program (if there is 
sufficient sample volume and if local regulations permit). 
• 
Disease characteristics and symptoms, and QOL.  
• 
Coarsening of facial features, as determined by Facial 
Dysmorphology Novel Analysis (FDNA).  
• 
SBC-103 concentration in CSF. 
• 
Changes in measures of sleep disorders or dysfunction, as 
assessed by the Children's Sleep Habits Questionnaire (CSHQ).  
• 
Changes in measures of behaviour, as determined by the 
Sanfilippo Behavior Rating Scale (SBRS). 
• 
Changes in subjective QoL measures, as determined by the Short 
Form Health Survey for Children (SF-10). 
• 
Changes in measures of caregiver QOL, as determined by the 
Zarit Burden Interview (ZBI) 12-item short form. 
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Onset and magnitude of changes in biomarkers and MPS IIIB disease 
characteristics and symptoms from the NGLU-CL01 study visit to 
baseline of the NGLU-CL01-T study (observational period):  
• 
Biomarkers: 
• 
Change in NRE HS derivatives in CSF, serum, and urine. 
• 
Changes in serum ferritin and chitotriosidase. 
• 
Changes in CSF disease-related biomarkers including, 
but not limited to, hepatocyte growth factor, calbindin D, 
Tau, pTau, amyloid β, albumin, IgG, glutamic acid, and 
glycine. 
• 
Changes in glutamic acid and glycine in relation to 
plasma (carrier-mediated excitatory amino acids that are 
markers of transport function). 
• 
Changes in inflammatory markers in serum. 
• 
Disease characteristics and symptoms. 
• 
Coarsening of facial features, as determined by FDNA.  
Statistical Methods 
General Considerations 
Descriptive summary statistics will be provided for baseline 
demographics, disease characteristics, and drug exposure (overall and by 
dose).  Disposition including number of subjects screened, enrolled, and 
percentage of subjects who discontinued from the study, along with 
reasons for discontinuations will be tabulated and described in listings. 
Continuous data will be summarised using descriptive statistics (number 
of subjects, mean, standard deviation, median, minimum, and maximum) 
and, where appropriate, graphic representation and 2-sided 95% 
confidence interval (CI) estimates; categorical data will be summarised 
by number of subjects, proportions, and 2-sided 95% CI estimates where 
possible. 
The sample size of up to 5 subjects is based on clinical and not statistical 
consideration.  The data from this study, along with data from other 
NGLU studies, will inform future development decisions for SBC-103.  
Analysis Datasets 
The Full Analysis Set (FAS), defined as all subjects for whom informed 
consent has been obtained, who have a confirmed diagnosis of MPS IIIB, 
and who have received any amount of SBC-103, will be used to 
summarise safety and tolerability data.  
Analysis will include datasets based on the following study periods: 
• 
Observational Period: the NGLU-CL01 study visit to baseline 
(pre-dose) of the NGLU-CL01-T study. 
• 
On-Treatment Period: baseline of the NGLU-CL01-T study to 
end of the NGLU-CL01-T study. 
• 
Overall Study (Observational+On-Treatment Period): the 
NGLU-CL01 study visit to end of the NGLU-CL01-T study. 
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To facilitate the descriptive summarisation of the above described  data  
sets, data contained in the NGLU-CL01 study database for these subjects, 
including medical history, demographics, concomitant medications, 
physical examination, safety laboratory assessments, CSF, serum, and 
urine HS, biomarkers, Vineland-II, and data from structural and diffusion 
MRI, will be copied and entered in the NGLU-CL01-T study database.  
On-study data from subjects in the NGLU-CL01 study for endpoints 
including NAGLU enzyme activity, concomitant medications, physical 
examination, vital signs, weight, ECG, Vineland-II, haematology, clinical 
chemistry, urinalysis, CSF, serum and urine HS, serum albumin, serum 
ferritin and chitotriosidase, plasma glutamic acid and glycine, CSF: 
calbindin, Tau, pTau, albumin, IgG, glutamic acid and glycine, routine 
analysis – cell counts, glucose and protein, and structural and diffusion 
MRI that are contained in the NGLU-CL01 study database will also be 
copied and entered in the NGLU-CL01-T study database. 
Also, any additional assessments (e.g., neurocognitive and developmental 
assessments, laboratory data including serum and urine HS, biomarker 
data, and concomitant medication) available in these subjects since the 
NGLU-CL01 study visit until baseline of the NGLU-CL01-T study will 
be copied and entered in the NGLU-CL01-T database. 
All available observational period data from subjects enrolled in the 
NGLU-CL01 study for assessments also performed in the NGLU-CL01-T 
study will be copied and entered in the NGLU-CL01-T study database to 
facilitate analysis of changes in these assessments over the untreated and 
treated periods. 
Details of the planned analyses will be provided in the statistical analysis 
plan (SAP).  
Safety Analysis 
Descriptive statistics will be computed for safety parameters as per FAS, 
as appropriate.  Number and percentage of subjects who discontinued 
from the study because of AEs, will be tabulated across doses; severity 
and frequency of AEs and SAEs will also be tabulated across doses.  All 
other safety data will be provided in listings.  Baseline (as described 
above), within study, end-of-study, and change from baseline in physical 
examination findings, ECG, clinical laboratory values, and vital signs will 
be summarised by dose.  
The number and proportion (percentage) of subjects with measurable 
antibodies to SBC-103 will be displayed.  In addition, incidence of IARs 
will be tabulated by dose and overall.  Medications to treat IARs, 
including any pre-treatment medications, will also be presented by dose 
and for the entire study period.  SBC-103 infusions in which the rate was 
slowed or discontinued due to IARs will be detailed in a separate data 
listing. 
Additional statistical evaluations may be carried out for select endpoints, 
if warranted.  All baseline and safety data collected during the study will 
be included in subject listings.  
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Pharmacokinetic Analysis  
PK analysis will be performed using non-compartmental analysis method.  
Graphs of PK concentration over time will be generated for each subject 
and also for all subjects by dose group.  Serum PK parameter (Cmax, Tmax, 
AUC∞, T1/2, Cl and Vss) assessments will be summarised descriptively for 
each subject, as well as for each dose group, using non-compartmental 
analysis method.  SBC-103 concentration in CSF will be summarised at 
available time points.  Additional analysis of PK data, including 
assessment of the impact of ADA, may be performed as appropriate.  
Further details will be provided in the PK section of the SAP or in a 
separate clinical pharmacology analysis plan. 
Pharmacodynamic/Efficacy Analyses  
Parameters describing total HS and exploratory disease-related 
biomarkers including NRE HS derivatives, will be provided in listings 
and may be tabulated as described previously. 
Parameters describing disease characteristics and symptoms, and QOL of 
subjects with MPS IIIB, including neurodegeneration (MRI), CSF-AI, 
neurocognitive and QOL (Vineland-II, BSID-III, KABC-II, BOT-2 Brief 
Form, CSHQ, CCC-2, SBRS, SF-10, ZBI 12-item) will be provided in 
listings and may be tabulated as appropriate.  
Pharmacodynamic, disease characteristics and symptoms, and QOL 
outcomes analyses will be performed for the FAS.  Observed 
measurements and changes or percent changes from baseline in HS and 
NRE HS derivatives and disease-related biomarkers will be summarised 
overall and by dosing regimen for each time point.  Change in relative 
proportion of grey and white matter volume and microstructural integrity 
will be summarised descriptively.  Scores and changes from baseline in 
neurocognitive function, disease characteristics and symptoms, and QOL 
questionnaires will be summarised by time point.  
Graphs of actual values and changes over time may be created as 
appropriate.  
Parameters describing facial features of subjects with MPS IIIB will be 
provided in listings and may be tabulated as appropriate.  
Further details of the pre-specified analyses will be provided in the SAP. 
Summaries of Data Prior to Study Completion   
Interim data may be summarised for presentation to Regulatory 
Authorities or to the scientific community to facilitate development of 
SBC-103. 
Details of the pre-specified statistical analyses will be provided in a 
separate SAP. 
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LIST OF ABBREVIATIONS 
Abbreviation 
Definition 
ADA 
Anti-drug antibody 
AE 
Adverse event 
ALT 
Alanine aminotransferase 
AST 
Aspartate aminotransferase 
AUC∞ 
Area-under-the-concentration-time curve extrapolated to 
infinity 
BBB 
Blood brain barrier 
BOT-2 
Bruininks-Oseretsky Test of Motor Proficiency, Second 
Edition 
BSID-III 
Bayley Scales of Infant and Toddler Development, Third 
Edition 
CCC-2 
Children’s Communication Checklist, Second Edition 
CFR 
Code of Federal Regulations 
CI 
Confidence interval 
Cl 
Clearance 
Cmax 
Maximum concentration 
CNS 
Central nervous system 
CRF 
Case report form 
CSF 
Cerebrospinal fluid 
CSF-AI 
Cerebrospinal fluid/serum albumin index 
CSHQ 
Children’s Sleep Habits Questionnaire 
CSR 
Clinical study report 
ECG 
Electrocardiogram 
ERT 
Enzyme replacement therapy 
EU 
European Union 
FAS 
Full Analysis Set 
FDNA 
Facial Dysmorphology Novel Analysis 
FIH 
First-in-human 
GAG 
Glycosaminoglycan 
GCP 
Good Clinical Practice 
HED 
Human equivalent dose 
HGF 
Hepatocyte growth factor 
HS 
Heparan sulphate 
IAR 
Infusion-associated reaction 
ICH 
International Conference on Harmonisation 
IEC 
Independent Ethics Committee 
IgE 
Immunoglobulin E 
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Abbreviation 
Definition 
IgG 
Immunoglobulin G 
IgM 
Immunoglobulin M 
IMP 
Investigational Medicinal Product 
IND 
Investigational New Drug 
INR 
International normalised ratio 
IRB 
Institutional Review Board 
IT 
Intrathecal 
IV 
Intravenous(ly) 
KABC-II 
Kaufman Assessment Battery for Children, Second 
Edition  
LLN 
Lower limit of normal 
LSD 
Lysosomal storage disorder 
M6PR 
Mannose-6-phosphate receptor 
MMR 
Macrophage mannose receptor 
MPS 
Mucopolysaccharidoses 
MPS I 
Mucopolysaccharidosis I 
MPS II 
Mucopolysaccharidosis II 
MPS IIIB, Sanfilippo B 
Mucopolysaccharidosis III, type B 
MRI 
Magnetic resonance imaging 
NAGLU 
Alpha-N-acetylglucosaminidase 
NOAEL 
No-observed-adverse-effect level 
NRE 
Non-reducing end 
NVI 
Non-verbal index 
PAD 
Pharmacologically active dose 
PD 
Pharmacodynamic(s) 
PET 
Positron emission tomography 
PI 
Principal Investigator 
PK 
Pharmacokinetic(s) 
PT 
Prothrombin time 
QOL 
Quality of life 
qow 
Every other week 
qw 
Once every week 
rhNAGLU 
Recombinant human alpha-N-acetylglucosaminidase 
SAE 
Serious adverse event 
SAP 
Statistical analysis plan 
SBRS 
Sanfilippo Behavior Rating Scale 
SF-10 
Short Form Health Survey for Children  
sMRI 
Structural magnetic resonance imaging 
SOA 
Schedule of Assessments 
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Abbreviation 
Definition 
SRC 
Safety Review Committee 
T1/2 
Half-life 
Tmax 
Time to maximum concentration 
ULN 
Upper limit of normal 
US 
United States (of America) 
Vineland-II 
Vineland Adaptive Behavior Scales, Second Edition 
Vss 
Apparent volume of distribution at steady state 
ZBI 
Zarit Burden Interview 12-item short form 
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TABLE OF CONTENTS 
APPROVAL SIGNATURE PAGE .....................................................................................2 
INVESTIGATOR STATEMENT .......................................................................................3 
CLINICAL STUDY SYNOPSIS .........................................................................................4 
LIST OF ABBREVIATIONS ............................................................................................14 
1 
INTRODUCTION .................................................................................................23 
1.1 
Background ................................................................................................23 
1.1.1 
Mucopolysaccharidosis Type IIIB ..............................................23 
1.1.2 
Medical Rationale for Enzyme Replacement Therapy 
for MPS IIIB ...............................................................................24 
1.2 
Investigational Medicinal Product (SBC-103)...........................................25 
1.3 
Nonclinical Data ........................................................................................25 
1.4 
Clinical Data ..............................................................................................27 
1.4.1 
Assessment of Neurodegeneration by Structural and 
Diffusion MRI.............................................................................28 
1.4.2 
Assessment of Blood Brain Barrier Integrity .............................29 
1.5 
Dose Rationale and Risk/Benefits .............................................................30 
1.5.1 
Study Dose Rationale..................................................................30 
1.5.2 
Risk/Benefit Assessment ............................................................31 
2 
Study Objectives ....................................................................................................34 
2.1 
Primary Objective ......................................................................................34 
2.2 
Secondary Objectives.................................................................................34 
2.3 
Exploratory Objectives ..............................................................................34 
3 
INVESTIGATIONAL PLAN ................................................................................35 
3.1 
Overall Design and Plan of the Study ........................................................35 
3.2 
Rationale for Study Design ........................................................................37 
3.3 
Rationale for Dose and Escalation Timing ................................................38 
3.3.1 
Decision for Continued Dosing after the First Dose 
in Each Subject ...........................................................................38 
3.3.2 
Decision for Dose Escalation Within a Subject after 
12 Weeks of Treatment ...............................................................39 
3.3.3 
Additional Dose Adjustment During the Study ..........................39 
3.4 
Study Endpoints .........................................................................................39 
3.4.1 
Primary Endpoint ........................................................................39 
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3.4.2 
Secondary Endpoints ..................................................................40 
3.4.3 
Exploratory Endpoints ................................................................41 
4 
Study Population ....................................................................................................43 
4.1 
Target Population .......................................................................................43 
4.2 
Number of Subjects....................................................................................43 
4.3 
Eligibility Criteria ......................................................................................43 
4.3.1 
Inclusion Criteria ........................................................................43 
4.3.2 
Exclusion Criteria .......................................................................43 
4.4 
Concomitant Medications and Treatments ................................................44 
4.5 
Discontinuation of Subjects .......................................................................45 
4.5.1 
Premature Withdrawal from Study Participation........................45 
4.5.2 
Procedures for Discontinuation ..................................................45 
4.6 
Subject Replacement Policy ......................................................................45 
4.7 
Subject Re-screening .................................................................................45 
5 
Study Procedures ...................................................................................................46 
5.1 
Study Assessments .....................................................................................46 
5.1.1 
Informed Consent/Assent ...........................................................46 
5.1.2 
Subject Eligibility .......................................................................46 
5.1.3 
Medical History ..........................................................................46 
5.1.4 
Demographic Information...........................................................47 
5.1.5 
Physical Examination .................................................................47 
5.1.6 
Height and Weight ......................................................................47 
5.1.7 
Vital Signs and Electrocardiogram .............................................47 
5.1.8 
Neurocognitive, Developmental and Quality of Life 
(QOL) Assessments ....................................................................48 
5.2 
Clinical Laboratory Assessments ...............................................................52 
5.2.1 
Routine Assessments and Biomarkers ........................................52 
5.2.2 
Facial Dysmorphology Novel Analysis ......................................59 
5.2.3 
General Anaesthesia/Sedation ....................................................59 
5.2.4 
Structural and Diffusion MRI .....................................................60 
5.2.5 
Telephone Calls ..........................................................................60 
6 
Study Treatments ...................................................................................................61 
6.1 
Treatments Administered ...........................................................................61 
6.1.1 
Dose Adjustments .......................................................................61 
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6.1.2 
Non-compliance with Study Treatment ......................................61 
6.2 
Stopping Rules ...........................................................................................61 
6.2.1 
Stopping Rules in Individual Subjects ........................................61 
6.2.2 
Stopping Rules for Multiple Subjects .........................................63 
6.3 
Description of SBC-103 .............................................................................63 
6.4 
Method for Assigning Subjects to Treatment Groups ...............................63 
6.5 
Storage and Disposition of SBC-103 .........................................................63 
6.5.1 
Receipt of Drug Supplies ............................................................63 
6.5.2 
Storage ........................................................................................63 
6.5.3 
Disposition ..................................................................................64 
6.6 
Preparation and administration of Study Drug ..........................................64 
6.6.1 
Preparation of Study Drug ..........................................................64 
6.6.2 
Administration of Study Drug ....................................................64 
6.7 
Blinding of SBC-103 .................................................................................65 
6.8 
Destruction of SBC-103 .............................................................................65 
7 
Assessment of Safety .............................................................................................66 
7.1 
Adverse Events and Laboratory Abnormalities .........................................66 
7.1.1 
Clinical Adverse Events..............................................................66 
7.1.2 
Laboratory Test Abnormality .....................................................68 
7.1.3 
Adverse Events of Special Interest (Infusion-
Associated Reactions) .................................................................68 
7.2 
Handling of Safety Parameters ..................................................................71 
7.2.1 
Serious Adverse Events and Infusion-Associated 
Reactions (Immediately reportable to the Sponsor) ...................71 
7.2.2 
Adverse Event Reporting Period ................................................71 
7.2.3 
Treatment and Follow-up of Adverse Events .............................71 
7.2.4 
Follow-up of Abnormal Laboratory Test Values .......................71 
7.2.5 
Pregnancy....................................................................................71 
7.3 
Recording of Adverse Events ....................................................................73 
7.4 
Reporting of Serious Adverse Events, Infusion-Associated 
Reactions, and Unanticipated Problems ....................................................73 
7.4.1 
Investigator Reporting: Notifying the Sponsor ...........................73 
7.4.2 
Investigator Reporting: Notifying the IRB/IEC..........................74 
7.4.3 
Sponsor Reporting: Notifying Regulatory Authorities ...............74 
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7.4.4 
Sponsor Reporting: Notifying Participating 
Investigators ................................................................................74 
7.5 
Independent Safety Review Committee (SRC) .........................................75 
8 
Statistical Plan ........................................................................................................76 
8.1 
General Considerations ..............................................................................76 
8.2 
Determination of Sample Size ...................................................................76 
8.3 
Analysis Sets ..............................................................................................76 
8.4 
Safety Analysis ..........................................................................................77 
8.5 
Pharmacokinetic Analysis ..........................................................................77 
8.6 
Pharmacodynamic/Efficacy Analyses .......................................................77 
8.7 
Summaries of Data Prior to Study Completion .........................................78 
9 
Subject Data Handling and Record Keeping .........................................................79 
9.1 
Confidentiality ...........................................................................................79 
9.2 
Source Documents .....................................................................................79 
9.3 
Case Report Forms .....................................................................................79 
9.4 
Records Retention ......................................................................................79 
10 
Study Monitoring, Auditing, and Inspecting .........................................................80 
10.1 
Study Monitoring Plan ...............................................................................80 
10.2 
Auditing and Inspecting .............................................................................80 
11 
Ethical Considerations ...........................................................................................81 
12 
Clinical Study Report and Data Disclosure ...........................................................82 
13 
References ..............................................................................................................83 
14 
Appendices .............................................................................................................88 
14.1 
Appendix A: Schedule of Study Assessments ...........................................89 
14.2 
Appendix B: NGLU-CL01-T Neurocognitive, Developmental 
and QOL Assessments .............................................................................104 
 
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LIST OF TABLES IN THE TEXT 
Table 1: 
Clinical Laboratory Tests ..................................................................................... 54 
Table 2: 
Pharmacokinetic Sampling .................................................................................. 57 
Table 3: 
Assessment of Causality ...................................................................................... 67 
Table 4: 
Guidelines for the Management of Infusion-associated Reactions 
(IARs) .................................................................................................................. 69 
Table 5: 
Acceptable Contraceptive Methods Which May Be Considered 
Highly Effective ................................................................................................... 72 
 
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LIST OF FIGURES IN THE TEXT 
Figure 1: 
NGLU-CL01-T Study Schematic ........................................................................ 36 
 
