Clinical trial NCT03811028
Conditions: Sanfilippo Syndrome Type A (MPS IIIA)
Sponsor: Swedish Orphan Biovitrum
Start date: 2019-01-19; Completion date: 2021-05-07
Enrollment: 6 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
MPS IIIA, also known as Sanfilippo A, is an inherited lysosomal storage disease (LSD). MPS IIIA is caused by a deficiency in sulfamidase, one of the enzymes involved in the lysosomal degradation of the glycosaminoglycan (GAG) heparan sulfate (HS). The natural course of MPS IIIA is characterized by devastating neurodegeneration with initially mild somatic involvement. The aim of the present study is to assess the safety, tolerability and efficacy of long-term SOBI003 treatment. SOBI003 is a chemically modified recombinant human (rh) Sulfamidase developed as an enzyme replacement therapy (ERT).

Detailed description:
This is an open, single-arm, multicenter extension study to assess the safety, tolerability and efficacy of long-term SOBI003 treatment in pediatric MPS IIIA patients. The study is an extension of the First in Human (FIH) SOBI003-001 study, allowing continuous treatment of SOBI003 for up to 2 years. Study patients who complete Week 24 of the FIH study (SOBI003-001) will be invited to continue to Week 25 in the extension study.

When entering the extension study, these patients will receive the highest dose that has been declared safe in the ongoing FIH study (SOBI003-001). Upon completion of the FIH study, an analysis aimed at selecting the dose for forthcoming studies will take place. Once the dose has been selected, this dose will be applied to all patients enrolled in the extension study. The total duration of the extension study for an individual patient is 80 weeks, resulting in a total of 104 weeks (2 years) of SOBI003 treatment.

Arms: arm 1: SOBI003 solution, 20 mg/mL, is mixed with NaCl 0.9% infusion solution prior to administration. For a bodyweight \< 25 kg, the total infusion volume is 100 mL. For a bodyweight ≥ 25 kg, the total infusion volume is 250 mL.

SOBI003 is administered as i.v. infusions given once weekly for a duration of 80 weeks (from Week 25 until Week 104 following the first 24 weeks of SOBI003 administration in the FIH study (SOBI003-001) study. The SOBI003 dose will be adjusted to the highest dose that has been declared safe by the safety review committee on the FIH study.Hence, dose adjustments may occur a couple of times on the extension study until the final decided dose has been determined.
Interventions: intervention 1: SOBI003
Intervention descriptions: intervention 1: weekly i.v. infusion

Protocol documents:
Prot_000.pdf: 
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An open, single-arm, multicenter extension study to assess the safety, 
tolerability and efficacy of long-term SOBI003 treatment in pediatric 
MPS IIIA patients 
Final Protocol of the Study 
SOBI003-002 
IND no. 128889 
Type of Study: Phase I/II Extension, Therapeutic Exploratory 
 
Sponsor’s Medical Director  
Principal Coordinating Investigator  
 
 
 
 
 
 
 
 
 
  
 
 
Signature 
Date 
Signature 
Date 
 
Sponsor’s Study Manager 
Sponsor’s Statistician 
 
 
 
 
 
 
Signature 
Date 
Signature 
Date 
 
Confidential 
This protocol contains confidential information belonging to Swedish Orphan Biovitrum. Except as may be 
otherwise agreed to in writing, by accepting or reviewing these materials, you agree to hold such information in 
confidence and not to disclose it to others (except where required by applicable law) nor use it for unauthorized 
purposes. In the event of actual or suspected breach of this obligation, Swedish Orphan Biovitrum should be 
promptly notified. 
 


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Investigator statement 
I have read the protocol entitled “An open, single-arm, multicenter extension study to assess the 
safety, tolerability and efficacy of long-term SOBI003 treatment in pediatric MPS IIIA patients” 
and the accompanying current investigator’s brochure. I agree to conduct the clinical 
investigation in compliance with the Final Protocol, Version 1.0, 29 Jun 2018, the International 
Council on Harmonisation (ICH) harmonised tripartite guideline E6(R2): Guideline for Good 
Clinical Practice, applicable regulatory/government regulations, and in accordance with the latest 
revision of the Ethical Principles for Medical Research Involving Human Subjects (the 
Declaration of Helsinki). I will not implement any changes to study procedures or conduct 
without prior approval from the sponsor and, when applicable, the Independent Ethics 
Committee/Institutional Review Board and Regulatory Authority. 
I agree to maintain the confidentiality of this study protocol, as described on the title page. 
Further, I will not publish results of the study without authorization from Swedish Orphan 
Biovitrum AB (publ). 
 
 
 
 
Signature of Principal Investigator 
 
Date 
 
 
 
 
 
 
Printed Name of Principal Investigator 
 
 
 
. 
 