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1 INTRODUCTION 
This document is a protocol for a human research study.  This study will be conducted 
according to Good Clinical Practice (GCP), as defined by the International Conference on 
Harmonisation (ICH) and the ethical principles underlying European Union (EU) 
Directives 2001/20/EC and 2005/28/EC; the United States (US) Code of Federal 
Regulations (CFR), Title 21, Parts 50 and 312 (21 CFR 50, 21 CFR 312); and all 
applicable government regulations and institutional research policies and procedures. 
1.1 Background 
1.1.1 Mucopolysaccharidosis Type IIIB 
The mucopolysaccharidoses (MPS) are a group of lysosomal storage disorders (LSDs) 
caused by a deficiency of enzymes catalysing the degradation of glycosaminoglycans 
(GAGs, also known as mucopolysaccharides).  The majority of LSDs share a propensity 
for a chronic and progressive disease course with multi-system involvement, although 
each MPS may present with unique clinical features (Neufeld, 2012, The Metabolic and 
Molecular Bases of Inherited Disease).  The type III MPS, referred to as Sanfilippo 
syndromes, are clinically very similar and demonstrate somatic complications that are 
commonly observed in the other MPS; however, MPS III is also characterised by severe 
degeneration of the central nervous system (CNS) which dominates the clinical picture 
(Heron, 2011, Am J Met Genet A; Neufeld, 2012, The Metabolic and Molecular Bases of 
Inherited Disease).  The MPS III syndromes are all characterised by the accumulation of 
heparan sulphate (HS) due to mutations in 1 of the 4 enzymes required for the 
degradation of HS.  Heparan N-sulfatase is deficient in type A, alpha-
N-acetylglucosaminidase (NAGLU) in type B, acetyl-CoA:alpha-glucosaminide 
acetyltransferase in type C, and N-acetyl glucosamine 6-sulfatase in type D.  
Mucopolysaccharidosis III, type B (MPS IIIB), also known as Sanfilippo B syndrome 
(OMIM #252920), is a very rare LSD associated with significant morbidity and mortality 
in affected patients.  Birth prevalence estimates for MPS IIIB, based on the available 
literature and defined as the number of diagnosed cases per 100,000 live births over 
1 year, range from 0.12 to 0.78 per 100,000 (Nelson, 1997, Hum Genet; Poorthuis, 1999, 
Hum Genet; Nelson, 2003, Am J Med Genet; Pinto, 2004, Eur J Hum Genet; Baehner, 
2005, J Inherit Metab Dis; Heron, 2011, Am J Met Genet A).  Regional variances may 
exist with respect to prevalence or the relative proportion of MPS IIIB to the other MPS 
subtypes.  The disease is caused by mutations in the NAGLU gene.  MPS IIIB patients 
typically have a normal to near-normal development during the first 2 years of life, 
followed by a slowing and full stagnation of development at around 3 to 4 years, and 
finally regression of cognitive capabilities.  Patients usually become fully dependent on 
care early in their teenage years.  Death typically occurs at the end of the second or the 
beginning of the third decade of life.  However, as with other LSDs, a broader spectrum 
of disease severity may exist.  An attenuated form of MPS IIIB has been described in a 
Dutch cohort of patients in which the progression of some disease manifestations appears 
to be slower, but progression still occurs with loss of functions such as speech and 
walking (Valstar, 2010, J Inherit Metab Dis; Wijburg, 2013, Acta Paediatr).  Patients 
with the attenuated phenotype may have a stable intellectual disability for many years.  
These patients also appear to have a longer preservation of motor functions and may live 
into adulthood (Valstar, 2011, Orphanet J Rare Dis). 
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There are currently no safe or effective therapies for the treatment of MPS IIIB.  
Supportive therapies are used in an attempt to mitigate some of the effects of the disease.  
Options for management of clinical symptoms are limited, and include the use of CNS 
medications to control seizures, behavioural problems, and sleep problems. 
1.1.2 Medical Rationale for Enzyme Replacement Therapy for MPS 
IIIB 
The medical rationale of enzyme replacement therapy (ERT), and specifically the 
potential medical benefit of intravenously (IV)-administered recombinant enzyme for 
MPS IIIB, is supported by the successful use of ERT, with favourable benefit/risk 
profiles, to treat other LSDs.  Furthermore, nonclinical data have demonstrated the 
benefit of substrate (HS) reduction in the CNS on CNS manifestations in LSDs, including 
the MPS III syndromes, and nonclinical data have also demonstrated the ability of 
IV-administered SBC-103, a recombinant human alpha-N-acetylglucosaminidase 
(rhNAGLU), to reduce substrate levels in the liver and the brain in the MPS IIIB animal 
model following once weekly (qw) as well as once every other week (qow) dosing.  In 
addition, the medical rationale for additional clinical study of SBC-103 is supported by 
available safety, tolerability and preliminary pharmacodynamics data in the currently 
ongoing first-in-human (FIH) study, NGLU-CL02 (see Section 1.4).  
The successful treatment of Gaucher’s disease with placental glucocerebrosidase in the 
1990s, with the follow-on enzyme produced by recombinant deoxyribonucleic acid 
technology, established the medical value and long-term safety of ERT for LSDs (Barton, 
1990, Proc Natl Acad Sci USA; Barton, 1991, N Engl J Med).  The scientific concepts 
established by these initial studies have now been extended to a broad range of disorders 
including: Pompe disease (van der Beek, 2006, Acta Neurol Belg), Fabry disease 
(Wilcox, 2004, Am J Hum Genet), MPS I (Wraith, 2004, J Pediatr), and MPS II 
(Muenzer, 2007, Mol Genet Metabol).  As a result, there is now extensive clinical 
experience with long-term ERT in subjects with LSDs (Desnick, 2012, Annu Rev 
Genomics Hum Genet). 
Early intervention with IV-administered ERT in other LSDs with CNS manifestations in 
sibling pair studies appears to modify disease progression.  In MPS II, 2 siblings, aged 
3 years and 4 months, respectively, initiated treatment by IV administration of the ERT 
idursulphase and outcomes were compared (Tajima, 2013, Mol Genet Metab).  At the 
start of treatment, the older brother showed typical neurodegenerative features of MPS II, 
including intellectual disability.  After 34 months of treatment with idursulphase, his 
somatic disease was stable or improved; however, he continued to decline cognitively.  
By comparison, after 32 months of treatment with idursulphase, his younger brother 
manifested only exudative otitis media, but remained free from most of the somatic 
features that appeared in his brother at the same age.  Of relevance to considerations for 
MPS IIIB, although the younger brother's developmental quotient trended downward 
over time to just below the normal range, his intellectual disability at 3 years of age was 
not as severe as the brother who started treatment later. 
Nonclinical studies with a variety of experimental therapeutic modalities have 
demonstrated that substrate reduction in the CNS in LSDs including the MPS III 
syndromes, is accompanied by improvements in CNS manifestations.  (Kim, 2009, Eur J 
Neurosci; Ou, 2014, Mol Genet Metab; Higuchi, 2012, Mol Genet Metab).  In addition, 
brain NAGLU enzyme levels required to maintain normal phenotype in wild type or 
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heterozygote carriers are substantially lower (> 50×) than enzyme activity levels in 
normal liver (Li, 1999, Proc Natl Acad Sci USA).  Furthermore, nonclinical studies with 
SBC-103 have demonstrated that IV administration of SBC-103 following qw as well as 
qow dosing reduces substrate levels in both systemic tissues (liver/kidney) and in the 
brain in the MPS IIIB animal model (Leavitt, 2013, LDN WORLD Conference; 
SBC103-P013 [data on file]). 
In summary, this knowledge and the precedent established for other LSDs, available 
safety, tolerability and preliminary pharmacodynamics (PD) data in the currently ongoing 
FIH study, (NGLU-CL02), provide a rationale that ERT with SBC-103 may benefit 
patients with MPS IIIB.  
This interventional study will provide data on the effects of treatment with SBC-103, as 
well as observational data in the same study subjects from NGLU-CL01.  
Developing a more complete understanding of the pharmacokinetics (PK), and 
PD/efficacy relationship of SBC-103 via this study and other studies in the SBC-103 
Phase I/II program will further inform the development of SBC-103 as an ERT for MPS 
IIIB, a disease with devastating CNS complications. 
1.2 Investigational Medicinal Product (SBC-103) 
SBC-103, rhNAGLU, is manufactured using transgenic Gallus, produced in egg white.  
SBC-103 is a highly purified recombinant human enzyme intended to be used as ERT for 
the treatment of MPS IIIB. 
The rhNAGLU transgene encodes the same amino acid sequence as reported for the 
native human enzyme (Weber, 1996, Hum Mol Genet; Zhao, 1996, Proc Natl Acad Sci 
USA).  Purified rhNAGLU is a glycoprotein that contains up to 7 potential N-linked 
glycosylation sites.  Specific glycans, including mannose-6-phosphate containing 
glycans, are thought to be critical for biodistribution and uptake of SBC-103 into the 
lysosomes of key target cells involved in pathogenesis of the disease.  NAGLU catalyses 
the hydrolysis of N-acetylglucosamine (GlcNAc)alpha(1-4))n to (GlcNAc alpha(1 4))n-1 
and 2 (acetylamino)-2-deoxy-beta-D-glucopyranose.  
SBC-103 is supplied as an aqueous solution which is essentially free of visible foreign 
particulate matter. 
1.3 Nonclinical Data 
In vitro studies with SBC-103 using NAGLU-deficient human fibroblasts have 
demonstrated efficient mannose-6-phosphate dependent cellular uptake with correction of 
intracellular enzyme deficiency.  In addition, mannose receptor-mediated uptake of 
SBC-103 by cells of macrophage lineage has also been demonstrated. 
Several nonclinical studies demonstrated a reduction in total HS in NAGLU-deficient 
mice following qw as well as qow IV administration of SBC-103 (4 to 6 repeated doses 
of 0.3 to 27 mg/kg) for up to 6 weeks.  The results demonstrated dose-dependency.  
Reductions in HS concentrations were accompanied by increases in measured NAGLU 
concentration.  Following SBC-103 administration, clinical signs such as lethargy, and 
ataxia were observed.  The majority of the observations occurred after the third or fourth 
dose.  These observations were not considered to be directly related to the 
pharmacological effect of SBC-103.  In these studies, hypersensitivity reactions, which 
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were sometimes fatal, were attributed to the repeat IV administration of a human 
recombinant protein to a heterologous species and are consistent with published literature 
(SBC103-P004, SBC103-P007, SBC103-P009, SBC103-P010, Hovland, 2007, Toxicol 
Pathol; Flaherty, 2012, Toxicological Sciences; Finkelman, 2007, J Allergy Clin 
Immunol; Khodoun, 2011, PNAS).  Pre-treatment with diphenhydramine was used to 
minimise the effects, but did not completely block the reactions.  This finding is 
consistent with the existence of two distinct pathways of anaphylaxis in mice; either by 
immunoglobulin E (IgE)-mediated histamine release from mast cells or by 
immunoglobulin G (IgG)-mediated platelet-activating factor release from macrophages 
(Finkelman, 2007, J Allergy Clin Immunol). 
In the study SBC103-P010, the potential for CNS uptake and activity following IV 
administration of SBC-103 was evaluated in NAGLU-deficient mice. These mice were 
administered SBC-103 at doses of 0.3, 1, 3, 5, or 10 mg/kg qw for 4 weeks. A statistically 
significant decrease in HS was demonstrated in both brain and liver following IV dosing 
with a pharmacologically active dose (PAD; the lowest dose tested with the intended 
pharmacologic activity) established at a dose level of 3 mg/kg (0.075 mg dose for a 25 
gram mouse) IV in the brain and 0.3 mg/kg (0.0075 mg dose) in the liver (SBC103-
P010). 
Several biodistribution studies were performed in rats and monkeys using 124I-labelled 
SBC-103 and 89Zr-labelled SBC-103 administered IV (SBC103-K004, SBC103-K005).  
All studies in the rat and monkey demonstrated IV delivery of SBC-103 to the brain and 
showed that the major fraction of the injected dose accumulated in the liver.   
Consistent with ICH guidelines (ICH S6 [Preclinical Safety Evaluation of 
Biotechnology-Derived Pharmaceuticals] and Addendum to ICH S6 [Preclinical Safety 
Evaluation of Biotechnology-Derived Pharmaceuticals S6{R1}]) the potential toxicity of 
SBC-103 was evaluated in two species, the Sprague-Dawley rat (4 weeks) and the 
Cynomolgus monkey (4 weeks and 3 months).  Since monkeys of 0.5 to 3 years of age 
correspond to a human child of 2 to 12 years (Barrow, 2007, FDA News; Tassisnari, 
2013, Wiley), and the MPS IIIB patient population includes children, juvenile 
Cynomolgus monkeys were studied in the 3-month toxicology study of SBC-103.  The 
monkey is considered the most relevant species for the toxicological assessment of 
SBC-103. 
The potential toxicity of SBC-103 was evaluated in Sprague-Dawley rats following 
repeated IV doses of SBC-103 (1, 3, or 10 mg/kg qw) for 4 weeks with a 2-week 
recovery period (SBC103-T007).  Overall, the IV administration of SBC-103 qw at a 
dose of 10 mg/kg resulted in transient clinical observations of decreased activity, 
decreased muscle tone and/or prostration generally after the third and fourth doses.  
Microscopically, findings of minimal to mild inflammation were observed in the liver at 
all doses and in the heart and lungs of individual animals at 10 mg/kg.  Most of these 
findings showed partial reversibility at the end of the recovery period.  The incidence of 
anti-SBC-103 IgG antibodies in samples collected at study termination was 100% in 
SBC-103 treated animals (irrespective of the dose) and no anti-SBC-103 antibody 
formation was detected in any control animals.  Based on the observed 
vascular/perivascular inflammation in the heart and lungs in the Sprague-Dawley rat, a 
no-observed-adverse-effect level (NOAEL) was established at a dose level of 3 mg/kg. 
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The potential toxicity of SBC-103 was evaluated in Cynomolgus monkeys following 
repeated IV doses of SBC-103 (1, 3, 10 or 20 mg/kg qw) for 4 weeks with a 2-week 
recovery period (SBC103-T008). There were no changes in clinical observations, 
macroscopic, organ weight or microscopic findings that were considered 
SBC-103-related. The incidence of anti-SBC-103 IgG antibodies in samples collected at 
study termination was approximately 80% in SBC-103 treated animals (irrespective of 
the dose). No anti-SBC-103 antibody formation was detected in any control animals. The 
administration of SBC-103 at these IV dose levels was well tolerated. Consequently, the 
NOAELs in this study were considered to be 10 mg/kg/dose qw and 20 mg/kg/dose qow. 
The potential toxicity of SBC-103 was evaluated in juvenile Cynomolgus monkeys 
following repeated qw IV doses of 3 and 10 mg/kg or qow at 20 mg/kg during a 3-month 
dosing period with a 4-week recovery period (SBC103-T009).  There were no 
SBC-103-related mortalities and no macroscopic, organ weight, or microscopic changes 
that were considered SBC-103-related.  Transient clinical signs were noted but there were 
no correlating findings in any of the other parameters evaluated.  The transient clinical 
signs included, but were not limited to, decreased activity, hunched posture, lying on 
side, abnormal gait, uncoordination, excessive scratching/cage manipulation and/or 
repetitive behaviour.  The presence of anti-SBC-103 IgG antibodies was confirmed in 
87%, 60% and 87% animals from 3 mg/kg, 10 mg/kg, and 20 mg/kg dose respectively 
and no animals in the control group were confirmed positive for anti-SBC-103 antibody.  
Antibody titres did not increase with dose level administered.  Consequently, the 
NOAELs were considered to be 10 mg/kg/dose (qw) and 20 mg/kg/dose (qow) in this 
study. 
Overall, the findings in two different toxicology species and data from NAGLU disease 
model at relevant IV doses suggest a hypersensitivity reaction to a foreign protein with 
some species differences. This is generally supported by the high incidence of 
anti-SBC-103 IgG antibodies in SBC-103 treated animals across species, and 
laboratory/clinical indicators of inflammation. While this is consistent with previous 
studies, it should be noted that nonclinical studies are not predictive of potential 
immunogenicity of humans (Garcia, 2007, Mol Genet Metab; Hemsley, 2007, Mol Genet 
Metab; McVie-Wylie, 2008, Mol Genet Metab; Hovland, 2007, Toxicol Pathol; Flaherty, 
2012, Toxicological Sciences; Finkelman, 2007, J Allergy Clin Immunol; Khodoun, 2011, 
PNAS; Brinks, 2011, Pharm Res; Ponce, 2009, Reg Toxicol Pharmacol). Additionally, it 
is important to note that high-dose IV SBC-103 resulted in microscopic findings in both 
the rat and Cynomolgus monkey in numerous tissues, presumably reflecting an 
exaggerated hypersensitivity reaction to a human protein. 
Refer to the Investigator Brochure for further information regarding the nonclinical 
studies with SBC-103. 
1.4 Clinical Data  
An FIH study with SBC-103 (NGLU-CL02) is currently enrolling subjects.  This study is 
entitled: A Phase I/II Open Label Study in MPS IIIB Subjects to Investigate the Safety, 
Pharmacokinetics, and Pharmacodynamics/Efficacy of SBC-103 Administered 
Intravenously (NGLU-CL02).  Approximately 9 MPS IIIB subjects (≥ 2 and < 12 years of 
age) will participate in the study which will investigate the safety, PK, and PD/efficacy of 
SBC-103 administered IV.  Approximately 9 subjects will be treated, 3 subjects in each 
of 3 sequential dose groups (0.3, 1, and 3 mg/kg SBC-103).  The total duration of the 
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NGLU-CL02 study is approximately 164 weeks.  This includes a screening period that 
will last up to 4 weeks, an initial study treatment period that includes 24 weeks on 
therapy and a 4-week period of time off therapy (Part A), an extended treatment period 
that will last up to 128 weeks (Part B), and a 4-week follow-up period after the last dose 
is administered.   
As of 30 April 2015, the NGLU-CL02 study is currently ongoing and 3 patients have 
been enrolled and treated with SBC-103 in each of the first 2 cohorts.  The available 
safety data for Cohort 1 (0.3 mg/kg SBC-103) and Cohort 2 (1.0 mg/kg SBC-103) have 
been reviewed by the Safety Review Committee (SRC) and the Sponsor.  The SRC has 
approved continued dosing of subjects in Cohorts 1 and 2.  The available preliminary 
safety data from the study to date show that SBC-103 has been administered without any 
remarkable safety observations that have led to changes in how the product is 
administered or how patients are monitored for safety.  Preliminary PD data show a 
decrease from baseline in serum HS.  
In addition, there is extensive human experience with ERTs for the treatment of other 
LSDs including: Gaucher’s, Pompe, and Fabry diseases, MPS I and II (see Section 1.1.2).  
While these diseases have distinct clinical manifestations and demonstrate differences in 
the targeting and biological effects of the ERT, there are relevant data from these studies 
that inform the use of investigational products in this class.  Substrate reduction, as 
evidenced by decreases in cerebrospinal fluid (CSF) GAG levels, has been demonstrated 
following intrathecal (IT) dosing in MPS IIIA and MPS II in ongoing clinical studies 
(Breen, 2013, ASHG, Wijburg, 2013, Acta Paediatr, Wijburg, 2013, ACMHGM, 
Muenzer, 2014, LDN poster).  No new significant safety findings have emerged to date 
from these studies based on publically available data.  Most of the adverse events (AEs) 
associated with clinical use of ERTs are comprised of infusion-associated reactions 
(IARs), which typically occur either during, or within 2 hours following completion of 
the infusion.  Given the propensity for IARs with ERT administration, measures have 
been incorporated in this protocol to minimise risk to subject safety from such events (see 
Section 7.1.3). 
1.4.1 Assessment of Neurodegeneration by Structural and Diffusion 
MRI 
Neurodegenerative diseases such as Alzheimer’s disease, multiple sclerosis, and multiple 
system atrophy are characterised by slow progressive loss of neurons in the CNS, which 
leads to deficits in specific brain functions.  Neurodegenerative diseases usually extend 
over a decade, and the actual onset of neurodegeneration may precede clinical 
manifestations by many years.  MPS III is also a neurodegenerative disorder, and it 
shares similar characteristics with the more traditional neurodegenerative diseases.  
In recent years, multimodal neuroimaging has become the most widely used approach to 
evaluate the pathophysiology of the diseased brain and these methods allow 
quantification of single or combined weight magnetic resonance imaging (MRI) 
parameters, to describe neurodegenerative processes.  Measurement of MRI parameters 
sensitive to complementary tissue characteristics (e.g., volume atrophy, iron deposition, 
and microstructural damage) has great potential for evaluating pathological changes in 
neurologic/psychiatric diseases.  Structural and diffusion MRI can provide indices of grey 
and white matter volume reductions and microstructural and white matter connection 
integrity, and may be used to assess neurodegeneration.  
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Structural magnetic resonance imaging (sMRI) obtains high resolution structural images 
that are useful for brain morphometry investigation.  In sMRI scans, two types of brain 
tissue - grey matter and white matter - are clearly perceptible and distinguishable.  Thus, 
sMRI allows for simultaneous analysis of these two tissues, which have most often been 
analysed separately in studies of both healthy and diseased brain (Preuss, 2005, Schizophr 
Res; Mitelman, 2007, Neuroimage; Hazlett, 2008, Schizophr Res).  This is an important 
advance, given the complex relationship between grey and white matters.  Grey matter is 
composed predominantly of cell bodies, while white matter is composed mainly of axons 
connecting cell bodies; both tissues are highly integrated within cerebral cortex and 
subcortical structures, and it has been proposed that spatial expansion of one could be 
associated with contraction of the other (Pfefferbaum, 1994, Arch Neurol; Cicchetti, 
2006, Ann N Y Acad Sci).  Therefore, it is reasonable to expect that morphometric 
changes in one tissue may result in, or be related to, disturbance of the other (Xu, 2012, 
Neurol Res Int). 
Diffusion MRI is routinely employed for the diagnosis and management of stroke and 
other diseases (e.g., tumours, multiple sclerosis, and epilepsy).  Diffusion MRI is a 
quantitative imaging technique that is sensitive to changes in the microstructure of 
tissues, meaning that it is influenced by alterations in cell packing, cell size and 
membrane permeability to water.  Most biomarkers derived by this modality are therefore 
sensitive to subtle alterations in tissue structure and are good biomarker candidates for 
early detection of pathological changes and for monitoring subtle changes over time.  
Accordingly, diffusion MRI has proven useful for obtaining information about the 
underlying mechanisms of neurodegenerative disorders (e.g., Alzheimer’s disease and 
other dementias, Parkinson’s disease, Huntington’s disease, amyotrophic lateral sclerosis, 
hereditary ataxias), and has potential utility to confirm diagnoses and predict prognoses 
and therapeutic response in patients with neurodegenerative disease.  
A structural and diffusion MRI will, therefore, be performed at baseline to assess 
neurodegeneration prior to treatment with SBC-103 and will also be used as a 
comparison to evaluate changes after extended treatment with SBC-103.  This structural 
and diffusion MRI, performed at baseline, will also be used as a comparison to evaluate 
changes from the time of the MRI performed for the NGLU-CL01 study (natural history 
data). 
1.4.2 Assessment of Blood Brain Barrier Integrity 
In addition, blood brain barrier (BBB) integrity will be assessed by calculating the 
CSF/serum albumin index (CSF-AI) before and after treatment with SBC-103.  The BBB 
partly prevents proteins from peripheral blood from entering the brain and the CSF, 
resulting in markedly lower concentrations of proteins in CSF than in serum (Davson, 
1969, The Cerebrospinal Fluid Handbook of Neurochemistry).  Albumin in CSF 
originates in the serum as it is synthesised only in the liver (Fishman, 1980, Adv Neurol).  
The relationship between the concentration of albumin in CSF and serum, that is the 
CSF-AI, is the most common method for evaluating BBB function (Ganrot, 1974, Clin 
Chem; Tibbling, 1977, Scand J Clin Lab Invest).  The CSF-AI performed at baseline will 
also be used as a comparison to evaluate changes from the time of the CSF-AI 
assessment performed for the NGLU-CL01 study (natural history data). 
The Sponsor has conducted a non-interventional/observational study in MPS IIIB entitled 
Evaluation of Blood Brian Barrier Integrity and Structural Abnormalities in MPS IIIB 
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Patients Using Multimodal Magnetic Resonance Imaging (Study NGLU-CL01, data on 
file).  In this study, BBB integrity and structural brain abnormalities were evaluated in 5 
MPS IIIB patients using CSF-AI and multimodal MRI.  Top-line data indicate that in 
MPS IIIB patients, there is evidence of mild BBB leakage based on the CSF-AI findings; 
these findings are reflected in the absence of clear evidence for BBB leakage on MRI.  
MRI volumetric measurements showed global and tissue-specific atrophy in these 
patients. 
The 5 subjects who participated in the NGLU-CL01 study will be eligible to participate 
in NGLU-CL01-T. 
1.5 Dose Rationale and Risk/Benefits 
1.5.1 Study Dose Rationale 
This study consists of open label dosing, with an opportunity for dose escalation after a 
minimum of 12-weeks dosing.  The intent is for 2 dose levels of SBC-103 (1 mg/kg and 
3 mg/kg) to be administered by IV infusion once qow.  If subjects are unable to tolerate 
these doses, the dose may be reduced from 3 mg/kg to 1.0 mg/kg or from 1.0 mg/kg to 
0.3 mg/kg.  All subjects will be dosed with a starting level of 1 mg/kg. 
The dose scaling across species for SBC-103 has used body weight.  This is based on 
reviews of the approach taken for other therapeutic proteins (Tang, 2004, J Pharm Sci; 
Mahmood, 2004, J Pharm Sci), particularly ERTs such as Elaprase®.  
The selection of the starting dose for SBC-103 of 1 mg/kg administered through IV 
infusion is based on available human safety, tolerability and PD data from the currently 
ongoing FIH study in MPS IIIB subjects (NGLU-CL02); PK/PD modelling; the 
pharmacological effects of SBC-103 in a highly relevant NAGLU-deficient nonclinical 
mouse model of MPS IIIB following qw as well as qow IV dosing; and the NOAEL 
defined in the Cynomolgus monkey (including a 3-month study in juvenile Cynomolgus 
monkey) and the Sprague-Dawley rat when SBC-103 was administered through IV 
infusion.  
Overall, as of 30 April 2015, there have been no remarkable safety observations with the 
doses administered in the first 2 cohorts of the NGLU-CL02 study (0.3 mg/kg and 
1 mg/kg) that have led to changes in how the product is administered or how subjects are 
monitored for safety. 
Pharmacological effects were seen in a highly relevant nonclinical mouse model of 
MPS IIIB (NAGLU deficient) with IV bolus doses of 0.3, 1, 3, 5, or 10 mg/kg of 
SBC-103 qw for 4 weeks (SBC103-P010).  Total HS in the brain was reduced following 
IV administration at 3 mg/kg dose establishing the PAD at 3 mg/kg IV (human equivalent 
dose [HED] = 3 mg/kg based on body weight).  HS in the liver was reduced following IV 
administration at 0.3 mg/kg establishing the PAD in the liver at 0.3 mg/kg 
(HED = 0.3 mg/kg based on body weight).  Similar pharmacological effects were also 
seen in NAGLU-deficient mice after qow IV bolus doses of SBC-103.  PK/PD modelling 
data supports a qow dose interval.  In addition, modelling data predict that the PAD for 
both brain and liver following IV infusion will be lower than the anticipated PAD 
following the IV bolus injection. 
In the Sprague-Dawley rat, a NOAEL was defined as 3 mg/kg based on the observed 
vascular/perivascular inflammation in the heart and lungs; this represents a 3.0 fold 
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margin over the proposed starting dose (1 mg/kg) on a mg/kg basis.  Transient clinical 
signs attributable to SBC-103 infusions were observed at a dose of 10 mg/kg, generally 
after the third and fourth doses (see Section 1.3).  Given the nature of the findings and the 
frequent presence of anti-SBC-103 antibodies, these likely reflect hypersensitivity to the 
administration of a human protein to a rat.   
In the juvenile Cynomolgus monkeys, which are considered the most relevant species, 
transient clinical signs attributable to SBC-103 IV infusions were observed (see 
Section 1.3). However, there were no correlating findings in any of the other parameters 
evaluated. A NOAEL was defined as 10 mg/kg/dose qw and 20 mg/kg/dose qow. This 
represents a 10 and 20 fold safety margin over the proposed starting dose (1 mg/kg) on a 
mg/kg body weight basis.   
Preclinical and human PD data after qow dosing, PK modelling data and affinity data for 
SBC-103 binding to the macrophage mannose receptor (MMR)- and the 
mannose-6-phosphate receptor (M6PR)-mediated delivery to lysosomes supports the qow 
dosing frequency that is planned in this study.  Based on available human safety, 
tolerability and PD data from the currently ongoing FIH study (NGLU-CL02), PK/PD 
modelling, the planned starting dose of 1 mg/kg is expected to provide possible 
therapeutic effect in this Phase I/II study.  The increment between the two doses in this 
study is approximately 3 fold, allowing for the assessment of safety, tolerability, PK, and 
PD/efficacy in MPS IIIB patients across a relevant 3 fold range of doses on a mg/kg basis 
(1 and 3 mg/kg). 
1.5.2 Risk/Benefit Assessment 
As discussed in Section 1.1.1, MPS IIIB is a very rare disease that is associated with 
significant morbidity and mortality in affected patients.  Currently, there are no safe or 
effective therapies for MPS IIIB. 
Nonclinical studies conducted in the Sprague-Dawley rat and Cynomolgus monkey 
(including a 3-month study in juvenile monkeys) by IV route were generally well 
tolerated at the doses planned in this study.  Minimal/mild microscopic findings were 
noted in the liver in some animals, and these changes appear to be limited and were seen 
at doses higher than planned in this study.  Clinical observations such as decreased 
activity, drowsiness/sluggishness, decreased muscle tone, abnormal gait, and repetitive 
behaviour were noted generally after the third or fourth dose of SBC-103.  These 
observations generally lasted for a short period of time and did not have any relationship 
with several tests performed using the blood and tissues (see Section 1.3).  These findings 
along with anti-SBC-103 IgG antibodies are suggestive of hypersensitivity, which is not 
unexpected when administering a recombinant human protein to a heterologous species.  
It should be noted that nonclinical studies are not predictive of potential immunogenicity 
of humans (Brinks, 2011, Pharm Res; Ponce, 2009, Reg Toxicol Pharmacol).  
Subjects in this clinical study will be monitored closely to identify any potential safety 
concerns, including monitoring liver parameters and antibody development.  See 
Sections 5.2 and 6.2 for more details regarding laboratory assessments and subject 
stopping rules, respectively.  
Extensive clinical experience with approved ERTs for other LSD indications is relevant 
for risk evaluation of SBC-103.  The main AEs associated with administration of 
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approved ERTs (including but not limited to Cerezyme®, VPRIV®, Fabrazyme®), are 
related to IARs (Cerezyme® prescribing information, 2011; VPRIV® prescribing 
information, 2013; Fabrazyme® prescribing information, 2010; Desnick, 2012, Annu Rev 
Genomics Hum Genet).  The observed IARs are usually mild and can be managed by 
changes in infusion rate and/or the administration of antipyretics and antihistamines.  
While severe infusion reactions, including anaphylaxis, and serious adverse events 
(SAEs) related to ERT administration rarely occur, medications and equipment for the 
treatment of hypersensitivity reactions will be available for immediate use.  They include, 
but are not limited to, oxygen, acetaminophen, antihistamines (e.g., diphenhydramine, 
parenteral and oral), corticosteroids, epinephrine (adrenaline), and cardiopulmonary 
resuscitation devices.  Anti-drug antibodies (ADAs) have also been reported with 
approved ERTs and may be associated with altered response to treatment and/or 
increased risk of IARs.  
As described in Section 1.1.2 and Section 1.3, pharmacologic activity has been observed 
following qw and qow IV dosing of SBC-103 in NAGLU-deficient mice including 
increased enzyme activity and reduction of the accumulated substrate (HS).  Although 
examination of the effects of long-term IV dosing on CNS manifestations in the mouse 
model has not been possible because of clinical symptoms related to the apparent 
hypersensitivity, there is a substantial body of data linking substrate reduction in brain 
tissue in MPS IIIB and other MPS disorders with improvements in CNS manifestations 
(Calias, 2012, PloS One; Hemsley, 2009, Int J Clin Pharmacol Ther). 
The design of this study is based on available human safety, tolerability and PD data from 
the currently ongoing FIH study (NGLU-CL02); in vivo pharmacology data in a relevant 
disease model supporting the potential for CNS activity following qw and qow IV 
administration (SBC103-P004, SBC103-P007, SBC103-P009, SBC103-P010, 
SBC103-P013 [data on file]), with supportive information from in vivo pharmacology 
data in a relevant disease model supporting the potential for CNS activity following 
IV/IT administration (SBC103-P011); tissue specific differences in NAGLU enzyme 
levels required to maintain normal phenotype (Li, 1999, Proc Natl Acad Sci USA); 
positron emission tomography (PET)/computed tomography investigations of the PK of 
radiolabelled SBC-103 in non-human primates (IV administration and IT administration) 
indicating access to the CNS following IV administration (SBC103-K004); and PK 
modelling data and affinity data for SBC-103 binding to MMR and M6PR.  
As described in Section 1.1.2, early IV administration of enzyme to an MPS II patient 
partially stabilised cognitive function and prevented the somatic complications seen in his 
affected older brother who started treatment later in life (Tajima, 2013, Mol Genet 
Metab).  There is extensive clinical evidence supporting the safety of ERT with known 
AEs for which to monitor.  Furthermore, based on available human safety, tolerability 
and PD data from the currently ongoing FIH study (NGLU-CL02), there is a reasonable 
basis to conclude that extended dosing of SBC-103 in this study may have beneficial 
effects on disease activity in MPS IIIB patients.  The data obtained on the effects of 
treatment with SBC-103  in this study, as well as the observational data in the same study 
subjects from NGLU-CL01, combined with data from the other Phase I/II studies with 
SBC-103, will guide and inform the development of SBC-103. 
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In addition to potential risks associated with Investigational Medicinal Product (IMP) 
administration, this study entails procedures that incur incremental risks that are critical 
for a thorough evaluation of the effects of SBC-103 on MPS IIIB.  Given the devastating 
complications associated with MPS IIIB and the inability to obtain important disease 
relevant information using other approaches, the risks are considered to be acceptable in 
this patient population.  Risk assessment for selected study procedures are described 
below. 
1.5.2.1 
Risk Assessment for Selected Study Procedures 
Anaesthesia 
Disease progression in patients with MPS IIIB is associated with cognitive decline and 
behavioural disturbances.  Conscious subjects will not be able to comply with study 
assessment requirements, including maintenance of appropriate positioning during MRI 
and lumbar puncture.  Thus subjects will receive general anaesthesia prior to, and during 
the MRI procedure (and lumbar puncture, as appropriate).  Sedation of children is 
associated with risks of hypoxaemia, inadequate sedation, and failed sedation.  General 
anaesthesia is a safe alternative to facilitate MRI scans in children perceived to be at 
increased risk for sedation-related AEs as for those with a history of failed sedation 
(Malviya, 2000, Br J Anaesth). 
Lumbar Puncture 
A lumbar puncture is necessary to determine if SBC-103 administration is able to reduce 
HS within the CNS.  A subject may experience discomfort or bruising of the skin at the 
site where the needle was inserted (similar to blood collection).  Mild headache is 
reported in less than 10% of cases. 
In rare instances, more severe headaches may occur, which usually respond quickly to 
treatment with over-the-counter pain relievers.  A very rare occurrence is infection from 
the sample collection itself.  The risk for such infection is less than that of a regular blood 
draw.  
Subjects will receive general anaesthesia prior to the lumbar puncture, if clinically 
appropriate.  See above regarding risks associated with anaesthesia. 
Magnetic Resonance Imaging 
The primary risks of MRI in patients with MPS IIIB are those associated with the 
administration of anaesthesia and the potential interference of MRI with metallic foreign 
objects in the body.  Subjects will be screened by MRI personnel, according to local 
guidelines, for any medical contraindications to MRI, including the presence of metallic 
foreign bodies in the brain or eye or cardiac pacemaker.  See above regarding risks 
associated with anaesthesia. 
In conclusion, the risks to subjects in this study from both exposure to IMP and the 
required procedures are reasonable in relation to the seriousness of the disease and the 
anticipated benefits and/or knowledge that can be expected from the results.  Appropriate 
measures have been incorporated into the protocol to minimise risk and to monitor 
subject safety. 
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2 STUDY OBJECTIVES 
2.1 Primary Objective 
To evaluate the safety and tolerability of IV administration of SBC-103 in previously 
studied, SBC-103 treatment-naïve subjects with mucopolysaccharidosis III, type B 
(MPS IIIB, Sanfilippo B) who participated in the NGLU-CL01 study.  The NGLU-CL01 
study was a non-interventional study that evaluated structural brain abnormalities and 
BBB integrity by MRI and CSF-AI. 
2.2 Secondary Objectives 
• To characterise the PK profile of SBC-103 administered IV. 
• To determine the effects of dosing with SBC-103 administered IV on the levels, 
onset and magnitude of changes in levels of total HS in CSF, serum, and urine. 
• To evaluate the PD/efficacy of treatment with SBC-103 administered IV as 
measured by neurocognitive and developmental function, changes in brain 
structure, and BBB integrity. 
• To evaluate change from the NGLU-CL01 study visit to baseline of the 
NGLU-CL01-T study (observational period) in the following where available: 
clinical laboratory tests including HS in CSF, in serum, and in urine, 
electrocardiograms (ECGs), physical examination, vital signs, concomitant 
medications, neurocognitive and developmental function, brain structure and 
microstructural integrity, and BBB integrity.  
2.3 Exploratory Objectives 
• To examine the onset and magnitude of  changes in biomarkers, SBC-103 
concentration in CSF, MPS IIIB disease characteristics and symptoms, and 
quality of life (QOL) after IV administration of SBC-103. 
• To evaluate the change in biomarkers and MPS IIIB disease characteristics and 
symptoms from the NGLU-CL01 study visit to baseline of the NGLU-CL01-T 
study (observational period). 
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3 INVESTIGATIONAL PLAN 
3.1 Overall Design and Plan of the Study 
This study (NGLU-CL01-T) is designed to evaluate the safety and tolerability of IV 
administration of SBC-103 for the treatment of MPS IIIB.  Up to 5 subjects, previously 
enrolled in the NGLU-CL01 study at 1 centre in the United Kingdom, will be eligible to 
participate in this study.  This interventional study will provide data on effects of 
treatment with SBC-103, and observational data in the absence of treatment in the same 
study subjects from study NGLU-CL01 to baseline of NGLU-CL01-T will be included in 
the analysis.  
All subjects will initially receive 1 mg/kg SBC-103 IV qow.  All subjects will be 
monitored in an in-patient setting for safety and tolerability for 24 hours following the 
first dose of SBC-103.  The decision to continue dosing in each subject will be made by 
the Sponsor in consultation with the Principal Investigator (PI) after review of 24-hour 
safety data from that subject and available safety data from all other subjects. 
With the intent of treating subjects with the lowest dose that is safe and tolerable and 
which has potential for efficacy, dose modification (either an increase to 3 mg/kg or a 
decrease to 0.3 or 1 mg/kg) may be proposed for individual subject(s) throughout the 
study, following ongoing evaluation of safety and tolerability data as well as biomarker 
and response to treatment data.  Dose reductions can be made at any point during the 
study, but dose escalation cannot occur before completion of at least 12 weeks of dosing.  
After a minimum of 12 weeks of dosing at 1 mg/kg, a review of safety, tolerability, and 
PD data from each subject will be conducted by the Sponsor in consultation with the PI to 
determine whether it is appropriate to escalate the dose to 3 mg/kg for that individual 
subject.  Dose frequency (e.g., weekly) modifications may also be considered by the 
Sponsor after consultation with the SRC and PI, based a review of safety, tolerability, and 
response to treatment data and with consideration of any other available data on 
SBC-103.  
Safety, PK and PD/efficacy assessments will be performed in all subjects throughout the 
study.   
At least 4 weeks after a subject’s last dose of SBC-103 is administered in this study, the 
subject (or the subject’s parent or caregiver) will receive a follow-up phone call to assess 
AEs and concomitant medications unless the subject has a scheduled follow-up study 
visit. 
As indicated in Figure 1, the planned total duration of the study is approximately 
164 weeks.  This will include a Screening period that will last up to 4 weeks, an initial 
study treatment period of 12 weeks at 1 mg/kg, 144 weeks of treatment at up to 3 mg/kg, 
and a 4-week follow-up period after the last dose is administered. 
 