 


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Table of contents 
1 
Synopsis ............................................................................................................................ 8 
2 
Abbreviations and definition of terms............................................................................. 15 
3 
Ethics ............................................................................................................................... 17 
3.1 
Independent ethics committee .................................................................................... 17 
3.2 
Ethical conduct of the study ....................................................................................... 18 
3.3 
Patient information and consent ................................................................................. 18 
4 
Study administrative structure ........................................................................................ 18 
4.1 
Sponsor ....................................................................................................................... 18 
4.2 
Clinical research organizations .................................................................................. 19 
4.2.1 
Study management................................................................................................. 19 
4.2.2 
Neurodevelopment assessments ............................................................................ 19 
4.3 
Central laboratories .................................................................................................... 19 
4.4 
Central MRI reading ................................................................................................... 20 
4.5 
Data monitoring committee ........................................................................................ 20 
5 
Introduction ..................................................................................................................... 20 
5.1 
Background ................................................................................................................ 21 
5.1.1 
MPS IIIA ............................................................................................................... 21 
5.1.2 
SOBI003 ................................................................................................................ 22 
5.1.3 
SOBI003 nonclinical development ........................................................................ 22 
5.1.4 
SOBI003 immune mediated reactions ................................................................... 23 
5.1.5 
Study rationale ....................................................................................................... 24 
5.2 
Potential risks and benefits ......................................................................................... 25 
6 
Study objectives and endpoints ....................................................................................... 26 
6.1 
Primary objective ....................................................................................................... 26 
6.1.1 
Primary endpoint ................................................................................................... 26 
6.1.2 
Secondary endpoints related to the primary objective ........................................... 26 
6.2 
Key secondary objectives ........................................................................................... 27 
6.2.1 
Key secondary endpoints ....................................................................................... 27 
6.3 
Secondary objectives .................................................................................................. 27 
6.3.1 
Secondary endpoints .............................................................................................. 28 
6.4 
Exploratory objectives ................................................................................................ 29 
6.4.1 
Exploratory endpoints ............................................................................................ 30 
7 
Investigational plan ......................................................................................................... 30 
7.1 
Overall study design and plan .................................................................................... 30 


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7.2 
Discussion of study design ......................................................................................... 32 
7.3 
Selection of study population ..................................................................................... 33 
7.3.1 
Inclusion criteria .................................................................................................... 33 
7.3.2 
Exclusion criteria ................................................................................................... 33 
7.3.3 
Withdrawal of patients from treatment or study .................................................... 34 
7.3.3.1 Withdrawal from treatment ............................................................................... 34 
7.3.3.2 Withdrawal from study ..................................................................................... 34 
7.3.4 
Replacement of withdrawn patients....................................................................... 35 
7.3.5 
Specific restrictions/requirements on patients ....................................................... 35 
7.4 
Treatments .................................................................................................................. 35 
7.4.1 
Treatments administered ........................................................................................ 35 
7.4.2 
Identity of investigational medicinal products ...................................................... 35 
7.4.3 
Method of assigning patients to a treatment group ................................................ 36 
7.4.4 
Selection of doses .................................................................................................. 36 
7.4.5 
Selection and timing of doses for each patient ...................................................... 36 
7.4.6 
Prior and concomitant therapy ............................................................................... 37 
7.4.7 
Treatment compliance ........................................................................................... 38 
7.5 
Efficacy, safety, pharmacokinetic, and pharmacodynamic assessments .................... 38 
7.5.1 
Study schedule ....................................................................................................... 38 
7.5.1.1 Schedule of events ............................................................................................ 38 
7.5.1.2 Week 25 / Enrolment ........................................................................................ 53 
7.5.1.3 Weeks 26 to 37, Weeks 39 to 51, Weeks 53 to 77 and Weeks 79 to 103 ......... 53 
7.5.1.4 Weeks 38 and 78 ............................................................................................... 54 
7.5.1.5 Week 52 ............................................................................................................ 54 
7.5.1.6 Week 104 / End of Study .................................................................................. 55 
7.5.1.7 Weeks of dose adjustments ............................................................................... 57 
7.5.1.8 Early withdrawal from treatment/study ............................................................ 58 
7.5.1.9 Estimated blood sampling volumes and sampling priority list ......................... 59 
7.5.2 
Demography .......................................................................................................... 59 
7.5.3 
Efficacy assessments ............................................................................................. 59 
7.5.3.1 Neurocognition ................................................................................................. 59 
7.5.3.2 Adaptive behavior ............................................................................................. 60 
7.5.3.3 Magnetic resonance imaging ............................................................................ 61 
7.5.3.4 Quality of life and caregiver burden ................................................................. 61 
7.5.3.5 Language ........................................................................................................... 62 
7.5.3.6 Motor function .................................................................................................. 62 


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7.5.3.7 Sleep pattern ...................................................................................................... 62 
7.5.4 
Safety assessments ................................................................................................. 63 
7.5.4.1 Adverse events .................................................................................................. 63 
7.5.4.2 Laboratory safety assessments .......................................................................... 67 
7.5.4.3 Immunogenicity ................................................................................................ 68 
7.5.4.4 Vital signs ......................................................................................................... 69 
7.5.4.5 Electrocardiograms ........................................................................................... 69 
7.5.4.6 Other safety assessments ................................................................................... 70 
7.5.4.7 Appropriateness of measurements .................................................................... 70 
7.5.4.8 Data safety monitoring board ............................................................................ 70 
7.5.5 
Pharmacokinetic assessments ................................................................................ 71 
7.5.5.1 Sampling procedures ......................................................................................... 71 
7.5.5.2 Bioanalytical method ........................................................................................ 72 
7.5.5.3 Non-compartmental pharmacokinetic analysis ................................................. 72 
7.5.5.4 Population PK analysis ..................................................................................... 72 
7.5.5.5 Population PK/PD analysis ............................................................................... 72 
7.5.6 
Pharmacodynamic assessments ............................................................................. 73 
7.5.6.1 Heparan sulfate ................................................................................................. 73 
7.5.6.2 Future bioanalytical research ............................................................................ 73 
7.5.6.3 Appropriateness of measurements .................................................................... 73 
8 
Quality control and quality assurance ............................................................................. 74 
9 
Statistical plan ................................................................................................................. 74 
9.1 
Determination of sample size ..................................................................................... 74 
9.2 
Definition of study populations .................................................................................. 74 
9.3 
Estimands ................................................................................................................... 75 
9.4 
Overall statistical and analytical plan ......................................................................... 76 
9.4.1 
General statistical issues ........................................................................................ 76 
9.4.2 
Demographics and baseline characteristics ........................................................... 76 
9.4.3 
Analysis related to primary objective .................................................................... 76 
9.4.4 
Analysis related to secondary objectives ............................................................... 76 
9.4.4.1 Key secondary endpoints at Week 104 ............................................................. 76 
9.4.4.2 Secondary endpoints and additional key secondary endpoints ......................... 78 
9.4.5 
Multiple comparison procedure ............................................................................. 78 
9.4.6 
Analysis related to exploratory objectives ............................................................. 79 
9.4.7 
Analysis of safety and tolerability data ................................................................. 79 
9.4.7.1 Adverse events .................................................................................................. 79 


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9.4.7.2 Physical examination ........................................................................................ 79 
9.4.7.3 Neurological examination ................................................................................. 79 
9.4.7.4 Laboratory variables ......................................................................................... 79 
9.4.7.5 Vital signs ......................................................................................................... 80 
9.4.7.6 ECG ................................................................................................................... 80 
9.4.8 
Interim analysis ...................................................................................................... 80 
9.4.9 
Multiple comparison/multiplicity .......................................................................... 80 
9.4.10 
Handling of missing data ....................................................................................... 80 
10 
Data collection, handling and record keeping ................................................................. 80 
10.1 
Data standards ............................................................................................................ 80 
10.2 
Case report form ......................................................................................................... 80 
10.3 
Source data ................................................................................................................. 81 
10.4 
Database closure ......................................................................................................... 81 
10.5 
Record retention ......................................................................................................... 81 
11 
End of study .................................................................................................................... 81 
12 
Sponsor’s discontinuation criteria ................................................................................... 82 
13 
Dissemination and publication of results ........................................................................ 82 
14 
References ....................................................................................................................... 83 
 
Table of tables 
Table 1 
Minimum hospitalization periods ............................................................ 32 
Table 2 
Schedule of events – Overview Enrolment to End of Study ................... 40 
Table 3 
Detailed Schedule of events – Enrolment and treatment weeks with 
weight assessment ................................................................................... 42 
Table 4 
Detailed Schedule of events – Treatment weeks without weight 
assessment ............................................................................................... 43 
Table 5 
Detailed Schedule of events – Weeks 38 and 78 ..................................... 44 
Table 6 
Detailed schedule of events – Weeks 52 and 104 –Day 1 ....................... 46 
Table 7 
Detailed schedule of events – Weeks 52 and 104 – Days 2 to 7 ............. 48 
Table 8 
Detailed schedule of events – Following a SOBI003 dose adjustment - 
first 3 weeks ............................................................................................. 50 
Table 9 
Detailed schedule of events – Following a SOBI003 dose adjustment – 
Weeks 4 and 8 ......................................................................................... 51 
Table 10 
Detailed PK blood sampling schedule ..................................................... 52 


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Table 11 
Selection of neurocognitive assessment method ..................................... 60 
Table 12 
Severity grade definitions according to NCI CTCAE (version 4.03) ..... 65 
Table 13 
Safety laboratory assessment time points ................................................ 68 
Table of figures 
Figure 1 
Overview for study design for study SOBI003-002 ................................ 31 
 


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1 
Synopsis  
STUDY IDENTIFIERS 
 
Title of study: 
An open, single-arm, multicenter extension study to assess the safety, tolerability 
and efficacy of long-term SOBI003 treatment in pediatric MPS IIIA patients 
Clinical study number: 
SOBI003-002 
Principal Coordinating 
Investigator: 
 
 
 
There will be up to 4 additional investigators. 
Study center(s): 
The planned study centers are in the U.S.A, Turkey, Netherlands and Germany. 
The study will be conducted at up to 5 study centers. 
 