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Figure 1: 
NGLU-CL01-T Study Schematic
NGLU-CL01-T Study 
 
 
NGLU-CLO1-T Screening, up to 4 weeks 
SBC-103 Dosing 
at up to 3 mg/kg for up to 144 weeks 
Key:  
qow = every other week; MRI = magnetic resonance imaging. 
 
Follow-up 4 weeks 
Observational Period  
(~18 months) 
Treatment Period  
(3 years) 
Dose escalation to a maximum of 3 mg/kg weekly is permitted. Dose reduction to a 
minimum of 0.3 mg/kg qow permitted in the event of tolerability issues. 
SBC-103 
Dosing 
Day 0  
SBC-103 
Dosing 
qow  
1 mg/kg 
for 12 
weeks 
NGLU-CL01 
Study 
(Including  
MRI and 
neurocognitive 
and biomarker 
assessments)  
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3.2 Rationale for Study Design 
This study (NGLU-CL01-T) will be conducted in MPS IIIB patients who participated in 
the NGLU-CL01 study.  The NGLU-CL01 study was a single time point evaluation of 
BBB integrity by Dynamic Contrast-Enhanced MRI and CSF-AI, and assessment of 
structural brain abnormalities by Structural and Diffusion MRI.  
All subjects in the NGLU-CL01 study were ≥ 5 years of age with rapidly progressing 
MPS IIIB.  All subjects had a definitive diagnosis of MPS IIIB, as determined by 
documented deficiency in NAGLU enzyme activity of < 10% of the lower limit of 
normal (LLN) or documented functionally-relevant mutations in both alleles of the 
NAGLU gene. 
The five subjects who participated in the NGLU-CL01 study, entered the study between 
27 December 2013 and 06 May 2014.  The NGLU-CL01-T study provides an opportunity 
to follow up these subjects and understand both the longitudinal stability and progression 
of important disease parameters (e.g., MRI and CSF-AI), over approximately 12 to 
18 months between these assessments in addition to the specific study objectives of this 
interventional study with SBC-103. 
This study will evaluate safety and tolerability of IV administration of SBC-103 in up to 
5 subjects with MPS IIIB  for up to 3 years (156 weeks). 
Safety and tolerability is the primary objective of this study but PD/efficacy assessments 
will be conducted at regular intervals throughout the study and will include, but not be 
limited to, CSF, blood and urine samples for biomarkers including HS, BBB integrity, 
neurocognitive and developmental function assessments, structural and diffusion MRI, 
and routine clinical assessments.  To reduce the burden on subjects, and as there was no 
clear evidence of BBB leakage shown by Dynamic Contrast-Enhanced MRI from the 
NGLU-CL01 study, BBB integrity will be assessed by CSF-AI in the NGLU-CL01-T 
study. 
Safety will be assessed by monitoring AEs, safety haematology and clinical chemistry, 
vital signs, and presence of ADA.  Stopping rules have been put in place for IARs and for 
liver enzyme abnormalities.  Regular data reviews, including after the first dose in each 
subject prior to continuing dosing, prior to consideration of a dose escalation after 
12 weeks, and throughout the study have been incorporated to minimise risk, to monitor 
subject safety and to assess PD data (see Sections 3.1 and 3.3).  
In light of the paediatric patient population intended for enrolment, it is important (and 
often required by regulation) to provide some prospect for benefit with the investigational 
treatment.  For an ERT for a chronic disease such as MPS IIIB, extended treatment is 
generally required to offer any prospect of benefit.  Nonclinical data, including a 3 month 
toxicology study in juvenile Cynomolgus monkeys, supports both chronic dosing and  
intra-subject dose escalation based on safety, tolerability and evidence of biological 
activity.  Therefore, this study design includes chronic dosing as well as intra-subject 
dose escalation, to assess the long term safety, tolerability and effects of treatment with 
SBC-103 on the somatic and neurological components of MPS IIIB.   
Based on the experience with neurodegenerative diseases, it is anticipated that clinical 
response to treatment, specifically on the neurological component of the disease, may not 
be observed sooner than 6 months after initiating treatment with SBC-103.  For this 
reason this study is designed with efficacy evaluations with MRI and neurocognitive and 
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developmental assessments starting after 6 months of treatment.  Effect of treatment on 
the biomarker HS is expected to be observed earlier and is assessed in CSF from 
12 weeks and from 4 weeks in serum and urine.   
There are emerging data on the advantages of earlier treatment with ERTs in other MPS 
subtypes particularly with regard to impact on disease manifestations which are 
eventually irreversible (Tajima, 2013, Mol Genet Metab; Gabrielli, 2010, Pediatrics; 
McGill, 2010, Clin Genet; Furujo, 2011, Mol Genet Metab).  Given the inevitable 
neurodegenerative manifestations of MPS IIIB, early intervention is an important 
consideration to avoid irreversible disease progression and, therefore, paediatric subjects 
have been included in this study. 
Data from a nonclinical disease model (NAGLU-deficient mice) demonstrate reductions 
in brain HS and increases in brain enzyme activity following IV dosing of SBC-103.  
Evaluating the accumulation of HS in the CSF via lumbar puncture  in this clinical study 
and in the NGLU-CL02 study will provide important insights into the utility of SBC-103 
administered IV in MPS IIIB patients. 
Important manifestations of MPS IIIB disease include developmental and cognitive delay 
and regression as well as sleep and behaviour disturbances.  This study includes periodic 
assessments to evaluate any changes in these parameters after treatment with SBC-103 
administered by IV infusion.   
As noted in Section 1.5.1, structural and diffusion MRI can provide indices of grey and 
white matter volume reductions and microstructural and white matter connection 
integrity.  For these reasons, structural and diffusion MRI will be used to assess 
neurodegeneration and any changes after treatment with SBC-103 administered by IV 
infusion.   
For the PD/efficacy variable MRI and for neurocognitive assessments, changes from the 
NGLU-CL01 study visit to baseline of the NGLU-CL01-T study will be evaluated 
(observational period). 
Changes in BBB integrity will be evaluated by measuring CSF-AI after treatment with 
SBC-103; these data will enable evaluation of changes from time points when CSF-AI 
was measured during the NGLU-CL01 study.  
The data obtained on the effects of treatment with SBC-103  in this study, as well as the 
observational data in the same study subjects from NGLU-CL01, combined with data 
from the other Phase 1/2 studies with SBC-103 will guide and inform the development of 
SBC-103. 
3.3 Rationale for Dose and Escalation Timing 
In this study all subjects will initially be administered 1 mg/kg SBC-103 qow by IV 
infusion, see Section 1.5.1 for dose justification.   
3.3.1 Decision for Continued Dosing after the First Dose in Each 
Subject 
Due to the relatively limited experience with SBC-103 in humans (as of 30 April 2015), 
24-hour in-patient safety monitoring following the first dose for each subject will be 
conducted in this study.  The Sponsor and PI will review safety data from the first dose in 
each subject prior to continuation of dosing in that subject. 
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3.3.2 Decision for Dose Escalation Within a Subject after 12 Weeks of 
Treatment 
Considering the potential for immunogenicity with a protein product, evaluation of the 
safety and tolerability following multiple rather than single doses prior to escalation is 
important (see Section 1.3).  Therefore, the decision to escalate to 3 mg/kg  will be made 
by the Sponsor and PI only after review of safety, tolerability and PD data from each 
subject after they have completed a minimum of 12 weeks of treatment.  This data review 
will include HS data from CSF evaluation at 12 weeks and the HS data from serum and 
urine samples every 4 weeks, along with multiple dose safety and tolerability data. 
3.3.3 Additional Dose Adjustment During the Study 
Additional dose modifications (including reductions in dose) may be considered by the 
Sponsor after consultation with the PI, based on review of safety and tolerability data as 
well as biomarker and response to treatment data. 
Dose modification of increasing the dose to 3 mg/kg can only occur after 12 weeks of 
treatment and review of data as described above. 
Dose modification of decreasing the dose to 1 mg/kg or 0.3 mg/kg can occur for 
individual subjects at any point in the study to manage subject safety and/or response to 
treatment data.  The independent SRC for the SBC-103 program will continue to provide 
oversight of subject safety through periodic reviews of safety data.  Dose frequency (e.g., 
weekly) modifications may be considered by the Sponsor after consultation with the SRC 
and PI, based on a review of safety, tolerability, and response to treatment data.   
During the study the SRC, Sponsor or PI may request a pause in dosing in individual, 
multiple or all subjects based on review of reported events and available data.  Dosing 
will resume only after the review of data and agreement to do so by the SRC, Sponsor 
and PI. 
3.4 Study Endpoints 
3.4.1 Primary Endpoint 
The primary endpoint of this study is safety and tolerability of SBC-103 in subjects with 
MPS IIIB.  The safety assessments will include the following: 
• Incidence of AEs, SAEs, and IARs. 
• Changes from baseline in clinical laboratory tests (haematology, serum chemistry, 
and urinalysis) and CSF findings (cell counts, glucose, and protein). 
• Changes from baseline in 12-lead ECGs. 
• Changes in vital signs during and post-infusion, relative to pre-infusion values. 
• Physical examination findings. 
• Use of concomitant medications/therapies. 
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• Incidence of ADAs, including seroconversion rate, time to seroconversion, and 
ADA titre by time point, peak ADA titre, and ADA titre status 
(positive/negative), and the effect of ADAs on the safety of SBC-103, including 
the relationship between ADA-positive subjects and the incidence of IARs. 
3.4.2 Secondary Endpoints 
The secondary endpoints of this study are:  
• PK profile of SBC-103 after single and multiple doses as measured by: 
• Serum maximum concentration (Cmax). 
• Time to maximum concentration (Tmax). 
• Area-under-the-concentration-time curve extrapolated to infinity (AUC∞). 
• Half-life (T1/2). 
• Clearance (Cl). 
• Apparent volume of distribution at steady state (Vss). 
• Onset and magnitude of changes in levels of total HS in CSF, serum, and urine 
following dosing with SBC-103 administered IV.  
• Change from the NGLU-CL01 study visit to baseline of the NGLU-CL01-T study 
(observational period) in CSF, serum, and urine HS in the absence of treatment. 
• Changes from the NGLU-CL01 study visit to baseline of the NGLU-CL01-T 
study (observational period) in the following: 
• Clinical laboratory tests (haematology, serum chemistry, and urinalysis) 
and CSF findings (cell counts, glucose, and protein). 
• 12-lead ECGs. 
• Vital signs. 
• Physical examination. 
• Use of concomitant medications/therapies. 
• Change in neurocognitive and developmental function during the NGLU-CL01-T 
study (on treatment), as determined by Vineland Adaptive Behavior Scales, 
Second Edition (Vineland-II). 
• Change in neurocognitive and developmental function from the NGLU-CL01 
study visit to baseline of the NGLU-CL01-T study (observational period), as 
determined by Vineland-II. 
• Change in neurocognitive and developmental function during the NGLU-CL01-T 
study (on treatment) as determined by the subject's age-appropriate scores, the 
Bayley Scales of Infant and Toddler Development, Third Edition (BSID-III) or 
Kaufman Assessment Battery for Children, Second Edition (KABC-II), 
Bruininks-Oseretsky Test of Motor Proficiency, Second Edition, Brief Form 
(BOT-2 Brief Form), and Children’s Communication Checklist, Second Edition 
(CCC-2).  
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• Changes in brain structure, as measured by the relative proportion of grey and 
white matter volume, and indices of microstructural integrity, as assessed by MRI 
of the brain during the NGLU-CL01-T study (on treatment). 
• Changes in brain structure, as measured by the relative proportion of grey and 
white matter volume, and indices of microstructural integrity, as assessed by MRI 
of the brain, from the NGLU-CL01 study visit to baseline of the NGLU-CL01-T 
study (observational period). 
• Changes in BBB integrity during the NGLU-CL01-T study (on treatment), as 
determined by CSF-AI. 
• Changes in BBB integrity from the NGLU-CL01 study visit to baseline of the 
NGLU-CL01-T study (observational period), as determined by CSF-AI. 
3.4.3 Exploratory Endpoints 
Onset and magnitude of changes in biomarkers, SBC-103 concentration in CSF, MPS 
IIIB disease characteristics and symptoms, and QOL after administration of SBC-103 (on 
treatment):  
• Biomarkers: 
• Change in NRE HS derivatives in CSF, serum, and urine. 
• Changes in serum ferritin and chitotriosidase. 
• Changes in CSF disease-related biomarkers including, but not limited to, 
hepatocyte growth factor, calbindin D, Tau, pTau, amyloid β, albumin, 
IgG, glutamic acid, and glycine. 
• Changes in glutamic acid and glycine in relation to plasma 
(carrier-mediated excitatory amino acids that are markers of transport 
function). 
• Changes in CSF IgG Index ([CSF/serum IgG ratio] / [CSF-AI]).  CSF IgG 
Index is a measure of IgG synthesis within the CNS.     
• Changes in inflammatory markers in serum. 
• Changes in other blood or urine biomarkers of interest that are identified 
during the course of this study based on emerging data from the scientific 
literature or the Sponsor’s MPS IIIB development program (if there is 
sufficient sample volume and if local regulations permit). 
• Disease characteristics and symptoms, and QOL.  
• Coarsening of facial features, as determined by Facial Dysmorphology Novel 
Analysis (FDNA).  
• SBC-103 concentration in CSF. 
• Changes in measures of sleep disorders or dysfunction, as assessed by the 
Children’s Sleep Habits Questionnaire (CSHQ).  
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• Changes in measures of behaviour, as determined by the Sanfilippo Behavior 
Rating Scale (SBRS). 
• Changes in subjective QoL measures, as determined by the Short Form Health 
Survey for Children (SF-10). 
• Changes in measures of caregiver QoL, as determined by the Zarit Burden 
Interview (ZBI) 12-item short form. 
Onset and magnitude of changes in biomarkers and MPS IIIB disease characteristics and 
symptoms from the NGLU-CL01 study visit to baseline of the NGLU-CL01-T study 
(observational period):  
• Biomarkers: 
• Change in NRE HS derivatives in CSF, serum, and urine. 
• Changes in serum ferritin and chitotriosidase. 
• Changes in CSF disease-related biomarkers including, but not limited to, 
hepatocyte growth factor, calbindin D, Tau, pTau, amyloid β, albumin, 
IgG, glutamic acid, and glycine. 
• Changes in glutamic acid and glycine in relation to plasma 
(carrier-mediated excitatory amino acids that are markers of transport 
function). 
• Changes in inflammatory markers in serum. 
• Disease characteristics and symptoms. 
• Coarsening of facial features, as determined by FDNA. 
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4 STUDY POPULATION 
4.1 Target Population 
The target population for this study is male and female subjects with documented MPS 
IIIB between 2 and 12 years old, who participated in the NGLU-CL01 study. 
4.2 Number of Subjects 
Up to 5 subjects may be recruited to this study.  
4.3 Eligibility Criteria 
4.3.1 Inclusion Criteria 
Subjects must meet all of the following criteria to be eligible for participation in this 
study: 
1. Previous participation in the NGLU-CL01 study. 
2. Subject consents or subject’s parent or legal guardian (if applicable) grants consent 
for the subject to participate in the study and provides informed consent prior to any 
study procedures being performed.  If the subject is of minor age, he/she is willing to 
provide assent where required per local regulations, and if deemed able to do so. 
3. Female subjects who are of childbearing potential at the time of consent or who 
become of childbearing potential during participation on study (a) must have a 
negative urine pregnancy test at Screening, (b) cannot be breast feeding, and (c) must 
use a highly reliable method of birth control (expected failure rate less than 5% per 
year) for the duration of the study and for 30 days after last dose of SBC-103. For 
acceptable contraceptive methods, refer to Section 7.2.5 of the protocol.Women may 
be considered of non-childbearing potential if they have not started their menses or 
are surgically sterile (i.e. hysterectomy, bilateral salpingectomy or bilateral 
oophorectomy). 
4. Male subjects must use a highly reliable method of birth control (expected failure rate 
less than 5% per year) during any sexual contact with females of childbearing 
potential while participating in the study and for 30 days following discontinuation 
from this study even if he has undergone a successful vasectomy. For acceptable 
contraceptive methods, refer to Section 7.2.5 of the protocol. 
5. Willingness and ability to comply with protocol requirements to the extent that may 
be expected of a subject with cognitive impairment. 
4.3.2 Exclusion Criteria 
Subjects meeting any of the following criteria will not be eligible for participation in this 
study: 
1. Received treatment with gene therapy at any time, or any investigational drug 
(including high dose genistein > 150 mg/kg/day) or device intended as a treatment for 
MPS IIIB within 30 days prior to Screening, or is currently being treated in another 
study that involves  an investigational drug or device.   
2. Has any internal or non-removable external metal items that may present a safety risk 
for study assessments that utilise magnetic fields, or any other medical condition or 
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circumstance in which an MRI is contraindicated according to local institutional 
policy.   
3. Previous hematopoietic stem cell or bone marrow transplant. 
4. Known or suspected hypersensitivity to anaesthesia or the use of a sedative is 
contraindicated for any other reason. 
5. History of poorly controlled seizure disorder. 
6. A bleeding disorder, or any other medical condition or circumstance in which a 
lumbar puncture (for collection of CSF) is contraindicated according to local 
institutional policy. 
7. Known hypersensitivity to eggs.  Subjects at high risk for food allergy that may 
include eggs should be tested according to local guidelines.   
8. Other medical conditions or comorbidities (e.g., alanine aminotransferase [ALT] or 
aspartate aminotransferase [AST] > 3 x the upper limit of normal [ULN], confirmed 
by repeat testing, analysed locally and based on the standardised reference range 
provided in the laboratory manual), or other markers of clinically significant liver 
dysfunction (e.g. elevated bilirubin, [with the exception of subjects with confirmed 
Gilbert’s disease] confirmed by repeat testing, or elevated prothrombin time 
[PT]/international normalised ratio [INR] confirmed by repeat testing analysed 
locally and based on the standardised reference range provided in the laboratory 
manual) which in the opinion of the Investigator, in consultation with the Sponsor, 
would interfere with study compliance, or confound data interpretation. 
4.4 Concomitant Medications and Treatments 
Concomitant medications include prescription and over-the-counter medications, 
prophylactic and therapeutic vaccines, herbal medications, vitamins, and 
dietary/nutritional supplements, as well as any investigational medications the subject 
may have received.  Concomitant treatments include diagnostic, palliative, or 
interventional procedures (e.g., hematopoietic stem cell transplant, bone marrow 
transplant). 
At the Screening visit, information on all medications and treatments received by the 
subject within the preceding 4 weeks will be recorded in the case report form (CRF).  
Thereafter, reasonable efforts will be made to ascertain all changes in concomitant 
medications and treatments from Screening until the subject completes the safety 
follow-up phone call.  Particular attention will be given to any changes in the dose or 
dosing regimen of genistein or melatonin, antihistamines, chloral hydrate, 
benzodiazepines, thioridazine, carbamazepine, and sodium valproate.  Note that subjects 
who are on a stable dosing regimen for any of the listed medications at the time of 
Screening, including a low dose of genistein (≤ 150 mg/kg/day), should remain on the 
dosing regimen during the study.  Dose adjustments or discontinuation of these 
medications should occur only when there is a clear medical reason and should be 
pre-approved by the Sponsor.  Information on all concomitant medications and treatments 
will be recorded in the CRF and will include the name of the medication (brand or 
generic) or therapy, reason for use, start date, stop date, dose, route of administration (if 
applicable), and frequency of administration. 
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4.5 Discontinuation of Subjects 
4.5.1 Premature Withdrawal from Study Participation 
Subjects have the right to withdraw from the study at any time for any reason, without 
prejudice to further treatment. 
The Investigator and Sponsor also have the right to withdraw subjects from the study at 
any time.  Specific reasons for discontinuation may include, but are not restricted to, the 
following: 
• Intercurrent illness. 
• AEs, including severe infusion reactions. 
• Pregnancy. 
• Clinically important protocol deviation or non-compliance. 
• Termination of the study by the Sponsor. 
4.5.2 Procedures for Discontinuation 
If a subject discontinues at any time after being dosed with SBC-103, all efforts should be 
made to have the subject complete follow-up visit procedures, including End of 
Study/Early Withdrawal Visit per Schedule of Assessments (SOA) (refer to Section 14.1, 
Appendix A).  All subjects who withdraw should be asked about the reason(s) for their 
discontinuation and about the presence of AEs.  The date and the reason for 
discontinuation will be recorded. 
When a subject fails to return for scheduled assessments, the following efforts should be 
made to contact him/her (this would generally apply to the parent/caregiver) to determine 
a reason for the failure to return: 3 phone attempts, including the date and time, to be 
documented in the subject’s chart.  If there is no response to the telephone calls, a 
certified letter should be sent.  After these efforts have been exhausted, a subject should 
be identified as lost to follow-up.  
4.6 Subject Replacement Policy 
Subjects will not be replaced. 
4.7 Subject Re-screening 
Subjects who were unable to complete all Screening procedures within the 28-day 
Screening window may be re-screened.  Safety laboratory tests (chemistry, haematology 
and urinalysis) and weight as well as assessments scheduled to be performed on Day 0 
will be repeated if performed more than 28 days prior to dosing.  The subject will be 
re-consented and Screening procedures will be repeated at the discretion of the 
Investigator after discussion with the Medical Monitor. 
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5 STUDY PROCEDURES 
5.1 Study Assessments 
A Schedule of Study Assessments is presented in Section 14.1.  The SOA provides 
detailed information regarding the time points for all of these assessments. 