Type of study: 
Phase I/II Extension; Therapeutic Exploratory 
 
STUDY OBJECTIVES 
 
The efficacy analysis will be based on data 2 years after the start of the FIH study 
(SOBI003-001), baseline being baseline assessments in the FIH study. 
Primary objective: 
To assess the long-term safety and tolerability of SOBI003. 
Secondary objectives: 
The key secondary objectives are: 
• 
To assess the effect of SOBI003 on neurocognition, as compared to 
untreated MPS IIIA patients from a natural history (NH) control 
• 
To evaluate the effect of SOBI003 on heparan sulfate (HS) levels in CSF  
 
The secondary objectives are: 
1. To assess the effect of SOBI003 on adaptive behavior, as compared to 
untreated MPS IIIA patients from a NH control 
2. To assess the effect of SOBI003 on HS levels in serum and urine  
3. To assess the effect of SOBI003 on brain magnetic resonance imaging 
(MRI) abnormalities  
4. To assess the effect of SOBI003 on liver and spleen volume 
5. To assess the effect of SOBI003 on Quality of Life 
6. To assess the effect of SOBI003 on language 
7. To assess the effect of SOBI003 on motor function 
8. To assess the effect of SOBI003 on sleep pattern  
9. To assess the immunogenicity of SOBI003 
10. To characterize steady-state pharmacokinetics (PK) of SOBI003 by the 
use of non-compartmental analysis (NCA) 
Exploratory objectives: 
The exploratory objectives are: 
1. To assess the effect of SOBI003 on adaptive behavior over time.  
2. To characterize the PK properties of SOBI003 following repeated 
administration by the use of population PK analysis 


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3. To evaluate the PK/PD relationship between SOBI003 concentrations in 
serum and effect of SOBI003 on HS levels in CSF, serum and urine by 
the use of population modelling analysis   
4. To evaluate the PK/PD relationship between SOBI003 concentrations in 
serum and CSF, and the effect of SOBI003 on other biomarkers than HS 
and neuro-cognitive measures by use of population modelling. 
As local regulations permit and provided that additional separate caregiver 
consent is given, the exploratory objectives are also to: 
5. Collect and store serum and CSF samples to enable analyses of 
biomarkers with possible relation to safety, tolerability, immunogenicity, 
PK and PD of SOBI003, as identified in future  
STUDY ENDPOINTS 
 
Primary endpoint: 
Treatment Emergent Adverse Events (TEAEs) and Serious Adverse Events 
(SAEs) 
Secondary endpoint(s): 
The secondary endpoints relating to the primary objective to evaluate the safety 
and tolerability of SOBI003 are: 
• 
Vital signs (blood pressure, heart rate, body temperature, respiratory 
rate and oxygen saturation) 
• 
Laboratory safety variables (hematology, coagulation, clinical 
chemistry and urine analysis) 
The endpoints relating to the key secondary objective are: 
Study efficacy evaluation will primarily be based on:  
• 
Change from baseline at Week 104 in Development Quotient (DQ) 
as assessed by the Bayley Scales of Infant and Toddler 
Development®, third edition (BSID-III) cognitive subtest or the 
Kaufman Assessment Battery for Children, Second edition (KABC-
II) 
• 
Change from baseline at Week 104 in CSF HS 
 
Additional key secondary endpoints are:  
• 
Change from baseline at Week 52 in Development Quotient (DQ) as 
assessed by the Bayley Scales of Infant and Toddler Development®, 
third edition (BSID-III) cognitive subtest or the Kaufman 
Assessment Battery for Children, Second edition (KABC-II) 
• 
Change from baseline at Weeks 52 and 104 in Age Equivalent 
(AEq) as assessed by the Bayley Scales of Infant and Toddler 
Development®, third edition (BSID-III) cognitive subtest or the 
Kaufman Assessment Battery for Children, Second edition (KABC-
II) 
• 
Change from baseline at Week 52 in CSF HS 
 
The endpoints relating to the 1st secondary objective are: 
• 
Change from baseline at Weeks 52 and 104 in adaptive behavior 
age-equivalence score (AEq) as assessed by Vineland Adaptive 
Behavior Scales, Second edition (VABS-II) 