5.1.1 Informed Consent/Assent 
The subject (or the subject’s parent or legal guardian) will be given a consent form as 
well as a verbal explanation of the study, including information about the study 
procedures, and will have all questions adequately addressed.  The subject (or the 
subject’s parent or legal guardian) must sign and date a consent form that has been 
approved by the appropriate Institutional Review Board (IRB)/Independent  Ethics 
Committee (IEC) within 90 days before Screening procedures are initiated, and will be 
given a copy of the signed and dated informed consent form.  Subjects will need to be 
re-consented if the consent form was signed and dated more than 90 days from first 
Screening assessment.  In addition, age and comprehension-appropriate assent will be 
obtained from subjects below the age of consent, as required by local regulations.   
5.1.2 Subject Eligibility 
All subjects will be assessed for eligibility against the inclusion and exclusion criteria 
described in Section 4.3.   
5.1.3 Medical History 
Any new medical history occurring since the screening date of the NGLU-CL01 study 
will be recorded. 
Medical history to be recorded includes, but is not limited to, the following: 
• Historical results of NAGLU enzyme activity testing and genetic mutation 
analysis, as applicable. 
• Presence (and date of onset, if known) of the following clinical manifestations or 
disorders as applicable: 
• Cognitive delay/difficulties. 
• Abnormal facial features (flat nasal bridge, enlarged lips, enlarged mouth 
and tongue, abnormal thickening/darkening/coarseness of eyebrows). 
• Hepatomegaly. 
• Language delay/difficulties or regression of language skills . 
• Abnormal behaviours (hyperactivity, aggressiveness, irritability, 
endangering behaviours). 
• Autism spectrum disorder. 
• Epilepsy. 
• Motor function delay/difficulties, including loss of independent walking. 
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• Sleep disturbances (settling difficulties, early awakening, complete 
reversal of day-night rhythm, obstructive sleep apnoea). 
• Ear-nose-throat problems (recurrent ear infections, adenoidectomy or 
tonsillectomy, grommets, documented history of hearing loss). 
• Difficulty swallowing. 
Data on family medical history will be obtained from the NGLU-CL01 database.  Any 
changes in family medical history since the subject’s participation in that study (such as 
new siblings, death of a sibling, or new diagnosis of MPS in a sibling) will be recorded. 
Refer to Section 4.4 for details on collection of medication history and concomitant 
medications/treatments. 
5.1.4 Demographic Information 
Demographic data collected for all subjects during their participation in the NGLU-CL01 
study. 
5.1.5 Physical Examination 
Complete, age-appropriate physical examinations will be performed by the Investigator 
or qualified designee at the time points specified in the SOA.  These examinations will 
include an assessment of the subject’s general appearance; skin; head, eyes, ears, nose, 
throat, and head circumference; heart; lungs; abdomen; extremities/joints; and 
neurological status.  Abnormal findings will be recorded in the CRF. 
5.1.6 Height and Weight 
Height and weight will be measured at the time points specified in the SOA.  
Weight-for-age, weight-for-height, height-for-age, and body mass index-for-age will be 
derived during data analysis, and percentiles or z-scores will be determined for each of 
these derived parameters by standardization to age- and gender-appropriate Centers for 
Disease Control growth charts. 
5.1.7 Vital Signs and Electrocardiogram 
Vital signs, including pulse rate, respiratory rate, systolic and diastolic blood pressure, 
and body temperature will be taken at the time points specified in the SOA in accordance 
with local institutional procedures.  On Day 1, vital signs will be taken prior to hospital 
discharge.  During dosing visits, vital signs will be taken within approximately 
30 minutes before dosing with SBC-103, approximately every 15 minutes during infusion 
and approximately every 15 minutes for 2 hours after completion of the infusion.  Vital 
signs should also be obtained after the lumbar puncture is completed as per the standard 
of care.  The duration of post-infusion vital signs monitoring may be shortened to 1 hour 
starting with Week 54, provided that there is no occurrence of IARs during the infusion. 
Every effort will be made to collect a 12-lead ECG during the time points specified in the 
SOA in accordance with local institutional procedures.  12-lead ECGs will be collected in 
triplicate for the first 6 months.  ECGs will be reviewed by the Investigator, or designee, 
and any abnormalities will be specified as clinically significant or not clinically 
significant.  
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Vital signs and ECG monitoring during general anaesthesia prior to the MRI scan will be 
performed in accordance with local institutional procedures. 
Due to the behavioural issues typical of subjects with MPS IIIB, ECG assessments may 
not be able to be completed, but should be attempted whenever possible.   
5.1.8 Neurocognitive, Developmental and Quality of Life (QOL) 
Assessments 
Neurocognitive, developmental, and QOL assessments are presented in Section 14.2 
(Appendix B) and will be performed at time points specified in the SOA.  The BSID-III, 
KABC-II, and BOT-2 Brief Form are administered to the subject.  All other assessments 
are administered to the parent or caregiver. 
The Investigator or designee should use clinical judgement to decide whether subject 
hearing or vision problems may preclude developmental testing.  Assessment of vision 
and hearing may be collected from medical history, parent report, or based on evaluation 
during Screening physical examination.  Assessment of hearing should be documented in 
the CRF. 
Assessments to be performed will include the Vineland-II, BSID-III and/or KABC-II, 
BOT-2 Brief Form and CCC-2, CSHQ, SBRS, ZBI, and the SF-10.  The Vineland-II, 
BSID-III or KABC-II, and BOT-2 Brief Form should be administered face to face by 
appropriately qualified professionals.  Assessments may be conducted over more than 
1 day.  
The selection of the appropriate neurocognitive test instrument administered to the child 
is normally dependent on the calendar age of the child.  However, since MPS IIIB 
patients are likely to show delayed development, the choice of test instrument at the 
Screening visit will be based on a subject’s Vineland-II age equivalent (developmental 
age) assessed using the survey interview form.  The BSID-III will be administered to 
subjects with a mean Vineland-II age-equivalent of < 3 years 6 months, and the 
KABC-II, BOT-2 Brief Form, and CCC-2 will be administered to subjects with a 
Vineland-II age-equivalent of ≥ 3 years 6 months.  
During the initial administration of the BSID-III or KABC-II, BOT-2 Brief Form, and 
CCC-2 at Screening, if the test administrator determines that the chosen test instrument 
appears unfit for the subject, he/she may switch to the alternate test instrument.  
However, after the Screening visit, the KABC-II should be first attempted.  If the subject 
appears to be failing the KABC-II, they may revert to the BSID-III.  If the subject passes 
the BSID-III, the KABC-II should be continued.  See Section 5.1.8.3 and Section 5.1.8.4 
for details. 
5.1.8.1 Vineland Adaptive Behavior Scales, Second Edition (Vineland-
II) 
The Vineland-II supports the diagnosis of cognitive and developmental disabilities in 
subjects from birth through age 90 years.  The Vineland-II assesses a subject’s abilities 
across 5 domains: communication, daily living skills, socialization, motor skills, and 
maladaptive behaviours.  In this study, all sections except for the critical items in the 
Maladaptive Behaviour domain will be used.  Standardised scores, percentile ranks, and 
adaptive levels are provided for each domain, as well as for an adaptive behaviour 
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composite measure.  Additionally, the Vineland-II allows for determination of V-scale 
scores, adaptive levels, and age equivalents for subdomains of each of the 5 adaptive 
behaviour domains.  Administration of the Vineland-II Survey Interview Form with the 
parent/caregiver takes approximately 20 to 60 minutes.  
For this study, the mean age equivalent is calculated by taking the average of all age 
equivalents of the subdomains under communication, daily living skills, socialization, 
and motor skills.  Maladaptive behaviour is not included in this calculation. 
The age equivalent and developmental quotient will be calculated for all Vineland-II 
domains and their subdomains.  This quotient is calculated as (Age equivalent/Calendar 
age)*100. 
5.1.8.2 Bayley Scales of Infant and Toddler Development, Third Edition 
(BSID-III) 
The BSID-III has been validated for children aged less than 3.5 years and takes 
approximately 25 to 60 minutes to administer (Connolly, 2012, Pediatr Phys Ther).  The 
test is administered to the subject and was designed to identify young children with 
developmental delays.  The BSID-III assesses developmental function across 5 domains: 
cognition; language (expressive and receptive); motor (fine and gross motor functioning); 
and social, emotional, and adaptive behaviour. 
In this study, cognition, language, and motor functioning will be assessed.  The social, 
emotional, and adaptive behaviour domains are not being used due to overlap with the 
Vineland scale. 
The age equivalent and developmental quotient will be calculated for the BSID-III 
domains and their subtests.  This quotient is calculated as (Age equivalent/Calendar 
age)*100. 
Switching from BSID-III to the Kaufman ABC-II (KABC-II) 
At the Screening visit, a child may perform better than expected based on the Vineland-II 
test.  If the score on the first subdomain (cognition) is higher or equal to 79, the KABC-II 
should be used in combination with BOT-2 Brief Form and CCC-2.  
During future study visits, the KABC-II should be attempted first as it was the 
assessment completed at the first visit.  If the subject appears to be failing the KABC-II, 
they may revert to the BSID-III. 
5.1.8.3 Kaufman Assessment Battery for Children, Second Edition 
(KABC-II) 
The KABC-II has been validated for children aged 3 to 18 years and takes approximately 
35 to 70 minutes to administer (Malda, 2010, Assessment).  The test is administered to the 
subject and was designed to identify strengths and weaknesses in cognitive ability and 
mental processing.  The KABC-II is comprised of 18 subtests, although not all subtests 
are required to be administered, and is typically used in conjunction with other cognitive 
or neuropsychological assessments. 
Order of completion of the subtests by MPS IIIB subjects 
Children with MPS IIIB may not be able to complete all subtests, due to a limited 
attention span and behavioural problems.  Therefore, we only require completion of the 
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non-verbal index (NVI) battery as appropriate for the developmental age of the child.  
Other skills (language and motor skills) will be assessed by the CCC-2 and BOT-2 Brief 
Form, respectively.  Priority should be given to the most informative domains, the NVI 
and the BOT-2 Brief Form.  The CCC-2 is completed by the parents.  After completion of 
the NVI and BOT-2 Brief Form, the rater can complete the optional domains in order of 
importance, and thus, relevance.  The NVI and BOT-2 Brief Form should be 
administered first.  The optional domains include Sequential/Gsm, Simultaneous/Gv, 
Learning/Glr, Planning/Gf (only for developmental ages 7 to 18 years), and 
Knowledge/Gc. 
The age equivalent and developmental quotient will be calculated for the KABC-II 
subtests.  This quotient is calculated as (Age equivalent/Calendar age)*100. 
Switching from KABC-II to the BSID-III 
At the Screening visit, a child may perform poorer than expected on the KABC-II.  In this 
case the BSID-III should be used.  It is likely that these children will have started with the 
NVI subtests for children aged 3 to 5 years.  The first tests for the NVI are Conceptual 
thinking and Face recognition.  If the raw scores for both these first 2 tests are ≤ 5 then 
the KABC-II should be discontinued and the BSID-III should be used.  
During future study visits, the KABC-II should be attempted first.  If the subject appears 
to be failing the KABC-II, they may revert to the BSID-III.  If the subject passes the 
BSID-III, the KABC-II should be continued at this visit when practical and subject 
compliance allows. 
5.1.8.4 Bruininks-Oseretsky Test of Motor Proficiency, Second Edition, 
Brief Form (BOT-2 Brief Form) 
The BOT-2 Brief Form is an individually administered test that uses engaging, 
goal-directed activities to measure a wide array of motor skills in children aged 4 through 
21 years (Bruininks, 2010, NCS).  The BOT-2 Brief Form contains 12 items to assess fine 
motor precision, fine motor integration, manual dexterity, bilateral coordination, balance, 
running speed and agility, upper-limb coordination, and strength.  The BOT-2 Brief Form 
will be administered to subjects who are also completing the KABC-II and takes 
approximately 20 minutes to complete. 
If the subject does not obtain any points in the first 2 tasks, the motor scales of the 
BSID-III should be used, even if the subject’s cognition was assessed by KABC-II. 
5.1.8.5 Children’s Communication Checklist, Second Edition (CCC-2) 
The CCC-2 is a 70-item questionnaire that was designed to rate aspects of 
communication in children including speech vocabulary, sentence structure, and social 
language skills.  Within the 2 domains of language and pragmatics, the following 
subdomains are evaluated: speech, syntax, semantics, coherence, initiation, scripted 
language, context, non-verbal communication, social relations, and interests (Volden, 
2010, Am I Speech Lang Pathol).  The CCC-2 takes approximately 5 to 15 minutes to 
administer to the parent/caregiver and has been validated for use in children between the 
ages of 4 to 16 years.  In this study, the CCC-2 will be administered to parents/caregivers 
who are assessed by the KABC-II in order to get an estimation of language and 
communication development of the subject.  Since language development assessment is 
already part of the BSID-III, the CCC-2 should not be completed by parents/caregivers of 
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the children who are assessed by BSID-III, unless as specified in Sections 5.1.8.3 and 
5.1.8.4. 
5.1.8.6 Children’s Sleep Habits Questionnaire (CSHQ) 
The CSHQ is a comprehensive, parent-reported screening survey that has been validated 
for children aged 4 to 10 years (Owens, 2000, Sleep); however, it will be completed, if 
possible, for all subjects treated in the study.  The design of the CSHQ is based on 
common clinical symptom presentations of the most prevalent paediatric diagnoses as 
described in the International Classification of Sleep Disorders (Thorpy, 1990, American 
Sleep Disorder Association).  The CSHQ takes approximately 20 minutes to complete 
and consists of 45 questions administered across 8 sleep-wake functions including 
bedtime resistance, sleep onset delay, sleep duration, sleep anxiety, night awakenings, 
sleep-disordered breathing, parasomnias, and daytime sleepiness. 
5.1.8.7 Sanfilippo Behavior Rating Scale (SBRS) 
The SBRS is a parent-reported assessment developed at the University of Minnesota 
specifically to assess patients with Sanfilippo syndrome or MPS III disease.  The SBRS 
assesses communication and expression as well as behaviour and is administered as 
3 sections.  The initial assessment includes Section I (Communication), Section II 
(Temper Tantrums), and Section III (Behavior), which evaluates 15 areas of function that 
are important for or unique to children with Sanfilippo Syndrome.  The 96 questions 
included in the initial assessment will take approximately 45 minutes to complete.  The 
follow-up assessments include a specific follow-up version of Sections I, II, and III of the 
SBRS.  This section will assess if there have been any changes since the last visit 
(increased, stayed the same, decreased).  It will take approximately 45 minutes for the 
parent to complete the 96 questions during the follow-up assessments. 
5.1.8.8 12-item Zarit Burden Interview (ZBI) 
The 12-item ZBI is a caregiver self-report measure that is used to evaluate levels of stress 
for caregivers of patients with Alzheimer’s disease or other forms of dementia.  The 
12-item ZBI, validated for use in cross-sectional, longitudinal, and interventional studies 
(Bédard, 2001, Gerontologist), represents a truncated form of the original 22-item ZBI 
thus enabling easier administration.  The assessment takes approximately 5 minutes to 
complete and measures the caregiver’s overall level of burden enabling physicians to 
identify caregivers who may be at high risk of developing physical and/or emotional 
problems.  
5.1.8.9 10-item Short Form Health Survey for Children (SF-10) 
The SF-10 is a parent-completed survey that contains 10 questions adapted from the 
Child Health Questionnaire and takes less than 5 minutes to complete.  The SF-10 has 
been validated in children aged 5 to 18 years (Zhang, 2008, Health Qual Life Outcomes); 
however, it will be completed, if possible, for all subjects treated in the study under the 
age of 5.  The SF-10 provides coverage across a wide range of domains, and is scored to 
produce physical and psychosocial health summary measures.  The survey provides a 
quick and efficient means to measure health status.  Due to its brevity, the SF-10 can be 
easily integrated and administered within a broader assessment, and is particularly 
applicable to large-scale child population surveys. 
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5.2 Clinical Laboratory Assessments 
5.2.1 Routine Assessments and Biomarkers 
A list of all clinical laboratory tests that will be performed is provided in Table 1; the 
time points for sample collection are specified in the SOA.     
Blood collected for standard haematology and serum chemistry (including coagulation 
parameters) will be analysed locally.   
During Screening, if a subject’s ALT or AST is greater than 3 x ULN, or a subject has 
elevated bilirubin or PT/INR, confirmatory testing will be completed.  Abnormal safety 
labs at Screening can be repeated within 1 to 2 weeks.  The difference between these 
2 pre-treatment values for each abnormal laboratory parameter should differ by < 20% 
for each subject.  
Efforts should be made by the Investigator to review subject medical history, 
concomitant medications and health status so that a clear explanation for the elevation is 
established.  The Investigator, in consultation with the Sponsor, shall make a 
determination of subject eligibility based on review of Exclusion Criterion 8.  
During the study, after treatment with SBC-103, in the event that a subject’s ALT or AST 
is 2 x ULN (when baseline ALT or AST was within normal limits) or 3 x ULN (when 
baseline ALT or AST was greater than 1.5 x ULN), or when a subject has an elevation in 
bilirubin or PT/INR a confirmatory test should be completed at the earliest possible time 
point, but not later than the next scheduled visit.  Upon positive confirmation of the 
elevated transaminases as described above, dosing will be paused until AST and ALT 
have returned to baseline or to study nadir (nadir values may be confirmed by additional 
laboratory sampling at the discretion of the Investigator, using the same laboratory for 
analysis of each sample),  or normalised if the baseline level was within normal limits.  
See Section 6.2 for stopping rules. 
Every effort will be made to collect urine for urinalysis testing.  If urine can be collected, 
a urine pregnancy test will be performed and analysed locally for females of 
child-bearing potential.  If a urine sample is not able to be provided, a serum pregnancy 
test will be performed and analysed locally.  
Serum, and where possible, urine, will be collected for analysis of MPS IIIB substrate 
(total HS) and other disease-related biomarkers including NRE HS derivatives.  CSF will 
be collected via lumbar puncture for analysis of total HS and other disease-related 
biomarkers including NRE HS derivatives.  All efforts will be made to obtain a blood 
sample to evaluate serum albumin and serum IgG at the same time as the CSF sample, as 
reflected in the SOA.  The CSF-AI will be calculated as the CSF albumin (mg/mL)/serum 
albumin (g/L).  IgG index will be calculated as the ( [CSF/serum IgG ratio] / [CSF-AI] ).  
Refer to Section 5.2.1.3 for details regarding the lumbar puncture.  
A specific sample for biomarker analysis is being collected in this study; however, 
remaining blood and urine samples collected in this study may also be used to analyse 
additional biomarkers of potential clinical interest, if there is sufficient sample and where 
local regulations permit.  As subjects with MPS IIIB may be incontinent, urine samples 
for routine assessments and biomarkers may not be able to be collected, but should be 
attempted whenever possible. 
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Due to the limitations on the volume of blood collection that is considered to be 
acceptable in young children with very small total circulating blood volumes; see 
Committee for Medicinal Products for Human Use and Paediatric Committee guidance 
(EMEA/536810/2008, adopted 25 June 2009), the blood laboratory tests will be ranked 
by tier.  Per individual, the study-related blood loss should not exceed 3% of the total 
blood volume during a period of 4 weeks and should not exceed 1% at any single time.  
The total volume of blood is estimated at 80 to 90 mL/kg body weight; 3% corresponds 
to about 2.4 to 2.7 mL blood per kg body weight.   
Tier 1 assessments (see Table 1) are considered mandatory and all efforts should be made 
to collect these samples in all subjects.  Samples for the Tier 2 or Tier 3 assessments will 
be collected if permitted based on the blood or CSF volume threshold for a subject’s 
weight, as well as the subject’s clinical status.  All tests will be performed by a qualified 
laboratory. 
Clinical laboratory samples will be stored by the Sponsor or designee in a secure and 
controlled environment until analysis, and will be destroyed by the Sponsor or designee 
after all worldwide obligations have been met, or sooner if required by local regulations.  
Refer to the laboratory manual for further details regarding the collection, processing, and 
storage of clinical laboratory samples. 
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Table 1: 
Clinical Laboratory Tests 
Laboratory 
Parameter 
Panel 
Tier 
Local or 
Central 
Analysis 
Matrix 
Tests 
Haematology 
1 
Local Lab 
Whole 
blood 
White blood cell count; red blood cell 
count; haemoglobin; haematocrit; MCV, 
MCH, MCHC; platelet count; neutrophils; 
lymphocytes; monocytes; eosinophils; 
basophils 
Serum 
Chemistry 
1 
Local Lab 
Serum 
ALT, AST, alkaline phosphatase, GGT, 
albumin, total bilirubin, serum electrolytes 
(sodium, potassium, chloride, calcium, 
magnesium, phosphorus), glucose, 
creatinine, bicarbonate, total protein, blood 
urea nitrogen 
Coagulation 
1 
Local Lab 
Plasma 
PT, INR 
Urinalysis 
N/A 
Local Lab 
Urine 
pH, clarity, colour, specific gravity, 
glucose, ketones, blood, protein, nitrite, 
and leukocytes (microscopic examination 
will only be done if urinalysis is positive 
for blood, nitrite, or leukocytes, or if 
protein is > 1+) 
Pregnancy 
testa 
N/A 
Local Lab 
Urine 
 
MPS IIIB 
Diagnostics 
1 
Central 
Lab 
Dried 
blood 
spot 
NAGLU enzyme activity 
PK 
1 
Central 
Lab 
Serum 
PK profile 
PK 
3 
Central 
Lab 
CSF 
SBC-103 concentration 
ADA 
1 
Central 
Lab 
Serum 
Anti-SBC-103 antibodies (IgM, IgG, and 
IgE).  Subjects who experience a moderate 
or severe IAR should have a serum sample 
collected for ADA during the next study 
visit (≥ 4 days after the IAR) prior to the 
infusion. 
Biomarkers 
1 
Central 
Lab 
Serum 
HS (total and NRE) 
2 
Central 
Lab 
Serum 
Ferritin and chitotriosidase 
2 
Central 
Lab 
Plasma 
Glutamic acid and glycine 
2 
Central 
Lab 
Serum 
IgG, inflammatory markers, and 
biomarkers 
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Table 1: 
Clinical Laboratory Tests 
Laboratory 
Parameter 
Panel 
Tier 
Local or 
Central 
Analysis 
Matrix 
Tests 
N/A 
Central 
Lab 
Urine 
HS (total and NRE) 
1 
Central 
Lab 
CSF 
HS (total and NRE) 
2 
Central 
Lab 
CSF 
HGF, calbindin D, Tau, pTau, amyloid β, 
albumin, IgG, glutamic acid and glycine 
1 
Central 
Lab 
CSF/ 
Serumb 
CSF/Serum Albumin Index (CSF-AI) and 
IgG index ( [CSF/serum IgG ratio] / 
[CSF-AI] ) 
2 
Local Lab 
CSF 
Routine findings (cell counts, glucose, 
protein) 
Serum 
Tryptase 
If 
clinically 
indicated 
Central 
Lab 
Serum 
Subjects who experience a moderate or 
severe IAR should have a serum sample 
collected for analysis of tryptase 1-3 hours 
after the IAR onset and another serum 
sample for tryptase and ADA during the 
next study visit (≥ 4 days after the IAR) 
prior to the infusion. 
Key: ADA = anti-drug antibodies; ALT = alanine aminotransferase; AST = aspartate aminotransferase; 
CSF = cerebrospinal fluid; CSF-AI = cerebrospinal fluid/serum albumin index; GGT = gamma-
glutamyl transpeptidase; HGF = hepatocyte growth factor; HS = heparan sulphate; IAR = infusion-
associated reaction; IgE = immunoglobulin E; IgG = immunoglobulin G; IgM = immunoglobulin M; 
INR= international normalised ratio; MCH = mean corpuscular haemoglobin; MCHC = mean 
corpuscular haemoglobin concentration; MCV = mean corpuscular volume; N/A = not applicable; 
NAGLU = alpha-N-acetylglucosaminidase; NRE = non-reducing end; PK = pharmacokinetics; PT = 
prothrombin time. 
a 
Test performed by a local laboratory for all female subjects of child-bearing potential.  If a urine 
sample is not able to be provided, a serum pregnancy test will be performed by a local laboratory. 
b 
Ensure that serum albumin is collected at each time point a CSF sample is collected.  If a serum 
chemistry is not scheduled at the same study visit, a serum albumin should be drawn. 
 
5.2.1.1 
Biomarkers 
Blood samples for serum isolation will be obtained at the time points specified in the 
SOA for exploratory analyses to identify and evaluate disease-related biomarkers, where 
local regulations and blood volume threshold permits.  A specific sample for biomarker 
analysis is being collected in this study; however, remaining blood or urine samples 
collected in this study may also be used to analyse additional biomarkers of potential 
clinical interest, if there is sufficient sample and where local regulations permit.  These 
samples will be used to identify baseline disease and dynamic markers that will help the 
Sponsor to better understand the pathogenesis of MPS IIIB and related comorbidities and 
response to treatment.  Given the rarity of MPS IIIB, the definitive list of analytes 
remains to be determined.   
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Collection of samples for biomarker analysis will be subject to discretionary approval 
from each centre’s IRB/IEC and the specific written consent of the subject or the 
subject’s parent or legal guardian.  This section of the protocol only applies if approval 
for collection of these additional samples has been granted by the IRB/IEC and consent is 
provided by the subject (or the subject’s parent or legal guardian). 
Samples will be stored by the Sponsor, or designee, in a secure and controlled 
environment until analysis, and will be destroyed by the Sponsor or designee after all 
worldwide obligations have been met, or sooner if required by local regulations.  
Biomarker assays will be performed by a central laboratory or, as appropriate, by 
academic research laboratories with expertise in the analysis of specific biomarkers. 
Refer to the laboratory manual for further details regarding the collection, processing, and 
storage of these samples.   
5.2.1.2 
Pharmacokinetic Assessments 
As described in Table 2 and the SOA, blood samples will be collected to determine 
SBC-103 serum concentrations using an enzyme-based PK assay.  PK samples collected 
concurrently with vital sign assessments will be taken prior to collection of blood 
pressure on the non-infusion arm.  PK samples collected at all other time points will be 
taken at least 5 minutes following deflation of the blood pressure cuff.  PK samples 
should not be taken from the same extremity where the infusion catheter is in place.  
CSF samples for determination of SBC-103 concentration in the CSF may also be 
collected from subjects if CSF volume limitations based on subject’s age and weight have 
not been exceeded. 
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Table 2: 
Pharmacokinetic Sampling  
 
Day 0 
Week 12 
Week 24 
Pre-infusion (within 30 minutes) 
X 
X 
X 
During Infusion 
 
 
 
5 minutes (±2 minutes) 
X 
 
 
10 minutes (±2 minutes) 
X 
 
 
30 minutes (±5 minutes) 
X 
X 
X 
50 minutes (±5 minutes) 
X 
 
 
70 minutes (±5 minutes) 
X 
 
 
90 minutes (±5 minutes)a 
X 
X 
X 
120 minutes/End of Infusionb 
(±5 minutes) 
X 
X 
X 
After Completion of Infusion 
 
 
 
5 minutes (±2 minutes) 
X 
 
 
15 minutes (±2 minutes) 
X 
X 
X 
30 minutes (±5 minutes) 
X 
X 
X 
60 minutes (±5 minutes) 
X 
X 
X 
90 minutes (±5 minutes) 
X 
X 
X 
120 minutes (±5 minutes) 
X 
X 
X 
4 hours (±5 minutes) 
X 
X 
X 
6 hours (±5 minutes) 
 
X 
 
8 hours (±15 minutes) 
X 
  
X 
12 hours (±15 minutes) 
X 
 
X 
24 hours (±15 minutes)a 
X 
 
X 
a Time points may be omitted, if necessary, to avoid exceeding blood volume limitations. 
b After the infusion bag has been emptied, but prior to the flush. 
 
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Table 2 (continued): Pharmacokinetic Sampling  
 
Week 52 Week 78 
Week 
104 
Week 
130 
Week 
156 
Pre-infusion (within 30 
minutes) 
X 
X 
X 
X 
X 
During Infusion 
 
 
 
 
 
30 minutes (±5 minutes) 
X 
  
X 
 
X 
90 minutes (±5 minutes)a 
X 
  
X 
 
X 
120 minutes/End of Infusionb 
(±5 minutes) 
X 
  
X 
 
X 
After Completion of Infusion 
 
 
 
 
 