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The endpoints relating to the 2nd secondary objective are: 
• 
Change from baseline at Weeks 52 and 104 in serum HS  
• 
Change from baseline at Weeks 52 and 104 in urine HS 
The endpoints relating to the 3rd secondary objective are: 
• 
Change from baseline at Weeks 52 and 104 in gray matter volume 
as assessed by brain volumetric MRI 
• 
Change from baseline at Weeks 52 and 104 in compound ventricular 
volume as assessed by brain volumetric MRI 
• 
Change from baseline at Weeks 52 and 104 in fractional anisotropy 
(FA) and mean diffusivity (MD) of corpus callosum as assessed by 
diffusion tensor imaging MRI 
• 
Change from baseline at Weeks 52 and 104 in FA and MD of 
cerebral white matter as assessed by diffusion tensor imaging MRI 
• 
Change from baseline at Weeks 52 and 104 in cerebral white matter 
as assessed by susceptibility weighting imaging (SWI) MRI 
• 
Change from baseline at Weeks 52 and 104 in basal ganglia as 
assessed by SWI MRI 
The endpoints relating to the 4th secondary objective are: 
• 
Change from baseline at Weeks 52 and 104 in liver volume as 
assessed by abdominal MRI 
• 
Change from baseline at Weeks 52 and 104 in spleen volume as 
assessed by abdominal MRI 
The endpoints relating to the 5th secondary objective are: 
• 
Change from baseline at Weeks 52 and 104 in Pediatric Quality of 
Life inventory (PedsQL) total score and PedsQL™ Family Impact 
Module total score 
The endpoints relating to the 6th secondary objective are: 
• 
Change from baseline at Weeks 52 and 104 in expressive language 
AEq score as assessed by the BSID-III language subtests or the 
KABC-II Expressive Vocabulary subtest, and the VABS-II 
communication domain 
• 
Change from baseline at Weeks 52 and 104 in receptive language 
AEq score as assessed by the BSID-III language subtests or the 
KABC-II Expressive Vocabulary subtest, and the VABS-II 
communication domain 
The endpoints relating to the 7th secondary objective are: 
• 
Change from baseline at Weeks 52 and 104 in gross motor function 
AEq score as assessed by the BSID-III motor subtests and the 
VABS-II 
• 
Change from baseline at Weeks 52 and 104 in fine motor function 
AEq score as assessed by the BSID-III motor subtest and the 
VABS-II 
The endpoints relating to the 8th secondary objective are: 
• 
Change from baseline at Weeks 52 and 104 in sleep pattern as 
assessed by the Children´s Sleep Habits Questionnaire (CSHQ) 


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score 
• 
Change from baseline at Weeks 52 and 104 in sleep-related 
variables as assesses by actigraphy (including total sleep time, total 
day- and night time sleep duration, sleep latency, sleep efficiency, 
number of nocturnal awakenings, and wake after sleep onset) 
The endpoints relating to the 9th secondary objective are: 
• 
Occurrence of anti-drug antibodies (ADAs) against SOBI003 in 
serum at Weeks 38, 52, 78 and 104, and adjacent to dose 
adjustments (seroconversion rate, time to seroconversion, 
transient/persistent). For patients with confirmed ADA positive 
serum samples, the following additional endpoints apply; ADA 
titers and IgG subclasses in serum, and presence of neutralizing 
antibodies (NAb) in serum. 
• 
Occurrence of ADAs against SOBI003 in CSF at Weeks 52 and 104 
(conversion rate, time to occurrence, transient/persistent). For 
patients with confirmed ADA positive CSF samples, the following 
additional endpoints apply: ADA titers and presence of NAb in 
CSF. 
The endpoints relating to the 10th secondary objective are: 
• 
Serum SOBI003 PK parameters at Weeks 39, 52, 78 and 104, and 
adjacent to dose adjustments; tEnd of inf, CEnd of inf, CPre-dose, CL, AUC0-
168h 
• 
SOBI003 concentrations in CSF at Weeks 52 and 104. 
Exploratory endpoint(s): 
The endpoints related to the 1st exploratory objective are: 
Change from baseline at Weeks 52 and 104 in adaptive behavior composite score 
as assessed by Vineland Adaptive Behavior Scales, Second edition (VABS-II). 
The endpoints related to the 2nd exploratory objective are: 
• 
Population PK model parameter estimates and associated covariates 
describing intra- and inter-individual variability in respective parameter 
estimate. The results of these analyses will not be included in the 
Clinical Study Report for this study, but reported separately. 
The endpoints related to the 3rd and 4th exploratory objective are: 
• 
Population PK/PD model parameter estimates and associated covariates 
describing intra- and inter-individual variability in respective parameter 
estimate. The results of these analyses will not be included in the 
Clinical Study Report for this study, but reported separately. 
STUDY DESIGN AND METHODS 
 
Study design: 
This is an open, single-arm, multicenter extension study to assess the safety, 
tolerability and efficacy of long-term SOBI003 treatment in pediatric MPS IIIA 
patients. The study is an extension of the First in Human (FIH) SOBI003-001 
study, allowing continuous treatment of SOBI003 for up to 2 years. Study 
patients who complete Week 24 of the FIH study (SOBI003-001) will be invited 
to continue to Week 25 in the extension study.  
As the phase I/II study has a sequential, ascending, multiple-dose design, the first 
patients will enter the extension study before finalization of the FIH study 
(SOBI003-001). When entering the extension study, these patients will receive 