30 minutes (±5 minutes) 
X 
  
X 
 
X 
2 hours (±5 minutes) 
X 
  
X 
 
X 
4 hours (±15 minutes) 
X 
  
X 
 
X 
6 hours (±15 minutes) 
X 
 
X 
 
X 
a Time points may be omitted, if necessary, to avoid exceeding blood volume limitations. 
b After the infusion bag has been emptied, but prior to the flush. 
5.2.1.3 
Lumbar Puncture (Cerebrospinal Fluid) 
Lumbar punctures will be performed for the collection of CSF at the time points specified 
in the SOA.  The lumbar puncture may be performed under general anaesthesia, if 
clinically appropriate, or under light sedation and will be performed as per local practices 
by a qualified professional in accordance with local institutional procedures.  The first 
10 mL of CSF will be collected and mixed gently to avoid gradient effects.  The actual 
volume may be adjusted based on subject age or size and local institutional guidelines.  If 
CSF volume is limited, the analysis of CSF HS (total and NRE) should be prioritised as 
noted in Table 1. 
Routine CSF findings will also be documented (e.g., cell counts, glucose, and protein 
levels), and MPS IIIB substrate (HS) and other CSF biomarkers will be analysed (see 
Table 1 for details). 
Per the SOA, collection of serum chemistry will not always coincide with the collection 
of CSF.  In order to measure the CSF-AI at each possible time point, a serum albumin 
sample should be collected at time points where a serum chemistry sample is not being 
collected at the same day as the CSF sample. 
After the lumbar puncture is completed, the subject should be observed as per institution 
standard practice.  Vital signs should be obtained prior to discharge.  Any AEs or changes 
to concomitant medications should also be assessed.  
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5.2.2 Facial Dysmorphology Novel Analysis  
Facial photographs will be obtained for FDNA at the time points specified in the SOA.  
This technology enables automatic detection and evaluation of subtle craniofacial 
dysmorphology associated with multiple rare diseases, by processing and analysing 
standard 2-dimensional facial photos.  The FDNA system uses proprietary computer 
algorithms to recognise and describe subtle craniofacial malformations (out of a list of 
clinically relevant anatomical facial features) in mathematical terms.  A ranked score, 
representing the probability of the genetic syndrome, is produced based on analysis of the 
severity of the facial alterations relative to variations in a normal population, as well as 
recognition of the face “gestalt” associated with certain rare diseases.  FDNA offers 
potential as a tool for screening large populations for MPS IIIB, which may enable wider 
and earlier diagnosis of MPS IIIB patients, as well as providing a means for monitoring 
progression of disease in patients diagnosed with MPS IIIB.  This study will evaluate 
FDNA technology as a means to evaluate both clinical characteristics and course of 
disease progression in MPS IIIB.  FDNA assessment will be optional based on 
subject/parent consent to participate.  A subject/caregiver may refuse this assessment and 
still participate in this study.  Once a subject/caregiver consents to this assessment, all 
attempts should be made to collect data at each study time point. 
5.2.3 General Anaesthesia/Sedation 
Subject compliance and maintenance of appropriate and stable positioning during the 
MRI procedure is complicated due to the anticipated behaviour disturbances 
characteristic of MPS IIIB subjects.  A key advantage of general anaesthesia is that it 
minimises any potential for stress or anxiety during the procedure and is independent of a 
subject’s ability to cooperate, which is critical with MPS IIIB subjects.  The whole 
process, including preparation and scan time, is more predictable, and the scan quality 
will benefit as a result of the subject being immobilised.   
Thus, subjects will receive general anaesthesia prior to the MRI procedure.  In principle 
all types of general anaesthesia techniques can be used as long as the subject is kept 
asleep during the MRI procedure.  The decision should depend on comorbidities, 
anatomy, and fasting status in the individual case and the procedures and practices of the 
institution.  In clinical practice and in earlier studies with subjects with MPS III, propofol 
sedation was used together with a laryngeal mask to guarantee a secure airway and to not 
unnecessarily prolong the procedure.  The IV properties of propofol make it an ideal 
anaesthetic for subjects undergoing imaging assessments.  An IV anaesthetic without 
endotracheal intubation allows for careful titration of sedation to achieve a clinical 
effect.  Propofol provides the ability to titrate an anaesthetic level rapidly and maintain 
stable drug concentrations during the procedure, thus ensuring that anaesthesia is 
administered in a timely and consistent manner.  Recovery from this type of anaesthesia 
is rapid and not accompanied by nausea or vomiting.  Often the anaesthetic can be 
delivered allowing the subject to breathe spontaneously.  Competency of airway is 
accomplished by the insertion of a laryngeal mask airway which allows ventilation of the 
subject in the cases required.  Appropriate local procedures should be utilised under 
supervision of a paediatric anaesthesiologist, however, in subjects aged 1 to 10 years, a 
dose of 100 mcg/kg/min will be sufficient to keep the subject asleep with no movement 
during the scan.  If the subject has an IV in place, then a bolus of 2 to 10 mg/kg 
(depending on age) can be given initially, followed by a continuous infusion of propofol.  
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If no IV is in place, then anaesthesia can be induced with an inhalative narcotic such as 
halothane or sevoflurane (with N2O and oxygen), and IV can be inserted, and then 
continuous infusion of propofol started (Schulte-Uentrop, 2010, Curr Opin Anaesthesiol). 
As indicated in Section 5.2.1.3, if clinically appropriate, lumbar punctures may also be 
performed under general anaesthesia in accordance with local institutional procedures.  
When applicable, the lumbar puncture should be performed just prior to the MRI scan 
and prior to dosing.  Lumbar puncture, when not performed alongside the MRI scan, may 
also be performed under light sedation. 
If clinically indicated, subjects may also receive general anaesthesia or sedation for 
central line placement for long-term vascular access, in accordance with institutional 
guidelines.  When possible, the procedure to place the central line should be performed 
while the subject is already anaesthetised or sedated for another study procedure. 
5.2.4 Structural and Diffusion MRI 
MRI will be performed at the time points specified in the SOA.   
High-resolution whole-brain T1-weighted and T2-weighted images will be acquired in 
order to enable measurements of brain volume and relative volumes of grey and white 
matter. 
Whole-brain diffusion MRI will also be acquired with multiple diffusion sensitization 
orientations, b value ≥ 1000 s/mm2.  This will enable measurement of diffusion tensor 
parameters, including mean diffusivity (mean apparent diffusion coefficient) and 
fractional anisotropy, as well as anatomical connectivity mapping.  
The estimated total scan time will be approximately 5 to 10 minutes for structural MRI 
sequences and 15 minutes for diffusion MRI sequences.  All imaging scans will be read 
centrally.  Detailed instructions on image acquisition and analysis will be provided in the 
Imaging Manual. 
5.2.5 Telephone Calls 
A follow-up telephone call will be made to each subject (or the subject’s parent or 
caregiver) within 24 hours after each of the subject’s second, third, and fourth doses to 
assess AEs.   
At least 4 weeks after a subject’s last dose of SBC-103 is administered, the subject (or the 
subject’s parent or caregiver) will receive a follow-up phone call to assess AEs and 
concomitant medications unless the subject has a scheduled follow-up study visit. 
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6 STUDY TREATMENTS 
6.1 Treatments Administered 
All subjects in the study will receive qow (every 14 days ± 5 days) IV SBC-103 for 
156 weeks.  Infusions must be administered at least 10 days apart.  All study visits will be 
scheduled relative to Day 0.  Each subject will receive 1 mg/kg for at least 12 weeks prior 
to consideration for a dose escalation.  After evaluation of an individual subject’s  safety, 
tolerability, and PD data, a dose increase to 3 mg/kg may be implemented for that subject 
if the 1 mg/kg dose is well tolerated. 
Subsequent modifications to the dosing schedule, or dose increases or decreases, may be 
considered by the Sponsor, after consultation with the PI, for each subject throughout the 
study based on a review of safety, tolerability, and PD data for that subject and other 
available safety data from the SBC-103 program. 
6.1.1 Dose Adjustments  
The maximum planned dose to be evaluated in this study is 3 mg/kg administered by 
IV infusion.  In the event of poor tolerability  at any time during the study the dose may 
be reduced or paused.  If a subject cannot tolerate the lowest dose (0.3 mg/kg qow) 
despite measures taken to manage any IARs or other significant safety events, the subject 
will be discontinued from treatment.  See Section 7.1.3 for guidelines for diagnosis and 
management of IARs and Section 6.2 for stopping rules for individual and multiple 
subjects.  
6.1.2 Non-compliance with Study Treatment 
If during the 156-week treatment period a subject misses ≥ 3 consecutive infusions, 
additional assessments will be required prior to resuming dosing, including safety labs 
(haematology, chemistry, coagulation, urinalysis and pregnancy test, where applicable), 
and serum and urine HS.  If ≥ 6 consecutive infusions are missed, additional assessments, 
including lumbar puncture for CSF collection, may be required prior to resuming dosing 
as determined by the Sponsor in consultation with the Investigator.  The next scheduled 
lumbar puncture would not be necessary if ≤ 2 months have elapsed since the previous 
lumbar puncture. 
6.2 Stopping Rules  
6.2.1 Stopping Rules in Individual Subjects  
During the study, subjects who experience a severe IAR, an AE considered related to 
SBC-103, or significant elevation in specific laboratory values, will have SBC-103 
dosing paused based on the rules described below. 
For IARs:  
• Subjects who develop a severe IAR as defined in Section 7.1.3, must stop 
treatment until their information is reviewed by the Sponsor and PI.  Dosing with 
alterations to the infusion regimen (e.g., pre-treatment or slowing the rate of 
infusion) may resume once the Sponsor and PI approve.  
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• Subjects with mild or moderate IARs can continue receiving SBC-103 in the 
study.  The Sponsor, in consultation with the PI, may recommend alterations to 
the infusion regimen (e.g., pre-treatment or slowing the rate of infusion).  
For all other AEs (i.e., AEs that are not characterised as IARs): 
• Any event considered related to SBC-103 which is either serious or severe will 
result in pausing additional dosing in an individual subject.  The Sponsor and PI 
will review the data and will resume dosing only after review and agreement. 
• Subjects with mild or moderate non-serious AEs can continue receiving SBC-103 
in the study.  
For laboratory values: 
• Dosing will be paused based on confirmed elevations in ALT or AST under the 
following circumstances:  
• In the event that a subject’s ALT or AST is ≥ 2 x ULN (when baseline 
ALT or AST was within normal limits). 
• In the event that a subject’s ALT or AST is ≥ 3 x ULN (if baseline ALT or 
AST greater than 1.5 x ULN). 
Dosing will only resume after ALT or AST have returned to baseline or to study nadir 
(nadir values may be confirmed by additional lab sampling at the discretion of the 
Investigator, using the same lab for analysis of each sample), or normalised if the 
baseline level was within normal limits. 
When dosing is resumed it should be restarted at a reduced dose.  For example, if a 
subject was receiving a dose of 3 mg/kg, he/she would be restarted at 1 mg/kg.  If a 
subject was receiving a 1 mg/kg dose, he/she would be restarted at 0.3 mg/kg.  In the 
event that the subject was receiving a dose of 0.3 mg/kg, he/she may resume at the 
0.3 mg/kg dose.  Dosing in an individual subject will be resumed only after ALT or AST 
have returned at least to baseline or to study nadir (nadir values may be confirmed by 
additional lab sampling at the discretion of the Investigator, using the same lab for 
analysis of each sample), or normalised if the baseline level was within normal limits.   
If after resuming treatment at the lower dose, the ALT or AST elevation recurs at greater 
than or equal to 2 x ULN (for those with ALT or AST within normal limits at baseline) or 
2 times the baseline value (for those with abnormal ALT or AST at baseline) study drug 
should be stopped and not resumed.   
Dosing will also be paused based on confirmed elevations in ALT or AST with 
accompanying elevations in any of the following: 
• Confirmed bilirubin > 1.5 x ULN. 
• Confirmed INR > 1.5 . 
• Eosinophilia (> 5%), rash, or fever. 
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If bilirubin and INR values normalise and the Sponsor and PI believes that it is safe to 
resume dosing, the subject may resume dosing with the dose reduced by 1 level (e.g., 
those previously receiving 3 mg/kg would reduce the dose to 1 mg/kg and patients 
receiving 1 mg/kg would reduce the dose to 0.3 mg/kg).  However, in this scenario, any 
subject developing recurrent elevations in ALT or AST (with or without elevations in 
total bilirubin, INR, eosinophilia [more than 5%], rash, or fever) should not be restarted 
on the study drug. 
6.2.2 Stopping Rules for Multiple Subjects  
If 2 subjects experience a similar severe event or SAE, or any subject experiences a life 
threatening AE  that is considered to be at least possibly related to SBC-103, dosing will 
be stopped for this study. The independent Safety Review Committee and the Sponsor 
will evaluate the data and will resume dosing only after review and agreement, including 
review and approval by local regulatory authorities, where required.   
Detailed information regarding the composition of the SRC, the safety data to be 
reviewed, and the data review process will be included in the SRC charter. 
Either of the SRC and Sponsor may request a pause in dosing of all subjects based on 
review of reported events and all available data from this and other studies in the 
program.  Dosing will resume only after the review of data and agreement to do so by the 
SRC and Sponsor. 
6.3 Description of SBC-103 
The reference document for SBC-103 is the Investigator Brochure.  SBC-103 must be 
administered under close supervision of the Investigator, or designee. 
The study drug will be provided in a 10-mL glass vial containing approximately 10.5 mL 
(including 5% overfill) of a buffered solution of SBC-103 at a concentration of 
2 mg/milk  The study drug contains no preservatives and vials are single use only.  
6.4 Method for Assigning Subjects to Treatment Groups 
Not applicable as there is only 1 treatment group in this study. 
6.5 Storage and Disposition of SBC-103 
6.5.1 Receipt of Drug Supplies 
Upon receipt of the study treatment supplies, an inventory must be performed and a drug 
receipt log filled out and signed by the person accepting the shipment.  It is important that 
the designated study staff counts and verifies that the shipment contains all the items 
noted in the shipment inventory.  Any damaged or unusable SBC-103 in a given 
shipment will be documented in the study files.  The Investigator must notify study 
Sponsor of any damaged or unusable study treatments that were supplied to the 
Investigator’s site. 
6.5.2 Storage 
All SBC-103 vials must be stored at a controlled temperature of 2°C to 8°C. Vials should 
not be frozen and should be protected from light during storage. 
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The infusion bag or syringe containing SBC-103 diluted in 0.9% saline should be 
prepared immediately before infusion.  Dilution should occur under controlled and 
validated aseptic conditions.  The prepared diluted infusion bag (or syringe) may be 
stored at room temperature (20°C to 25°C) for no more than 8 hours, although it is 
preferable that prepared solution be used within 4 hours of dilution.  Shaking or other 
forms of agitation of vials or infusion bags should be avoided.  Refer to the IMP Manual 
for detailed instructions.  
6.5.3 Disposition 
The Investigator or designee (e.g., a licensed pharmacist) will be responsible for 
maintaining accurate records for all supplies used.  Opened vials of SBC-103 containing 
residual volume will be stored at room temperature for SBC-103 accountability.  
Following SBC-103 accountability, the Sponsor will provide authorisation to the 
Investigator to return or destroy any remaining investigational product as instructed. 
Under no circumstances will SBC-103 be used other than as directed in the protocol.  
Refer to the IMP Manual for additional details. 
6.6 Preparation and administration of Study Drug 
6.6.1 Preparation of Study Drug 
Dose preparation and administration should be performed using sterile, non-pyrogenic 
disposable materials including, but not restricted to syringes, needles, transfer tubing, and 
stopcocks.   
The infusion bag (or syringe) containing SBC-103 should be prepared just prior to the 
start of IV infusion.  It is preferable that the prepared diluted infusion is used within 
4 hours of dilution, although it may be stored at room temperature for up to 8 hours. 
Prior to preparation of the infusion, the vials of study drug should be visually inspected.  
The solution should not be used if it contains foreign particulate matter or is discoloured.  
The solution may be used if a small number of visible translucent to opalescent or white 
amorphous or threadlike particles are present in the vial.  The contents should NOT be 
warmed using a microwave or other heat source.  SBC-103 is a protein and should be not 
be shaken but should be handled and mixed gently to prevent foaming. 
The subject’s most recent protocol-scheduled weight measurement, rounded to the 
nearest 0.1 kg, will be used for calculating the volume of study drug to be withdrawn 
from the vial(s) to prepare the IV infusion.  Study drug will be diluted in 0.9% saline for 
injection.   
Refer to the IMP Manual for detailed instruction regarding the preparation of the IV 
infusion.  
6.6.2 Administration of Study Drug 
All infusions must be administered under close supervision of the Investigator, or 
designee.  Study drug should not be infused with other products in the same infusion 
tubing, as the compatibility of SBC-103 in solution with other products has not been 
evaluated.  It is recommended that all infusions of study drug be administered using 
in-line filtration with a low protein binding 0.2 µm filter. 
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The recommended duration of the infusion is 2 hours at a constant rate.  The protocol 
allows for a change in rate should the subject experience an IAR.  At the discretion of the 
Investigator, and in consultation with the Sponsor, in circumstances such as a prior IAR 
or other like situations where subject safety is a concern, an extended duration of infusion 
or a variable rate is acceptable.  If the infusion is not well tolerated, the infusion rate may 
be decreased or interrupted as noted in Section 7.1.3 and Section 6.2.  All changes to 
infusion rate must be carefully recorded in the CRF, including the start and stop time of 
each rate change. 
Refer to the IMP Manual for detailed instruction on the administration of SBC-103. 
6.7 Blinding of SBC-103 
This is an open label study with no requirement for blinding. 
6.8 Destruction of SBC-103 
If any unused study drug material is remaining upon completion of the study, the material 
will be returned to the Sponsor or designee or destroyed only after the Sponsor or 
designee has performed final drug accountability and provided written authorization for 
the return or destruction of study drug.  Refer to the IMP Manual for further instructions. 
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7 ASSESSMENT OF SAFETY 
The methods for collecting safety data are described below.  All personnel involved with 
the study must ensure they are familiar with the content of this section. 
7.1 Adverse Events and Laboratory Abnormalities 
7.1.1 Clinical Adverse Events 
An AE is any untoward medical occurrence in a subject, which does not necessarily have 
to have a causal relationship with the administration of a study drug.  An AE can 
therefore be any unfavourable and unintended sign, symptom or disease temporally 
associated with the use of the study drug, whether or not considered related to the 
medicinal product.  Pre-existing conditions that worsen in severity during the course of 
the study are to be reported as AEs. 
All AEs occurring during the clinical study will be reported in the AE page of the CRF.   
The Investigator will assess the severity, causality (relationship to study drug), and 
seriousness of each AE. 
Severity: The Investigator will assess the severity of all AEs/SAEs as mild, moderate, or 
severe, based on the following definitions, developed from Clinical Data Interchange 
Standards Consortium Study Data Tabulation Model standard terminology v3.1.1). 
• Mild: A type of AE that is usually transient and may require only minimal 
treatment or therapeutic intervention.  The event does not generally interfere with 
usual activities of daily living.  
• Moderate: A type of AE that is usually alleviated with additional specific 
therapeutic intervention.  The event interferes with usual activities of daily living, 
causing discomfort, but poses no significant or permanent risk of harm to the 
research participant. 
• Severe: A type of AE that interrupts usual activities of daily living, or 
significantly affects clinical status, or may require intensive therapeutic 
intervention.  
Causality: AEs will be assessed as not related, unlikely related, possibly related, or 
related to study drug.  Table 3 provides general guidance on the assessment of causality.  
For data reporting purposes, AEs assessed as not related or unlikely related will be 
classified as unrelated to study drug, and AEs assessed as possibly related or related will 
be classified as related to study drug.  Assessment of causality should be based on the 
Investigator’s medical judgment and the observed symptoms associated with the event.  
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Table 3: 
Assessment of Causality 
Relationship to Study 
Drug 
Criteria for Judgment 
Related 
Reasonable temporal relationship of the clinical event to 
study drug administration AND cannot be reasonably 
explained by other factors (such as the subject’s clinical 
state, concomitant therapy, and/or other interventions). 
Possibly Related 
The temporal relationship of the clinical event to study 
drug administration makes causal relationship possible 
but not unlikely AND other drugs, therapeutic 
interventions, or underlying conditions do not provide a 
sufficient explanation for the observed event. 
Unlikely Related 
The temporal relationship of the clinical event to study 
drug administration makes causal relationship unlikely 
but not impossible AND other drugs, therapeutic 
interventions, or underlying conditions provide a plausible 
explanation for the observed event. 
Not Related 
Data are available to clearly identify an alternative cause 
for the reaction. 
Seriousness: AEs will be classified as serious or non-serious according to the definitions 
provided below.  
An SAE is any AE that is or leads to any of the following:  
• Death. 
• Immediately life threatening.  An AE is considered “life threatening” if, in the 
view of either the Investigator or Sponsor, its occurrence places the subject at 
immediate risk of death.  It does not include an AE that, had it occurred in a more 
severe form, might have caused death. 
• Requires in-patient hospitalisation or prolongation of existing hospitalization. 
• Congenital anomaly/birth defect. 
• Persistent or significant disability or incapacity. 
• An important medical event that may not result in death, be life threatening, or 
require hospitalization may be considered an SAE when, based upon appropriate 
medical judgment, the event may jeopardise the subject and may require medical 
or surgical intervention to prevent one of the outcomes listed above. 
A planned hospitalization to accommodate a study procedure is not considered an SAE.  
However, during the hospitalization, AEs will be collected and assessed for seriousness 
and reported appropriately (i.e., important medical event or prolonged hospitalization).  
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All AEs that do not meet any of the criteria for an SAE should be regarded as 
non-serious AEs. 
All SAEs and IARs must be reported to the Sponsor as described in Section 7.4.1. 
7.1.2 Laboratory Test Abnormality 
Laboratory test results will be recorded, or appear on the laboratory reports submitted 
directly from the laboratory.  Out-of-range laboratory test values should not be reported 
as AEs unless they are considered to be clinically significant abnormalities by the 
Investigator. 
7.1.3 Adverse Events of Special Interest (Infusion-Associated 
Reactions) 
IARs will be considered AEs of special interest.  Any AE that occurs during the infusion 
or within 4 hours after the infusion is completed and is assessed by the Investigator as at 
least possibly related to study drug will be designated as an IAR.  In addition, if, at any 
time during the study, the Investigator observes symptoms that he/she considers to be 
consistent with an IAR or hypersensitivity reaction related to administration of study 
drug, the symptoms should be recorded as an AE(s) and designated as an IAR(s).  
Individual AE terms should be recorded rather than the terms IAR or Infusion Associated 
Reaction. 
As with any ERT, medications and equipment for the treatment of hypersensitivity 
reactions must be available for immediate use in case of unexpected, severe 
hypersensitivity reaction.  These supplies include, but are not limited to, oxygen, 
antipyretics, antihistamines (e.g., diphenhydramine: parenteral and oral), corticosteroids, 
epinephrine, beta-adrenergic inhalers, and cardiopulmonary resuscitation devices. 
General guidelines for classifying the severity of a reaction are provided in Section 7.1.1. 
For similar biological products, most acute IARs occur within 2 hours of the infusion.  
Signs of a possible acute IAR may include:  
• Hyperemia, flushing, fever and/or chills, nausea, pruritus, urticaria, 
gastro-intestinal symptoms (vomiting, diarrhoea, abdominal cramping), 
cardiopulmonary reactions, including chest pain, cardiac arrhythmias, dyspnoea, 
wheezing, stridor, hypotension, or hypertension.  
Table 4 includes dose modifications required for all IARs and general guidance for the 
diagnosis and management of IARs in accordance with the institution’s standard of care.  
The Investigator should use clinical judgement in the management of IARs in individual 
subjects participating in this study.  In the case of a severe life-threatening reaction, 
current medical standards for emergency treatment are to be followed. 
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Table 4: 
Guidelines for the Management of Infusion-associated Reactions 
(IARs) 
Symptoms 
Action 
Mild Reaction 
Common 
• 
Hyperemia (flushing) 
• 
Flushing 
• 
Lightheadedness  
• 
Nausea 
• 
Mild chest discomfort (tightness) 
Less Common 
• 
Fever and/or shivering 
• 
Palpitations 
• 
Headache 
• 
Irritability (especially in young children) 
• 
Slow infusion rate by 50% 
• 
Administer antipyretic and/or antihistamine 
• 
Decrease infusion rate by a further 25% if 
symptoms persist 
• 
If the event resolves, the infusion should 
continue at a reduced rate for a minimum of 
30 minutes before the infusion is increased to 
75% of original rate.  If the subject tolerates 
the infusion at 75% of the original rate for at 
least 30 minutes the original rate may be 
restored for the remainder of the infusion. 
• 
If reactions persist despite rate reduction, stop 
infusion 
• 
Pre-treat with antihistamine and antipyretic 
prior (approximately 1.5 hours) to next 
infusion  
• 
e.g., diphenhydramine (1 mg/kg) by 
mouth and acetaminophen (15 mg/kg) by 
mouth 
Moderate Reaction 
• 
Hyperemia (flushing) 
• 
Chest discomfort 
• 
Itching and/or raised urticarial rash 
• 
Severe headache 
• 
Gastrointestinal symptoms, vomiting, 
diarrhoea, abdominal cramping 
• 
Stop infusion 
• 
Give antihistamine IV and consider IV or oral 
steroids in accordance with institutional 
standard of care 
• 
Consider giving a beta-adrenergic inhaler 
treatment if appropriate 
• 
If the event resolves, the infusion may 
continue at a reduced rate of 50% of the 
original for a minimum of 30 minutes before 
the infusion is increased to 75% of the original 
rate.  If the subject tolerates the infusion at 
75% of the original rate for at least 30 minutes 
the original rate may be restored for the 
remainder of the infusion.  
• 
If reaction persists despite rate reduction stop 
infusion 
• 
Pre-treat with oral antihistamine and 
antipyretic prior to next infusion 
• 
Collect serum for analysis of tryptase 
1-3 hours after the IAR onset and another 
serum sample for tryptase and ADA during the 
next study visit (≥ 4 days after the IAR) prior 
to the infusion. 
• 
Consider skin testing 
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Table 4: 
Guidelines for the Management of Infusion-associated Reactions 
(IARs) 
Symptoms 
Action 
Severe Reaction 
• 
Clinically significant cardiovascular effects: 
e.g., hypertension or hypotension defined as 
a decline approaching 20-30% of their 
preinfusion value without alternative 
aetiology (agitation, pain, fluid overload, 
dehydration)  
• 
Respiratory symptoms:  Significant 
shortness of breath, stridor, wheezing, 
laryngeal oedema, swelling of tongue 
• 
Cardiac arrhythmias 
• 
Anaphylactic/anaphylactoid shock with 
hypotension and circulatory collapse 
• 
Stop infusion 
• 
Give oxygen, if available 
• 
Give epinephrine (adrenaline)  
• 
Give antihistamines IV and steroids IV 
• 
Consider giving a beta-adrenergic inhaler 
treatment if appropriate 
• 
Collect serum sample for tryptase 1-3 hours 
after the IAR onset and another serum sample 
for tryptase and ADA during the next study 
visit (≥ 4 days after the IAR) prior to the 
infusion  
• 
Consider skin testing 
• 
Dosing of the subject will be suspended until 
the SRC has completed review of the IAR, and 
any other relevant safety data and any other 
relevant safety data (Section 6.2) 
• 
In the event subject is approved by the SRC 
for resumption of dosing: 
• 
Pre-treat with antihistamine and 
antipyretic prior to next infusion 
• 
Slowly up-titrate the infusion rate during 
the subsequent infusion: e.g., if previous 
rate was 50 mL/h, begin at 0.25 x previous 
rate (12.5 mL/h) x 15 min, then increase 
to 0.5 x rate (25 mL/h) x 15 min, then 
increase to 0.75 x rate (37.5 mL/h) x 
15 min, then increase to full rate 
(50 mL/h) for the remainder of the 
infusion 
Key: ADA = anti-drug antibodies; IAR = infusion-associated reaction; IV = intravenously; SRC = Safety 
Review Committee. 
 
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7.2 Handling of Safety Parameters 
7.2.1 Serious Adverse Events and Infusion-Associated Reactions 
(Immediately reportable to the Sponsor) 
All SAEs and all IARs (serious and non-serious), irrespective of the treatment received 
by the subject, must be reported to the Sponsor or designee immediately and no later than 
24 hours of the Investigator’s first knowledge of the event (expedited reporting). 
The definition and reporting requirement are in accordance with ICH Guideline for 
Clinical Safety Data Management, Definitions and Standards for Expedited Reporting 
(Topic E2, 1995). 
7.2.2 Adverse Event Reporting Period 
The study period during which AEs must be reported is defined as the period from 
signature of the informed consent to the end of the study treatment follow-up.  AEs 
occurring after signing the informed consent but prior to the first dose of study 
medication will only be recorded if assessed as related to protocol procedures or 
requirements.  For this study, the study treatment follow-up is defined as a minimum of 
30 days following the last administration of study treatment.  If a subject experiences an 
SAE that is considered to be related to study treatment at any time after the study, it must 
be reported to the Sponsor.  
7.2.3 Treatment and Follow-up of Adverse Events 
During the study, all AEs and SAEs will be followed up until they have returned to 
baseline status or stabilised or until the Investigator and Sponsor or designee agree that 
follow-up is no longer necessary.  If a clear explanation is established, it should be 
documented.  
Treatment of AEs is at the discretion of the Investigator and should follow the standards 
of medical care at the Investigator’s institution. 
7.2.4 Follow-up of Abnormal Laboratory Test Values 
In the event of unexplained clinically significant abnormal laboratory values, the tests 
should be repeated immediately and followed up until they have returned to baseline 
values and/or an adequate explanation of the abnormality is found.  If a clear explanation 
is established, it should be recorded.  All subjects showing possible drug-induced liver 
injury should be evaluated by a hepatologist for other causes of elevated hepatic function 
tests and followed until all abnormalities return to normal or baseline, or are deemed not 
to be related to the study drug.  
See Sections 5.2.1 and 6.2.1 regarding pausing rules for subjects with significantly 
elevated transaminases.  
7.2.5 Pregnancy 
Female subjects who are of childbearing potential at the time of consent or who become 
of childbearing potential during participation on study must agree to use a highly reliable 
method of birth control (expected failure rate less than 5% per year) for the duration of 
the study and for 30 days after the last dose of SBC-103.  
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Male subjects and their partners, must use a highly reliable method of birth control 
(expected failure rate less than 5% per year) for the duration of the study and for 30 days 
after last dose of SBC-103.  
As described in the Clinical Trial Facilitation Group Recommendations related to 
contraception and pregnancy testing in clinical trials dated 2014-09-13, acceptable 
contraceptive methods which may be considered as highly effective are summarized in 
Table 5. 
Table 5: 
Acceptable Contraceptive Methods Which May Be Considered Highly 
Effective 
Contraceptive Methods 
Notes 
Oral, intravaginal or transdermal combined 
(estrogen and progestogen containing) 
hormonal contraception associated with 
inhibition of ovulation 
 
 
Hormonal contraception may be susceptible to interaction 
with the IMP, which may reduce the efficacy of the 
contraception method. 
 
Implantable progestogen-only hormonal contraception is a 
contraceptive method that is considered to have low user 
dependency. 
Oral, injectable or implantable 
progestogen-only hormonal contraception 
associated with inhibition of ovulation 
Intrauterine device (IUD) 
 
 
These contraceptive methods are considered to have low 
user dependency. 
Intrauterine hormone-releasing system  
(IUS) 
Bilateral tubal occlusion 
Vasectomised partner 
A vasectomized partner is a contraceptive method that is 
considered to have low user dependency.  In addition a 
vasectomized partner is a highly effective birth control 
method provided that partner is the sole sexual partner of 
the WOCBP trial participant and that the vasectomised 
partner has received medical assessment of the surgical 
success. 
Sexual abstinence 
 
Sexual abstinence is considered a highly effective method 
only if defined as refraining from heterosexual intercourse 
during the entire period of risk associated with the study 
treatments.  The reliability of sexual abstinence needs to 
be evaluated in relation to the duration of the clinical trial 
and the preferred and usual lifestyle of the subject.  
Reference: Clinical Trial Facilitation Group; Recommendations related to contraception and pregnancy 
testing in clinical trials, FINAL VERSION 2014-09-13 
 
A female subject must immediately inform the Investigator if she becomes pregnant 
during the study and must not receive further SBC-103 infusions.  Pregnancies occurring 
up to 90 days after the completion of the last infusion must be reported to the 
Investigator.  The Investigator must report all pregnancies to the Sponsor within 24 hours 
of notification.  The Investigator should counsel the subject discussing the risks of 
continuing with the pregnancy and the possible effects on the foetus.  Monitoring of the 
subject should continue until conclusion of the pregnancy. 
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Pregnancy occurring in the partner of a subject participating in the study within 90 days 
of completion of the last infusion must also be reported to the Investigator and Sponsor.  
The partner should be counselled and followed as described above. 
7.3 Recording of Adverse Events 
At each contact with the subject (and the subject’s parent or caregiver), the Investigator 
must seek information on AEs by specific questioning and, as appropriate, by 
examination.  Information on all AEs should be recorded immediately in the source 
documentation and in the CRF.  All clearly related signs, symptoms, and abnormal 
diagnostic procedures results should be recorded under a single diagnosis.  
AEs will be recorded from the time of signing of the informed consent until completion 
of the last scheduled visit, i.e., the follow-up visit.  AEs occurring after signing the 
informed consent but prior to the first dose of study medication will only be recorded if 
assessed as related to protocol procedures or requirements.  Any AEs remaining 
unresolved should be recorded as ongoing.  Ongoing AEs/SAEs should continue to be 
followed up for the period specified in Section 7.2.2 but without further recording in the 
CRF.  However, follow-up information on SAEs must be reported to the Sponsor or 
designee as described in Section 7.4.1.  Any SAE that occurs after the study period and is 
considered to be possibly related to the study treatment or study participation should be 
recorded and reported immediately. 
Any AE that occurs within 24 hours of the infusion will be recorded by time and date.  
AEs occurring more than 24 hours after the infusion will be recorded by date only.  The 
date and time, or the date when the AE started and stopped, as well as the intensity, 
seriousness, action taken with regard to the SBC-103, causality assessment and outcome 
of the event will be recorded for each AE. 
7.4 Reporting of Serious Adverse Events, Infusion-Associated 
Reactions, and Unanticipated Problems 
Investigators and the Sponsor must conform to the AE reporting timelines, formats, and 
requirements of the various entities to which they are responsible (§13 GCP-V; Detailed 
guidance on the collection, verification and presentation of AE/reaction reports arising 
from clinical trials on medicinal products for human use [‘CT-3’]; US CFR Title 21, 
§312.32, Investigational New Drug [IND] safety reporting).  The Sponsor or designee 
will report all reportable events to all Regulatory Authorities, IECs or IRBs, and 
Investigators as required by local regulations. 
All SAEs and IARs, and other reportable events (see Section 7.4.3) must be reported to 
the Sponsor or designee in an expedited manner according to timelines described in 
Section 7.4.1. 
7.4.1 Investigator Reporting: Notifying the Sponsor 
Periodic safety reporting to Regulatory Authorities will be done by the Sponsor according 
to national and local regulations.  Any SAE, IAR, or unanticipated problem posing risk of 
harm to subjects, must be reported to the Sponsor or designee immediately and no later 
than 24 hours after the Investigator’s first knowledge of the event.  To report such events, 
an SAE/IAR form must be completed by the Investigator and sent within 24 hours.  The 
Investigator will keep a copy of this SAE/IAR form on file at the study site.  
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The Investigator will provide any additional information within 24 hours of becoming 
aware of this information.  This should include a copy of the completed SAE or IAR 
form, and any other information that will assist with the understanding of the event.  
Significant new information on ongoing SAEs or IARs must be reported to the Sponsor 
or designee immediately and no later than 24 hours after the Investigator’s becomes 
aware of this information.  
Report SAEs and IARs by fax to: 
PPD Pharmacovigilance Fax 
EU 
+44 1223 374102 
 