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the highest dose that has been declared safe in the ongoing FIH study (SOBI003-
001). Upon completion of the FIH study, an analysis aimed at selecting the dose 
for forthcoming studies will take place. Once the dose has been selected, this dose 
will be applied to all patients enrolled in the extension study.  
SOBI003 is administered as weekly i.v. infusions over a period of time of 1 to 
4 hours. Prior to initiation of each infusion, the patients are pretreated with a 
single dose of non-sedative antihistamine. If infusion-related reactions occur, then 
the infusion duration may be expanded up to 24 hours and supportive medication 
may be administered, at the discretion of the investigator.  
The long-term safety, tolerability and immunogenicity of SOBI003 will be 
assessed throughout the extension study whereas measurements of clinical 
efficacy and disease-related biomarkers will be performed at Weeks 52 and 104. 
The potential of SOBI003 to improve the neurocognitive function will be 
compared to published data from a recent NH study. 
The independent DMC employed in the FIH study (SOBI003-001) will continue 
to monitor safety and tolerability data in the SOBI003-002 study at pre-specified 
intervals.  
The total duration of the extension study for an individual patient is 80 weeks, 
resulting in a total of 104 weeks (2 years) of SOBI003 treatment.  
Number of subjects 
planned: 
9-12 
Diagnosis and main 
criteria for inclusion: 
A patient must fulfill the following criteria in order to be included in the study: 
1. Completion of study SOBI003-001 
2. Informed consent obtained from the patient’s legally authorized 
representative(s)  
Assessments for safety 
and tolerability evaluation: 
AEs are recorded from the time of obtained informed consent until End of Study.  
Blood pressure, heart rate, body temperature, respiratory rate and oxygen 
saturation measured by pulse oximetry are assessed prior to each infusion, mid-
infusion and within 1 hour of completion of each infusion. Intensified 
assessments are applied for dose adjustments.  
Blood and urine samples for central laboratory analyses of hematology, 
coagulation, and clinical chemistry are collected prior to each infusion at Weeks 
38, 52, 78 and 104, as well as during dose adjustment periods and at Early 
Termination.  
12-lead ECGs are obtained Weeks 52 and 104, and at Early Termination.  
A physical and neurological examination will be performed at Weeks 52 and 104, 
and at Early Termination. General appearance and skin are examined prior to and 
within 1 hour of completion of each infusion.  
Blood samples for central laboratory analyses of ADAs are taken pre-infusion at 
Weeks 38, 52, 78 and 104, and at Early Termination. For patients discontinuing 
treatment, ADA is assessed 30 to 40 days after last SOBI003 administration. 
CSF samples for central laboratory analysis of ADAs are collected at Weeks 52 
and 104. 


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Assessments for 
pharmacokinetic (PK) and 
pharmacodynamics (PD) 
evaluation: 
Serum concentration are collected for determination of SOBI003 multiple-dose 
PK parameters at Weeks 38, 52, 78 and 104 and adjacent to dose-adjustments. In 
addition, serum PK samples are collected when ADA samples are obtained. 
SOBI003 concentration in CSF is assessed at Weeks 52 and 104.  
HS is assessed in urine and serum at Weeks 38, 52, 78 and 104. HS in CSF is 
assessed at Weeks 52 and 104. 
Assessments for efficacy 
evaluation: 
Neurocognition is assessed by the BSID-III and/or KABC-II at Weeks 52 and 
104. Adaptive behavior is assessed by the VABS-II at Weeks 52 and 104. Gray 
matter volume is assessed by MRIs Weeks 52 and 104. The PedsQL is completed 
by the parent/primary caregiver at Weeks 52 and 104. 
Assessments for other 
efficacy evaluation: 
Clinical manifestations, including language, motor function, and sleep pattern are 
assessed at Weeks 52 and 104. Brain and abdominal MRIs are performed at 
Weeks 52 and 104 to assess ventricles, white matter, basal ganglia, and liver and 
spleen volumes. 
Test product; dose and 
mode of administration: 
SOBI003, 20 mg/ml, concentrate for solution for i.v. infusion. When entering the 
extension study, these patients will receive the highest dose that has been 
declared safe in the ongoing FIH study (SOBI003-001). Upon completion of the 
FIH study, an analysis aimed at selecting the dose for forthcoming studies will 
take place. Once the dose has been selected, this dose will be applied to all 
patients enrolled in the extension study. 
Reference product; dose 
and mode of 
administration: 
Not applicable.  
Duration of treatment(s): 
80 weeks (104 weeks total of SOBI003 treatment) 
Statistical methods: 
Safety tabulations of AE data and laboratory data are performed. Continuous 
variables are summarized using the number of patients, the mean, the standard 
deviation, the median, the minimum value, and the maximum value. Categorical 
variables are summarized using frequency counts and percentages. 
Change from baseline in DQ of neurocognitive development at Week 104 and 
change from baseline in CSF HS at Week 104 will be evaluated jointly in a 
hierarchical approach.  
DQ of neurocognitive development will be evaluated using a repeated measures 
analysis with the DQ measurements at the individual time points as response, and 
visit and visit-treatment interaction as fixed factors, baseline age as covariate and 
an unstructured covariance matrix will be used to estimate the covariance pattern.  
The control is an untreated group of MPS IIIa patients from a NH trial. 
The null hypothesis of no treatment effect will be tested with a significance test 
for the treatment*time-effect in the second step of the multiple testing procedure. 
The difference between 104 weeks and baseline will be used as the contrast of 
interest for the test. 
To assess the PD effect of SOBI003 on HS levels in CSF, serum and urine, linear 
models are used to model the change from baseline in HS levels as dependent 
variable, for both logged HS levels and untransformed HS levels, and baseline 
level and age as continuous covariates, and accumulated dose as covariate and 
sex as factor. The analyses are conducted for each assessment time point. In 
addition, linear analyses with HS levels, both logged HS levels and 
untransformed HS levels, in CSF, serum and urine, as dependent variable, and 
baseline level and age as continuous covariates, and accumulated dose as 
covariate and sex as factor will be performed across all assessments, with 


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assessment as a repeated factor. 
For the purpose of the multiple testing procedure, the linear repeated measures 
analysis with untransformed HS levels will be used, identical to the DQ analysis 
with the exception of the treatment factors. 
The time effect is used to judge the HS level change in CSF. The null hypothesis 
of no change will be tested with a significance test for the time-effect in the first 
step of the multiple testing procedure. The difference between 104 weeks and 
baseline will be used as the contrast of interest for the test.PK results are 
presented by dose level using descriptive statistics.  
Immunogenicity is summarized using frequency counts and percentages by dose 
level and will be evaluated regarding antibody prevalence (pre-existing 
antibodies), antibody incidence, titer and boosting following dosing, impact on 
PK and PD. 
Adaptive behavior will be analyzed with the same repeated measures model as 
DQ, but adapted for one group (i.e. no treatment*visit interaction term). 
To assess the PD effect of SOBI003 on MRI, linear models are used to model the 
change from baseline in MRI as dependent variable for both logged MRI and 
untransformed MRI, and baseline level and age as continuous covariates, and 
accumulated dose (including the FIH study) as covariate and sex as factor. The 
analyses will be conducted for each assessment time point: week 52 and 104. 
In addition, linear analyses with MRI levels (both logged MRI levels and 
untransformed MRI levels), as dependent variable, and baseline level and age as 
continuous covariates, and accumulated dose as covariate and sex as factor will 
be performed across all assessments (including the FIH study), with assessment 
as a repeated factor. 
Endpoints relating to other neurocognitive variables, liver and spleen volume, 
QoL, language, motor function and sleep pattern are summarized using 
descriptive statistics. 
PK results are presented by dose level using descriptive statistics. In addition, 
results are presented by demographic characteristics, e.g., age-group and 
bodyweight, as applicable. 


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2 
Abbreviations and definition of terms 
ADA 
Anti-drug antibody 
ADL 
Activities of daily living 
AE 
Adverse event 
AEq 
Age-equivalence 
ALT 
Alanine transaminase 
APTT 
Activated partial thromboplastin time 
AST 
Aspartate transaminase 
AUC 
Area under curve 
AUC0-168h 
The area under the serum concentration-time curve from time 0 h to 
168 h after dose 
BBB 
Blood-brain barrier 
BSID-III 
Bayleys Scales of Infant and Toddler Development®, third edition 
CAP 
College of American Pathologists 
CDISC 
Clinical data interchange standards consortium 
CL 
Clearance 
CLIA 
Clinical Laboratory Improvement Amendments 
CEnd of inf 
The observed serum concentration at the end of infusion of 
SOBI003 
Cmax 
Maximum observed serum concentration 
CTrough 
The minimum observed serum concentration 
CNS 
Central nervous system 
CPre-dose 
The observed serum concentration immediately before the start of 
infusion of SOBI003 
CRF 
Case report form 
CRIM 
Cross reactive immunological material 
CRO 
Contract research organization 
CSF 
Cerebrospinal fluid 
CSHQ 
Children´s sleep habits questionnaire 


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DMC 
Data monitoring committee 
DQ 
Development quotient 
ECG 
Electrocardiogram 
ERT 
Enzyme replacement therapy 
FAS 
FIH 
Full-analysis set 
First-in-Human 
GCP 
Good clinical practice 
GLP 
Good laboratory practice 
HS 
Heparan sulfate; throughout this protocol, the term “HS” is also 
used for the disaccharide levels detected in the bioanalytical assay 
(refer to Section 7.5.6.1) 
i.v. 
Intravenous 
ICF 
Informed consent form 
ICH 
International council on harmonisation 
IEC 
Independent ethics committee 
IL 
Interleukin 
IMP 
Investigational medicinal product 
IRB 
Institutional review board 
ITI 
Immune Tolerance Induction 
KABC-II 
Kaufman assessment battery for children, second edition 
LSD 
Lysosomal storage disease 
MABEL 
Minimal anticipated biological effect level  
MAR 
Missing at random 
MPS IIIA 
Mucopolysaccharidosis type IIIA 
MRI 
Magnetic resonance imaging 
MRSD 
Maximum recommended starting dose 
MTD 
Maximum tolerated dose 
NAb 
Neutralizing antibody 
NCA 
Non-compartmental analysis 
NCI CTC 
National cancer institute common terminology criteria 
NH 
Natural history 