7.4.2 Investigator Reporting: Notifying the IRB/IEC 
Unanticipated problems posing risks to subjects or others as noted above will be reported 
to the IRB/IEC according to local regulations.  Copies of each report and documentation 
of IRB/IEC notification and receipt will be kept in the Investigator’s study file. 
7.4.3 Sponsor Reporting: Notifying Regulatory Authorities 
The Sponsor is required to report certain study events in an expedited manner to the US 
Food and Drug Administration, the European Medicines Agency, and to all country 
Regulatory Authorities where the study is being conducted.  The following describes the 
safety reporting requirements by timeline for reporting and associated type of event: 
• Immediately and within 7 calendar days 
• Any suspected adverse reaction that is: associated with the use of the study 
drug, unexpected, and fatal or life threatening.   
• Follow-up information must be reported in the following 8 calendar days. 
• Immediately and within 15 calendar days 
• Any suspected adverse reaction that is: associated with the use of the study 
drug, unexpected, and serious, but not fatal or life threatening. 
• Any finding from tests in laboratory animals that: suggest a significant 
risk for human subjects including reports of mutagenicity, teratogenicity, 
or carcinogenicity.  
• Any event in connection with the conduct of the study or the development 
of the IMP that may affect the safety of the study subjects. 
• Follow-up information must be reported within 15 calendar days. 
The Sponsor will comply with all additional local safety reporting requirements, as 
applicable.  Periodic safety reporting to competent authorities will be done by the 
Sponsor or designee according to national and local regulations. 
7.4.4 Sponsor Reporting: Notifying Participating Investigators 
It is the responsibility of the Sponsor or designee to immediately notify all participating 
Investigators of any AE associated with the use of the drug that is both serious and 
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unexpected, as well as any finding from tests in laboratory animals that suggest a 
significant risk for human subjects.   
7.5 Independent Safety Review Committee (SRC) 
It will be the responsibility of the PI to oversee the safety of the study at his/her site.  
Additional oversight of the subject safety in the study will be provided by an independent 
SRC composed of individuals with pertinent medical expertise, who will serve in 
advisory capacity to the Sponsor, to provide an additional level of scrutiny to minimise 
the chance that clinical study participants are exposed to unreasonable or unnecessary 
risks.  The SRC will provide additional oversight for safety through a bi-annual review of 
safety data, and will also be available for consultation on modification of dosing 
frequency, stopping of dosing in individual subjects or all subjects in accordance with the 
stopping rules (see Section 6.2).  The composition of the SRC and their specific activities 
will be outlined in the SRC Charter which will be ratified during the initial meeting, prior 
to commencement of dosing of the study subjects.  The SRC will be tasked with ongoing 
review of safety data in order to advise the Sponsor regarding continued dosing and dose 
escalation decisions for the study (see Section 3.3.3).  These safety monitoring functions 
and the oversight of such activities will be distinct from the requirement for study review 
and IRB/IEC approvals. 
Core members of the SRC will not participate in the study as Investigators or 
sub-Investigators, as members of any team otherwise participating in the study, or in any 
other capacity that may compromise their privileged activities on the SRC.  Neither 
members of the SRC nor their immediate family members will have a direct financial 
interest in the Sponsor or an interest that is dependent of the outcome of the study.  To be 
considered for SRC membership, all candidates must disclose all actual or potential 
conflicts of interest, including any financial interest in, or research activity on a 
competing product.  SRC members will be compensated at an appropriate market rate for 
time spent reviewing, discussing, and attending the meetings.  The Sponsor will also 
reimburse SRC members for any out-of-pocket travel expenses required for attendance at 
the meetings.  Aside from the above, SRC members will receive no additional 
compensation for their membership on the committee as outlined in the SRC Charter. 
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8 STATISTICAL PLAN 
8.1 General Considerations 
Descriptive summary statistics will be provided for baseline demographics, disease 
characteristics, and drug exposure.  Subject disposition including number of subjects 
screened, enrolled, dosed, and percentage of subjects who discontinued from the study, 
along with reasons for discontinuations will be tabulated and described in listings. 
Continuous data will be descriptively summarised (by number of subjects, mean, 
standard deviation, median, minimum, and maximum), and, where appropriate, graphic 
representation and 2-sided 95% confidence interval (CI) estimates.  Categorical data will 
be summarised by sample size, proportions, and 2-sided 95% CIs where possible. 
Descriptive summaries of data will be presented overall for all treated subjects and by 
dose cohort.  
8.2 Determination of Sample Size 
The sample size of up to 5 subjects is determined by the number of subjects enrolled in 
the prior NGLU-CL01 study, based on clinical and not statistical consideration.  Along 
with data from other NGLU studies this data, including PD/efficacy data, will inform 
dose selection, regimen, and study design for future studies. 
8.3 Analysis Sets 
The Full Analysis Set (FAS), defined as all subjects for whom informed consent has been 
obtained, who have a confirmed diagnosis of MPS IIIB, and who have received any 
amount of SBC-103, will be used to summarise safety and tolerability data.  
Analysis will include datasets based on the following study periods: 
• Observational Period: the NGLU-CL01 study visit to baseline (pre-dose) of the 
NGLU-CL01-T study. 
• On-Treatment Period: baseline of the NGLU-CL01-T study to end of the 
NGLU-CL01-T study. 
• Overall Study (Observational+On-Treatment Period): the NGLU-CL01 study visit 
to end of the NGLU-CL01-T study. 
To facilitate the descriptive summarisation of the above described data sets, baseline data 
contained in the NGLU-CL01 study database for these subjects, including medical 
history, demographics, concomitant medications, physical examination, safety labs, CSF, 
serum and urine HS, biomarkers, Vineland-II, and data from structural and diffusion 
MRI, will be transferred to and merged with the NGLU-CL01-T study database.  
On-study data from subjects in the NGLU-CL01 study for endpoints including NAGLU 
enzyme activity, concomitant medications, physical examination, vital signs, weight, 
ECG, Vineland-II, haematology, clinical chemistry, urinalysis, CSF, serum and urine HS, 
serum albumin, serum ferritin and chitotriosidase, plasma glutamic acid and glycine, 
CSF: calbindin, Tau, pTau, albumin, IgG, glutamic acid and glycine, routine analysis-cell 
counts, glucose and protein, structural and diffusion MRI that are contained in 
NGLU-CL01 database will also be copied and merged with NGLU-CL01-T database. 
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Also any additional assessments (e.g., neurocognitive and developmental assessments, 
lab data including serum and urine HS, biomarker data and concomitant medication) 
available in these subjects since the NGLU-CL01 study visit until the baseline of 
NGLU-CL01-T will also be captured in the NGLU-CL01-T database. 
All available observational period data from subjects enrolled in the NGLU-CL01 study 
for assessments also performed in the NGLU-CL01-T study will be copied and merged 
with the NGLU-CL01-T study database in order to facilitate analysis of changes in these 
assessments over both the untreated and treated periods. 
Details of the planned analyses will be provided in the statistical analysis plan (SAP). 
8.4 Safety Analysis  
Descriptive statistics will be computed for safety parameters as per FAS, as appropriate.  
Number and percentage of subjects who discontinued from the study because of AEs, 
will be tabulated across doses; severity and frequency of AEs and SAEs will also be 
tabulated across doses.  All other safety data will be provided in listings.  Baseline (as 
described in Section 8.3), within study, end of study, and change from baseline in 
physical examination findings, ECG, clinical laboratory values, and vital signs will be 
summarised by dose.  
The number and proportion (percentage) of subjects with measurable antibodies to 
SBC-103 will be displayed.  In addition, incidence of IARs will be tabulated by dose and 
overall.  Medications to treat IARs, including any pre-treatment medications, will also be 
presented by dose and for the entire study period.  SBC-103 infusions in which the rate 
was slowed or discontinued due to IARs will be detailed in a separate data listing. 
Additional statistical evaluations may be carried out for select endpoints, if warranted.  
All baseline and safety data collected during the study will be included in subject listings. 
8.5 Pharmacokinetic Analysis  
PK analysis will be performed using non-compartmental analysis method.  Graphs of PK 
concentration over time will be generated for each subject and also for all subjects in a 
dose group.  Serum PK parameter (Cmax, Tmax, AUC∞, T1/2, Cl, and Vss) assessments will 
be summarised for each subject, as well as for each dose group, using non-compartmental 
analysis method.  SBC-103 concentration in CSF will be summarised at available time 
points.  Additional analysis of PK data, including assessment of the impact of ADA, may 
be performed as appropriate.   
Further details will be provided in the PK section of the SAP or in a separate clinical 
pharmacology analysis plan. 
8.6 Pharmacodynamic/Efficacy Analyses  
Parameters describing total HS and exploratory disease-related biomarkers including 
NRE HS derivatives, will be provided in listings and may be tabulated as described 
previously. 
Parameters describing disease characteristics, symptoms, and QOL of subjects with MPS 
IIIB, including neurodegeneration (MRI), CSF-AI, neurocognitive and QOL 
(Vineland-II, BSID-III, KABC-II, BOT-2 Brief Form,  CCC-2, SBRS, CSHQ, SF-10, 
ZBI 12-item) will be provided in listings and may be tabulated as appropriate.  
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PD, disease characteristics, symptoms, and QOL outcomes analyses will be performed 
for the FAS.  Observed measurements and changes or percent changes from baseline in 
HS and NRE HS derivatives and disease-related biomarkers will be summarised overall 
and by dosing regimen for each time point.  Change in relative proportion of grey and 
white matter volume and microstructural integrity will be summarised.  
Scores and changes from baseline in the neurocognitive, disease characteristics, 
symptoms and QOL questionnaires will be summarised by time point.  
Graphs of actual values and changes over time may be created as appropriate.   
Parameters describing facial features of subjects with MPS IIIB will be provided in 
listings and may be tabulated as appropriate.  
Further details of the planned analyses will be provided in the SAP. 
8.7 Summaries of Data Prior to Study Completion 
Interim data may be summarised for presentation to Regulatory Authorities or to the 
scientific community to facilitate the development of SBC-103. 
Details of the pre-specified statistical analyses will be provided in a separate SAP. 
 
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9 SUBJECT DATA HANDLING AND RECORD KEEPING 
9.1 Confidentiality 
Information about study subjects will be kept confidential and managed according to the 
requirements of applicable local regulations. 
9.2 Source Documents 
Source data is all information, original records of clinical findings, observations, or other 
activities in a clinical study necessary for the reconstruction and evaluation of the study.  
Source data are contained in source documents.  Examples of these original documents 
and data records include: hospital records, clinical and office charts, laboratory notes, 
memoranda, subjects’ diaries or evaluation checklists, pharmacy dispensing records, 
recorded data from automated instruments, copies or transcriptions certified after 
verification as being accurate and complete, microfiches, photographic negatives, 
microfilm or magnetic media, x-rays, subject files, and records kept at the pharmacy, at 
the laboratories, and at medico-technical departments. 
The MRI images plus auxiliary information will be stored locally but also transmitted to 
the Sponsor in Digital Imaging and Communications in Medicine format for potential 
further internal analyses and for generation of illustrative images.  
9.3 Case Report Forms 
Required data for this study will be captured on CRFs via electronic data capture unless 
otherwise specified in this document.  Except for data points for which the protocol 
indicates that the CRF may serve as source documentation, data are to be obtained from 
the subject’s source documents and then entered into the CRF by authorised personnel.  
Clinical data that are not recorded on the CRF will be captured and transferred to the 
Sponsor or its designee.  
9.4 Records Retention 
It is the Investigator’s responsibility to retain study essential documents for at least 
2 years after the last approval of a marketing application for SBC-103 in their country 
and until there are no pending or contemplated marketing applications in their country or 
at least 2 years have elapsed since the formal discontinuation of clinical development of 
SBC-103.  These documents should be retained for a longer period if required by the 
local legislation requirements or an agreement with the Sponsor.  In such an instance, it is 
the responsibility of the Sponsor to inform the Investigator/Institution as to when these 
documents no longer need to be retained. 
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10 STUDY MONITORING, AUDITING, AND INSPECTING 
10.1 Study Monitoring Plan 
This study will be monitored according to the study monitoring plan.  The Investigator 
will allocate adequate time for such monitoring activities.  The Investigator will also 
ensure that the monitor or other compliance or quality assurance reviewer is given access 
to all the above noted study-related documents and study-related facilities (e.g., 
diagnostic laboratory), and has adequate space to conduct the monitoring visit. 
10.2 Auditing and Inspecting 
The Investigator will permit study-related monitoring, audits, and inspections by the 
IRB/IEC, the Sponsor (or their designee), government regulatory bodies, and quality 
assurance groups of all study-related documents (e.g., source documents, regulatory 
documents, data collection instruments, study data).  The Investigator will ensure the 
capability for inspections of applicable study-related facilities (e.g., diagnostic 
laboratory). 
Participation as an Investigator in this study implies acceptance of potential inspection by 
government Regulatory Authorities and applicable compliance and quality assurance 
offices. 
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11 ETHICAL CONSIDERATIONS 
This study is to be conducted in accordance with international standards of GCP (ICH, 
EU Directives 2001/20/EC and 2005/28/EC, and US 21 CFR 50 and 21 CFR 312), as 
well as all other applicable government regulations and institutional research policies and 
procedures. 
This protocol and any amendments will be submitted to a properly constituted IRB/IEC, 
in agreement with local legal prescriptions, for formal approval of the study conduct.  
The decision of the IRB/IEC concerning the conduct of the study will be made in writing 
to the applicant and a copy of this decision will be provided to the Sponsor before 
commencement of this study.  The IRB/IEC will be requested to provide a list of 
IRB/IEC members.  A member who is affiliated with the Sponsor should not participate 
in voting on the IRB/IEC opinion. 
Each subject (or the subject’s parent or legal guardian) will be given a consent form 
describing this study and providing sufficient information to allow the subject (or the 
subject’s parent or legal guardian) to make an informed decision about the subject’s 
participation in this study.  This consent form will be submitted with the protocol for 
review and approval by the IRB/IEC for the study.  The formal consent of a subject (or a 
subject’s parent or legal guardian), using the IRB/IEC-approved consent form, must be 
obtained before that subject undergoes any study procedure.  The consent form must be 
signed by the subject (or the subject’s parent or legal guardian), and the 
Investigator-designated research professional obtaining the consent.  
Any changes in the study protocol, such as changes in the study design, objectives or 
endpoints, inclusion and exclusion criteria, and/or procedures (except to eliminate an 
immediate hazard) will be implemented only after the mutual agreement of the 
Investigator and the Sponsor or designee.  All protocol changes must be documented in 
protocol amendment(s).  Protocol amendment(s) must be signed by the Investigator and 
approved (if applicable) by the IRB/IEC prior to implementation.  Any changes in study 
conduct that result from a pending amendment will be considered protocol deviations 
until IRB/IEC approval is granted.  Documentation of IRB/IEC approval must be 
returned to the Sponsor or designee. 
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12 CLINICAL STUDY REPORT AND DATA DISCLOSURE 
A clinical study report (CSR) will be produced upon completion of the study.  A 
coordinating Investigator will be designated to review and sign the completed CSR.  
Information about this study will be posted on the http://clinicaltrials.gov and 
https://www.clinicaltrialsregister.eu websites and, where applicable, on other websites 
required by the local Regulatory Authorities of participating countries. 
It is intended that the results from this research will be submitted to a peer-reviewed 
medical publication, once the study is completed. 
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14 APPENDICES 
 
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14.1 Appendix A: Schedule of Study Assessments 
Assessments 
Screening 
Day  
0 
Day  
1 
Week 
2 
Week 
4 
Week 
6 
Week 
8 
Week 
10 
Week 
12 
Week 
14 
Week 
16 
Week 
18 
Week 
20 
Week 
22 
Week 
24 
Week 
26 
Visit Window (Days) 
-28 to 0 
-5 to 
0 
days 
 
±5 
days 
±5 
days 
±5 
days 
±5 
days 
±5 
days 
±5 
days 
±5 
days 
±5 
days 
±5 
days 
±5 
days 
±5 
days 
±5 
days 
±5 
days 
Informed 
Consent/Assent*  
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Inclusion/Exclusion 
Criteria 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical History  
(review of changes 
from NGLU-CL01) 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Physical Examination 
X 
XP 
X 
 
XP 
 
XP 
 
XP 
 
XP 
 
XP 
 
XP 
 
Height and Weight 
X 
XP 
 
 
XP 
 
XP 
 
XP 
 
XP 
 
XP 
 
XP 
 
Vital Signs 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
12-lead ECG 
(Triplicate) 
X 
XP 
 
 
 
 
 
 
XP 
 
 
 
 
 
XP 
 
FDNA 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
Vineland-II , BSID-III, 
KABC-II, BOT-2 
Brief Form,  CCC-2, 
SBRS,CSHQ, ZBI, 
SF-102 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
XP 
 
Haematology, Serum 
Chemistry (including 
Coagulation), 
Urinalysis3 
X 
XP 
X 
 
XP 
 
XP 
 
XP 
 
XP 
 
XP 
 
XP 
 
Pregnancy Test 
(Urine)4 
X 
XP 
 
 
XP 
 
XP 
 
XP 
 
XP 
 
XP 
 
XP 
 
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NGLU-CL01-T Protocol  
24 February 2016 
Assessments 
Screening 
Day  
0 
Day  
1 
Week 
2 
Week 
4 
Week 
6 
Week 
8 
Week 
10 
Week 
12 
Week 
14 
Week 
16 
Week 
18 
Week 
20 
Week 
22 
Week 
24 
Week 
26 
Visit Window (Days) 
-28 to 0 
-5 to 
0 
days 
 
±5 
days 
±5 
days 
±5 
days 
±5 
days 
±5 
days 
±5 
days 
±5 
days 
±5 
days 
±5 
days 
±5 
days 
±5 
days 
±5 
days 
±5 
days 
Serum and Urine 
Heparan Sulphate 
(Total and NRE) 
X 
XP 
 
 
XP 
 
XP 
 
XP 
 
XP 
 
XP 
 
XP 
 
Serum Ferritin and 
Chitotriosidase 
X 
XP 
 
 
XP 
 
XP 
 
XP 
 
XP 
 
XP 
 
XP 
 
Plasma Glutamic Acid 
and Glycine 
X 
XP 
 
 
XP 
 
XP 
 
XP 
 
XP 
 
XP 
 
XP 
 
NAGLU enzyme 
activity 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Serum Biomarkers 
(Exploratory including 
IgG, inflammatory 
markers) 
 
XP 
 
 
XP 
 
XP 
 
XP 
 
XP 
 
XP 
 
XP 
 
Serum 
Pharmacokinetic 
Profile5 
 
X 
 
 
 
 
 
 
X 
 
 
 
 
 
X 
 
SBC-103 ADA6 
 
XP 
 
 
XP 
 
XP 
 
XP 
 
XP 
 
XP 
 
XP 
 
General 
Anaesthesia/Sedation7 
 
XP 
 
 
 
 
 
 
XP 
 
 
 
 
 
XP 
 
Lumbar Puncture7,8 
 
XP 
 
 
 
 
 
 
XP 
 
 
 
 
 
XP 
 
Heparan Sulphate 
(Total and NRE) in 
CSF 
 
XP 
 
 
 
 
 
 
XP 
 
 
 
 
 
XP 
 
Calbindin D, HGF, 
Tau, pTau, Amyloid β, 
Albumin, IgG in CSF 
 
XP 
 
 
 
 
 
 
XP 
 
 
 
 
 
XP 
 
Glutamic Acids and 
Glycine in CSF 
 
XP 
 
 
 
 
 
 
XP 
 
 
 
 
 
XP 
 
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NGLU-CL01-T Protocol  
24 February 2016 
Assessments 
Screening 
Day  
0 
Day  
1 
Week 
2 
Week 
4 
Week 
6 
Week 
8 
Week 
10 
Week 
12 
Week 
14 
Week 
16 
Week 
18 
Week 
20 
Week 
22 
Week 
24 
Week 
26 
Visit Window (Days) 
-28 to 0 
-5 to 
0 
days 
 
±5 
days 
±5 
days 
±5 
days 
±5 
days 
±5 
days 
±5 
days 
±5 
days 
±5 
days 
±5 
days 
±5 
days 
±5 
days 
±5 
days 
±5 
days 
Routine Findings  
(Cell Counts, Glucose, 
Protein) in CSF3 
 
XP 
 
 
 
 
 
 
XP 
 
 
 
 
 
XP 
 
SBC-103 in CSF 
 
XP 
 
 
 
 
 
 
XP 
 
 
 
 
 
XP 
 
Structural and 
Diffusion MRI7 
 
XP 
 
 
 
 
 
 
 
 
 
 
 
 
XP 
 
Telephone call 
 
 
 
X 
X 
X 
 
 
 
 
 
 
 
 
 
 
SBC-103 Dosing 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Adverse Events10 
CONTINUOUS 
Concomitant 
Medications11 
CONTINUOUS 
 
 
 
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NGLU-CL01-T Protocol  
24 February 2016 
Assessments 
Week 
28 
Week 
30 
Week 
32 
Week 
34 
Week 
36 
Week 
38 
Week 
40 
Week 
42 
Week 
44 
Week 
46 
Week 
48 
Week 
50 
Week 
52 
Visit Window (Days) 
±5  
days 
±5  
days 
±5  
days 
±5  
days 
±5  
days 
±5  
days 
±5  
days 
±5  
days 
±5  
days 
±5  
days 
±5  
days 
±5  
days 
±5  
days 
Physical Examination 
XP 
 
XP 
 
XP 
 
XP 
 
XP 
 
XP 
 
XP 
Height and Weight 
XP 
 
XP 
 
XP 
 
XP 
 
XP 
 
XP 
 
XP 
Vital Signs 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
12-lead ECG1 
 
 
 
 
 
 
 
 
 
 
 
 
XP 
FDNA 
 
 
 
 
 
 
 
 
 
 
 
 
X 
Vineland-II , BSID-III, 
KABC-II, BOT-2 Brief 
Form, CSHQ, CCC-2, 
SBRS, ZBI, SF-102 
 
 
 
 
 
 
 
 
 
 
 
 
XP 
Haematology, Serum 
Chemistry (incl. 
Coagulation), Urinalysis3 
XP 
 
 
 
XP 
 
 
 
XP 
 
 
 
XP 
Pregnancy Test (Urine) 4 
XP 
 
XP 
 
XP 
 
XP 
 
XP 
 
XP 
 
XP 
Serum and Urine Heparan 
Sulphate (Total and NRE) 
XP 
 
 
 
XP 
 
 
 
XP 
 
 
 
XP 
Serum Ferritin and 
Chitotriosidase 
XP 
 
 
 
XP 
 
 
 
XP 
 
 
 
XP 
Plasma Glutamic Acid and 
Glycine 
XP 
 
 
 
XP 
 
 
 
XP 
 
 
 
XP 
Serum Biomarkers 
(Exploratory including IgG, 
inflammatory markers) 
XP 
 
 
 
XP 
 
 
 
XP 
 
 
 
XP 
Serum Pharmacokinetic 
Profile5 
 
 
 
 
 
 
 
 
 
 
 
 
X 
SBC-103 ADA6 
XP 
 
XP 
 
XP 
 
XP 
 
XP 
 
XP 
 
XP 
General 
Anaesthesia/Sedation7 
 
 
 
 
XP 
 
 
 
 
 
 
 
XP 
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NGLU-CL01-T Protocol  
24 February 2016 
Assessments 
Week 
28 
Week 
30 
Week 
32 
Week 
34 
Week 
36 
Week 
38 
Week 
40 
Week 
42 
Week 
44 
Week 
46 
Week 
48 
Week 
50 
Week 
52 
Visit Window (Days) 
±5  
days 
±5  
days 
±5  
days 
±5  
days 
±5  
days 
±5  
days 
±5  
days 
±5  
days 
±5  
days 
±5  
days 
±5  
days 
±5  
days 
±5  
days 
Lumbar Puncture7,8 
 
 
 
 
XP 
 
 
 
 
 
 
 
XP 
Heparan Sulphate (Total and 
NRE) in CSF 
 
 
 
 
XP 
 
 
 
 
 
 
 
XP 
Calbindin D, HGF, Tau, 
pTau, Amyloid β, Albumin, 
IgG in CSF 
 
 
 
 
XP 
 
 
 
 
 
 
 
XP 
Glutamic Acids and Glycine 
in CSF 
 
 
 
 
XP 
 
 
 
 
 
 
 
XP 
Routine Findings (Cell 
Counts, Glucose, Protein) in 
CSF3 
 
 
 
 
XP 
 
 
 
 
 
 
 
XP 
SBC-103 in CSF 
 
 
 
 
XP 
 
 
 
 
 
 
 
XP 
Structural and Diffusion 
MRI7 
 
 
 
 
 
 
 
 
 
 
 
 
XP 
SBC-103 Dosing 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Adverse Events10 
CONTINUOUS 
Concomitant Medications11 
CONTINUOUS 
 
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NGLU-CL01-T Protocol  
24 February 2016 
Assessments 
Week  
 54 
Week  
56 
Week 
58 
Week 
60 
Week 
62 
Week 
64 
Week 
66 
Week 
68 
Week 
70 
Week  
72 
Week 
74 
Week 
76 
Week  
78 
Visit Window (Days) 
±5  
days 
±5  
days 
±5  
days 
±5  
days 
±5  
days 
±5  
days 
±5  
days 
±5  
days 
±5  
days 
±5  
days 
±5  
days 
±5  
days 
±5  
days 
Physical Examination 
 
XP 
 
XP 
 
XP 
 
XP 
 
XP 
 
XP 
 
Height and Weight 
 
XP 
 
XP 
 
XP 
 
XP 
 
XP 
 
XP 
 
Vital Signs12 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
12-lead ECG1   
 
 
 
 
 
 
 
 
 
 
 
 
XP 
FDNA 
 
 
 
 
 
 
 
 
 
 
 
 
X 
Vineland-II , BSID-
III, KABC-II, BOT-2 
Brief Form, CSHQ, 
CCC-2, SBRS, ZBI, 
SF-102 
 
 
 
 
 
 
 
 
 
 
 
 
XP 
Haematology, Serum 
Chemistry (including 
Coagulation), 
Urinalysis3 
 
 
 
XP 
 
 
 
XP 
 
 
 
 
XP 
Pregnancy Test 
(Urine) 4 
 
XP 
 
XP 
 
XP 
 
XP 
 
XP 
 
XP 
 
Serum and Urine 
Heparan Sulphate 
(Total and NRE) 
 
 
 
XP 
 
 
 
XP 
 
 
 
 
XP 
Serum Ferritin and 
Chitotriosidase  
 
 
 
XP 
 
 
 
XP 
 
 
 
 
XP 
Plasma Glutamic 
Acid and Glycine 
 
 
 
XP 
 
 
 
XP 
 
 
 
 
XP 
Serum Biomarkers 
(Exploratory 
including IgG, 
inflammatory 
markers) 
 
 
 
XP 
 
 
 
XP 
 
 
 
 
XP 
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NGLU-CL01-T Protocol  
24 February 2016 
Assessments 
Week  
 54 
Week  
56 
Week 
58 
Week 
60 
Week 
62 
Week 
64 
Week 
66 
Week 
68 
Week 
70 
Week  
72 
Week 
74 
Week 
76 
Week  
78 
Visit Window (Days) 
±5  
days 
±5  
days 
±5  
days 
±5  
days 
±5  
days 
±5  
days 
±5  
days 
±5  
days 
±5  
days 
±5  
days 
±5  
days 
±5  
days 
±5  
days 
Serum 
Pharmacokinetic 
Profile5 
 
 
 
 
 
 
 
 
 
 
 
 
X 
SBC-103 ADA6 
 
XP 
 
XP 
 
XP 
 
XP 
 
XP 
 
XP 
 
General 
Anaesthesia/Sedation7 
 
 
 
 
 
 
 
XP 
 
 
 
 
XP 
Lumbar Puncture7,8 
 
 
 
 
 
 
 
XP 
 
 
 
 
XP 
Heparan Sulphate 
(Total and NRE) in 
CSF 
 
 
 
 
 
 
 
XP 
 
 
 
 
XP 
Calbindin D, HGF, 
Tau, pTau, Amyloid 
β, Albumin, IgG in 
CSF 
 
 
 
 
 
 
 
XP 
 
 
 
 
XP 
Glutamic Acids and 
Glycine in CSF 
 
 
 
 
 
 
 
XP 
 
 
 
 
XP 
Routine Findings 
(Cell Counts, 
Glucose, Protein) in 
CSF3 
 
 
 
 
 
 
 
XP 
 
 
 
 
XP 
SBC-103 in CSF 
 
 
 
 
 
 
 
XP 
 
 
 
 
XP 
SBC-103 Dosing 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Adverse Events10 
CONTINUOUS 
Concomitant 
Medications11 
CONTINUOUS 
 
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NGLU-CL01-T Protocol  
24 February 2016 
Assessments 
Week 
80 
Week 
82 
Week 
84 
Week 
86 
Week 
88 
Week 
90 
Week 
92 
Week 
94 
Week 
96 
Week 
98 
Week 
100 
Week 
102 
Week 
104 
Visit Window (Days) 
±5  
days 
±5  
days 
±5  
days 
±5  
days 
±5 
days 
±5  
days 
±5  
days 
±5  
days 
±5  
days 
±5  
days 
±5  
days 
±5  
days 
±5  
days 
Physical Examination 
XP 
 
XP 
 
XP 
 
XP 
 
XP 
 
XP 
 
XP 
Height and Weight 
XP 
 
XP 
 
XP 
 
XP 
 
XP 
 
XP 
 
XP 
Vital Signs12 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
12-lead ECG1  
 
 
 
 
 
 
 
 
 
 
 
 
XP 
FDNA 
 
 
 
 
 
 
 
 
 
 
 
 
X 
Vineland-II , BSID-III, 
KABC-II, BOT-2 Brief 
Form, CSHQ, CCC-2, 
SBRS, ZBI, SF-102 
 
 
 
 
 
 
 
 
 
 
 
 
XP 
Haematology, Serum 
Chemistry (including 
Coagulation), 
Urinalysis3 
 
 
 
XP 
 
 
 
XP 
 
 
 
 
XP 
Serum albumin sample 
 
 
 
 
 
XP 
 
 
 
 
 
 
 
Pregnancy Test (Urine) 
4 
XP 
 
XP 
 
XP 
 
XP 
 
XP 
 
XP 
 
XP 
Serum and Urine 
Heparan Sulphate 
(Total and NRE) 
 
 
 
XP 
 
XP 
 
XP 
 
 
 
 
XP 
Serum Ferritin and 
Chitotriosidase 
 
 
 
XP 
 
 
 
XP 
 
 
 
 
XP 
Plasma Glutamic Acid 
and Glycine 
 
 
 
XP 
 
 
 
XP 
 
 
 
 
XP 
Serum Biomarkers 
(Exploratory including 
IgG, inflammatory 
markers) 
 
 
 
XP 
 
 
 
XP 
 
 
 
 
XP 
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NGLU-CL01-T Protocol  
24 February 2016 
Assessments 
Week 
80 
Week 
82 
Week 
84 
Week 
86 
Week 
88 
Week 
90 
Week 
92 
Week 
94 
Week 
96 
Week 
98 
Week 
100 
Week 
102 
Week 
104 
Visit Window (Days) 
±5  
days 
±5  
days 
±5  
days 
±5  
days 
±5 
days 
±5  
days 
±5  
days 
±5  
days 
±5  
days 
±5  
days 
±5  
days 
±5  
days 
±5  
days 
Serum Pharmacokinetic 
Profile5 
 
 
 
 
 
 
 
 
 
 
 
 
X 
SBC-103 ADA6 
XP 
 
XP 
 
XP 
 
XP 
 
XP 
 
XP 
 
XP 
General 
Anaesthesia/Sedation7 
 
 
 
 
 
XP 
 
 
 
 
 
 
XP 
Lumbar Puncture7,8 
 
 
 
 
 
XP 
 
 
 
 
 
 
XP 
Heparan Sulphate 
(Total and NRE) in 
CSF 
 
 
 
 
 
XP 
 
 
 
 
 
 
XP 
Calbindin D, HGF, Tau, 
pTau, Amyloid β, 
Albumin, IgG in CSF 
 
 
 
 
 
XP 
 
 
 
 
 
 
XP 
Glutamic Acids and 
Glycine in CSF 
 
 
 
 
 
XP 
 
 
 
 
 
 
XP 
Routine Findings (Cell 
Counts, Glucose, 
Protein) in CSF3 
 
 
 
 
 
XP 
 
 
 
 
 
 
XP 
SBC-103 in CSF 
 
 
 
 
 
XP 
 
 
 
 
 
 
XP 
Structural and Diffusion 
MRI7 
 
 
 
 
 
 
 
 
 
 
 
 
XP 
SBC-103 Dosing 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Adverse Events10 
CONTINUOUS 
Concomitant 
Medications11 
CONTINUOUS 
 
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NGLU-CL01-T Protocol  
24 February 2016 
Assessments 
Week  
106 
Week 
108 
Week 
110 
Week 
112 
Week 
114 
Week 
116 
Week 
118 
Week 
120 
Week 
122 
Week 
124 
Week 
126 
Week 
128 
Week 
130 
Week 
132 
Visit Window (Days) 
±5 
days 
±5 
days 
±5 
days 
±5 
days 
±5 
days 
±5 
days 
±5 
days 
±5 
days 
±5 
days 
±5 
days 
±5 
days 
±5 
days 
±5 
days 
±5 
days 
Physical Examination 
 
XP 
 
XP 
 
XP 
 
XP 
 
XP 
 
XP 
 
XP 
Height and Weight 
 
XP 
 
XP 
 
XP 
 
XP 
 
XP 
 
XP 
 
XP 
Vital Signs12 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
12-lead ECG1   
 
 
 
 
 
 
 
 
 
 
 
 
XP 
 
FDNA 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
Vineland-II , BSID-III, 
KABC-II, BOT-2 Brief 
Form, CSHQ, CCC-2, 
SBRS, ZBI, SF-102 
 
 
 
 
 
 
 
 
 
 
 
 
XP 
 
Haematology, Serum 
Chemistry (including 
Coagulation), Urinalysis3 
 
 
 
XP 
 
 
 
XP 
 
 
 
 
XP 
 
Pregnancy Test (Urine) 4 
 
XP 
 
XP 
 
XP 
 
XP 
 
XP 
 
XP 
 
XP 
Serum and Urine Heparan 
Sulphate (Total and NRE) 
 
 
 
XP 
 
 
 
XP 
 
 
 
 
XP 
 
Serum Ferritin and 
Chitotriosidase  
 
 
 
XP 
 
 
 
XP 
 
 
 
 
XP 
 
Plasma Glutamic Acid and 
Glycine 
 
 
 
XP 
 
 
 
XP 
 
 
 
 
XP 
 
Serum Biomarkers 
(Exploratory including 
IgG, inflammatory 
markers) 
 
 
 
XP 
 
 
 
XP 
 
 
 
 
XP 
 
Serum Pharmacokinetic 
Profile5 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
SBC-103 ADA6 
 
XP 
 
XP 
 
XP 
 
XP 
 
XP 
 
XP 
 
XP 
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NGLU-CL01-T Protocol  
24 February 2016 
Assessments 
Week  
106 
Week 
108 
Week 
110 
Week 
112 
Week 
114 
Week 
116 
Week 
118 
Week 
120 
Week 
122 
Week 
124 
Week 
126 
Week 
128 
Week 
130 
Week 
132 
Visit Window (Days) 
±5 
days 
±5 
days 
±5 
days 
±5 
days 
±5 
days 
±5 
days 
±5 
days 
±5 
days 
±5 
days 
±5 
days 
±5 
days 
±5 
days 
±5 
days 
±5 
days 
General 
Anaesthesia/Sedation7 
 
 
 
 
 
 
 
XP 
 
 
 
 
XP 
 
Lumbar Puncture7,8 
 
 
 
 
 
 
 
XP 
 
 
 
 
XP 
 
Heparan Sulphate (Total 
and NRE) in CSF 
 
 
 
 
 
 
 
XP 
 
 
 
 
XP 
 
Calbindin D, HGF, Tau, 
pTau, Amyloid β, 
Albumin, IgG in CSF 
 
 
 
 
 
 
 
XP 
 
 
 
 
XP 
 
Glutamic Acids and 
Glycine in CSF 
 
 
 
 
 
 
 
XP 
 
 
 
 
XP 
 
Routine Findings (Cell 
Counts, Glucose, Protein) 
in CSF3 
 
 
 
 
 
 
 
XP 
 
 
 
 
XP 
 
SBC-103 in CSF 
 
 
 
 
 
 
 
XP 
 
 
 
 
XP 
 
SBC-103 Dosing 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Adverse Events10 
CONTINUOUS 
Concomitant Medications11 
CONTINUOUS 
 
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NGLU-CL01-T Protocol  
24 February 2016 
Assessments 
Week  
134 
Week 
136 
Week 
138 
Week 
140 
Week 
142 
Week 
144 
Week 
146 
Week 
148 
Week 
150 
Week 
152 
Week 
154 
Week 156/ 
End of 
Treatment/ 
Early 
Termination 
Week 
160 
Visit Window (Days) 
±5 
days 
±5 
days 
±5 
days 
±5 
days 
±5 
days 
±5 
days 
±5 
days 
±5 
days 
±5 
days 
±5 
days 
±5 
days 
±5  
days 
±5 
days 
Physical Examination 
 
XP 
 
XP 
 
XP 
 
XP 
 
XP 
 
XP 
 
Height and Weight 
 
XP 
 
XP 
 
XP 
 
XP 
 
XP 
 
XP 
 
Vital Signs12 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
12-lead ECG1   
 
 
 
 
 
 
 
 
 
 
 
XP 
 
FDNA 
 
 
 
 
 
 
 
 
 
 
 
X 
 
Vineland-II , BSID-III, 
KABC-II, BOT-2 Brief Form, 
CSHQ, CCC-2, SBRS, ZBI, 
SF-102 
 
 
 
 
 
 
 
 
 
 
 
XP 
 
Haematology, Serum 
Chemistry (including 
Coagulation), Urinalysis3 
 
 
XP 
 
 
 
XP 
 
 
 
 
XP 
 
Serum Albumin sample 
 
 
 
 
X 
 
 
 
 
 
 
 
 
Pregnancy Test (Urine) 4 
 
XP 
 
XP 
 
XP 
 
XP 
 
XP 
 
XP 
 
Serum and Urine Heparan 
Sulphate (Total and NRE) 
 
 
XP 
 
XP 
 
XP 
 
 
 
 
XP 
 
Serum Ferritin and 
Chitotriosidase  
 
 
XP 
 
 
 
XP 
 
 
 
 
XP 
 
Plasma Glutamic Acid and 
Glycine 
 
 
XP 
 
 
 
XP 
 
 
 
 
XP 
 
Serum Biomarkers 
(Exploratory including IgG, 
inflammatory markers) 
 
 
XP 
 
 
 
XP 
 
 
 
 
XP 
 
Serum Pharmacokinetic 
Profile5 
 
 
 
 
 
 
 
 
 
 
 
X 
 
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NGLU-CL01-T Protocol  
24 February 2016 
Assessments 
Week  
134 
Week 
136 
Week 
138 
Week 
140 
Week 
142 
Week 
144 
Week 
146 
Week 
148 
Week 
150 
Week 
152 
Week 
154 
Week 156/ 
End of 
Treatment/ 
Early 
Termination 
Week 
160 
Visit Window (Days) 
±5 
days 
±5 
days 
±5 
days 
±5 
days 
±5 
days 
±5 
days 
±5 
days 
±5 
days 
±5 
days 
±5 
days 
±5 
days 
±5  
days 
±5 
days 
SBC-103 ADA6 
 
XP 
 
XP 
 
XP 
 
XP 
 
XP 
 
XP 
 
General 
Anaesthesia/Sedation7 
 
 
 
 
XP 
 
 
 
 
 
 
XP 
 
Lumbar Puncture7,8 
 
 
 
 
XP 
 
 
 
 
 
 
XP 
 
Heparan Sulphate (Total and 
NRE) in CSF 
 
 
 
 
XP 
 
 
 
 
 
 
XP 
 
Calbindin D, HGF, Tau, 
pTau, Amyloid β, Albumin, 
IgG in CSF 
 
 
 
 
XP 
 
 
 
 
 
 
XP 
 
Glutamic Acids and Glycine 
in CSF 
 
 
 
 
XP 
 
 
 
 
 
 
XP 
 
Routine Findings (Cell 
Counts, Glucose, Protein) in 
CSF3 
 
 
 
 
XP 
 
 
 
 
 
 
XP 
 
SBC-103 in CSF 
 
 
 
 
XP 
 
 
 
 
 
 
XP 
 
Structural and Diffusion MRI7 
 
 
 
 
 
 
 
 
 
 
 
XP 
 
Telephone call9 
 
 
 
 
 
 
 
 
 
 
 
 
X 
SBC-103 Dosing 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Adverse Events10 
CONTINUOUS 
Concomitant Medications11 
CONTINUOUS 
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NGLU-CL01-T Protocol  
24 February 2016 
Assessments 
Week  
134 
Week 
136 
Week 
138 
Week 
140 
Week 
142 
Week 
144 
Week 
146 
Week 
148 
Week 
150 
Week 
152 
Week 
154 
Week 156/ 
End of 
Treatment/ 
Early 
Termination 
Week 
160 
Visit Window (Days) 
±5 
days 
±5 
days 
±5 
days 
±5 
days 
±5 
days 
±5 
days 
±5 
days 
±5 
days 
±5 
days 
±5 
days 
±5 
days 
±5  
days 
±5 
days 
Key:  ADA = anti-drug antibodies; BOT-2 Brief Form  = Bruininks-Oseretsky Test of Motor Proficiency, Second Edition, Brief Form; BSID-III = Bayley Scales of 
Infant and Toddler Development, Third Edition; CCC-2 = Children’s Communication Checklist, Second Edition;  CSF = cerebrospinal fluid; CSHQ = Children’s Sleep 
Habits Questionnaire; D = day; ECG = electrocardiogram; FDNA = Facial Dysmorphology Novel Analysis; HGF = hepatocyte growth factor; IgG = immunoglobulin G; 
KABC-II = Kaufman Assessment Battery for Children, Second Edition; NAGLU = alpha-N-acetylglucosaminidase; MRI = magnetic resonance imaging; NRE = non-
reducing end; SBRS = Sanfilippo Behavior Rating Scale; SF-10 = Short Form Health Survey for Children; Vineland-II = Vineland Adaptive Behavior Scales, Second 
Edition; Wk = week; ZBI = Zarit Burden Interview, 12-item. 
*All study visits will be scheduled relative to Day 0.  Infusions will be administered every 14 days ± 5 days and must be administered at least 10 days apart.  Informed 
consent may be granted before the beginning of the screening period.  All screening assessments other than informed consent should be completed within a 28-day 
window. 
XP Assessments to be performed pre-dose 
1 ECG assessments after 6 months do not need to be performed in triplicate. 
2 The Vineland-II, BSID-III or KABC-II, BOT-2 Brief Form, and CCC-2 should be administered in-person by an appropriately qualified professional.  
3 Local lab ranges will be used for those labs analysed locally.  If samples are taken within 3 days of Day 0, samples do not need to be repeated on Day 0.  However, a 
Day 0 serum sample for albumin should be collected at the same time as the CSF collection, to enable calculation of CSF-AI.  Central laboratory parameter reference 
ranges will be used throughout the study, including in the event that laboratory parameters are analysed locally.  All attempts should be made to draw laboratory 
samples for central laboratory analysis when samples are needed for local analysis.  Day 1 samples will be analysed locally, all other samples may be analysed 
centrally. 
4 If a urine sample is not able to be provided, a serum pregnancy test will be performed by a local laboratory. 
5 Refer to Section 5.2.1.2 for directions and timing of PK sampling. 
6 In addition to time points indicated, obtain a sample for ADA determination anytime subject experiences a moderate-to-severe IAR during the next study visit 
(≥ 4 days after the IAR) and prior to the infusion.  
7 Lumbar puncture and MRI procedures may be performed under general anaesthesia or light sedation, as clinically appropriate in accordance with local 
institutional procedures.  If clinically indicated, subjects may also receive general anaesthesia or sedation for central line placement for long-term vascular 
access, in accordance with institutional guidelines.  When possible, the procedure to place the central line should be performed while the subject is already 
anaesthetised or sedated for another study procedure.  After the lumbar puncture is completed, the subject should be observed as per institution standard 
practice.  Vital signs, adverse events, and concomitant medications should be assessed before the subject is discharged from the site. 
8 During study visits where CSF is collected, and no serum chemistry sample is indicated per the SOA, a serum albumin sample should be collected to assess CSF-AI.  
After the lumbar puncture is completed, the subject should be observed as per institution standard practice. 
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Assessments 
Week  
134 
Week 
136 
Week 
138 
Week 
140 
Week 
142 
Week 
144 
Week 
146 
Week 
148 
Week 
150 
Week 
152 
Week 
154 
Week 156/ 
End of 
Treatment/ 
Early 
Termination 
Week 
160 
Visit Window (Days) 
±5 
days 
±5 
days 
±5 
days 
±5 
days 
±5 
days 
±5 
days 
±5 
days 
±5 
days 
±5 
days 
±5 
days 
±5 
days 
±5  
days 
±5 
days 
9 A telephone follow-up call will be made 4 weeks after the last dose received of SBC-103 after Week 156 End of Treatment or after the Early Termination visit.   
10 All AEs should be followed until they have returned to baseline values or stabilised or until the Investigator and Sponsor or designee agree that follow-up is no longer 
necessary.  
11 Information on all medications and treatments received by the subject within the 4 weeks preceding the Screening visit through the final visit will be recorded in the 
CRF.   
12 Starting at Week 54, vital signs may be taken pre-dose (within approximately 30 minutes), approximately every 15 minutes during infusion and approximately every 
15 minutes for 1 hour after completion of the infusion, provided there is no occurrence of IARs during the infusion.  Vital signs will be obtained after any lumbar 
puncture as per site standard of care. 
 
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14.2 Appendix B: NGLU-CL01-T Neurocognitive, Developmental and 
QOL Assessments 
 
Assessment* 
Administered to 
Special Instructions 
Vineland-II 
Parent/Caregiver 
Must be administered prior to the other 
developmental tests at Screening (i.e., 
BSID-III, KABC-II, BOT-2 Brief Form, 
CCC-2).  
Administered in-person 
BSID-III1 
Subject 
 
At Screening, administered to subjects with 
Vineland-II age equivalent of < 3 years, 
6 months). 
Administered in-person  
KABC-II1 
Subject 
 
At Screening, administered to subjects with 
Vineland-II age equivalent of ≥ 3 years, 
6 months. 
Administered in-person  
BOT-2 Brief 
Form2 
Subject 
Administered only to subjects who 
complete the KABC-II. 
CCC-22 
Parent/Caregiver 
Administered only to subjects completing 
the KABC-II. 
ZBI, 12-item 
Parent/Caregiver 
 
SF-10 
Parent/Caregiver 
 
SBRS 
Parent/Caregiver 
 
CSHQ 
Parent/Caregiver 
 
* All neurocognitive, developmental and QOL assessments are administered during the Screening visit.  
Assessments can be performed over multiple days. 
1 Either the BSID-III or KABC-II will be administered to the subject depending on the mean age 
equivalent determined by the Vineland-II at Screening. 
2 Administered only to subjects completing the KABC-II 
 
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