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NOAEL 
No observed adverse effect level 
NVI 
Nonverbal index 
PAD 
Pharmacologically Active Dose 
PD 
Pharmacodynamic 
PedsQL 
Pediatric quality of life inventory 
PK 
Pharmacokinetic 
PT/INR 
Prothrombine time/international normalized ratio 
SAE 
Serious adverse event 
SAF 
Safety analysis set 
SGSH 
N-Sulfoglucosamine sulfohydrolase 
Sobi 
Swedish Orphan Biovitrum AB (publ) 
SRC 
Safety review committee 
t 
Time 
tEnd of inf 
The time of the end of the infusion of SOBI003 
tmax 
The time at which the maximum serum concentration is observed  
t1/2 
Half-life 
TBV 
Total blood volume 
TEAE 
Treatment-emergent adverse event 
TNF 
Tumor necrosis factor 
ULN 
Upper limit of normal 
VABS-II 
Vineland adaptive behavior scales, second edition 
Vd 
Volume of distribution 
 
 
3 
Ethics 
3.1 
Independent ethics committee 
It is the responsibility of the investigator to obtain approval of the study protocol, possible 
amendments and the written patient information and informed consent form (ICF) from the 
Institutional Review Board (IRB)/Independent Ethics Committee (IEC). The investigator should 


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file all correspondence with the IRB/IEC. Copies of IRB/IEC correspondence and approvals 
should be forwarded to the contract research organization (CRO) INC Research.  
3.2 
Ethical conduct of the study 
This study will be conducted in compliance with this protocol, the International Council on 
Harmonisation (ICH) Guideline for Good Clinical Practice (GCP) (1), applicable regulatory 
requirements, and in accordance with the latest revision of the Ethical Principles for Medical 
Research Involving Human Subjects (the Declaration of Helsinki) (2). 
3.3 
Patient information and consent 
It is the responsibility of the investigator to give each patient’s legally authorized 
representative(s), prior to any study-related activities, full and adequate verbal and written 
information regarding the objective and procedures of the study and the possible risks involved. 
The patient’s legally authorized representative(s) must be informed about their right to withdraw 
from the study at any time. The written patient information and/or consent form must not be 
changed without prior discussion with Swedish Orphan Biovitrum AB (publ) (Sobi). Before any 
revisions are implemented, the revised written patient information and/or consent form must be 
approved by the IRB/IEC. 
It is the responsibility of the investigator to obtain signed informed consent (or witnessed verbal 
consent according to applicable regulations) from the patient’s legally authorized 
representative(s) prior to any study-related activities. The local regulations will be followed in 
the definition of legally authorized representative. Even where not legally required, if it is 
considered desirable by the investigator or IRB, informed consent can be obtained from both 
legally authorized representatives.  
The patient’s legally authorized representative(s) should receive a copy of the written 
information and signed ICF/assent form.  
4 
Study administrative structure 
4.1 
Sponsor 
The sponsor of the study is Swedish Orphan Biovitrum AB (publ), Stockholm, Sweden (Sobi). 


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4.2 
Clinical research organizations 
4.2.1 
Study management 
The following study-related duties are transferred to INC Research LLC, with its principal place 
of business at 3201 Beachleaf Court, Raleigh, NC 27604-1547, U.S.A: monitoring, development 
of master written patient information and ICF, pharmacokinetics (PK), data management, 
biostatistics, submission of Clinical Trial Application to applicable regulatory authorities, and 
investigational product management (including secondary packaging, labeling and distribution).   
Handling of serious adverse event (SAE) reporting is a shared responsibility between Sobi and 
INC Research. Upon receipt of an SAE report from a study site, INC Research will process the 
report and forward it to the Drug Safety Department at Sobi. Requests for complementary 
follow-up information are sent to investigators through INC Research. Notification of expedited 
SAEs to regulatory authorities is a shared responsibility of Sobi and INC Research. INC 
Research is responsible for notifications to IRB/IEC, investigators and the regulatory authorities, 
except for notifications to the regulatory authority in USA, where Sobi is responsible. Sobi is 
responsible for the compilation of Development Safety Update Reports based on data outputs 
from INC Research. INC Research is responsible for the compilation of Periodic Line Listings, if 
applicable, and the submission of these reports to the applicable regulatory authorities, and for 
the distribution to IRB/IEC and investigators, when applicable. Sobi is responsible for the 
submissions of periodic reports to the regulatory authority in USA. 
Contact relating to project management and monitoring are to be directed to INC Research. 
4.2.2 
Neurodevelopment assessments 
For the neurodevelopment assessments, the following study-related duties are assigned to 
NeuroCog Trials Holdings, Inc., 3211 Shannon Road, Suite 300, Durham, NC 27707, U.S.A.: 
development of a study-specific assessment manual, study-specific training and certification of 
local child-development assessors, central data quality assurance of completed assessment forms, 
calculation of final scores and determination of Age Equivalence scores, and data management.  
The development of the study-specific manual will be in collaboration with Shapiro 
Neuropsychology Consulting LLC, 820 NW 12 Ave. Apt. 304, Portland, OR 97209, U.S.A. 
4.3 
Central laboratories 
Four central laboratories are used in this study. The analyses of SOBI003, heparan sulfate (HS) 
and SOBI003 anti-drug-antibodies (ADA) in serum and CSF, including method validation, are 
assigned to York Bioanalytical Solutions Limited, Cedar House, Northminster Business Park, 
Upper Poppleton, York YO26 6QR, United Kingdom. This is a Good Laboratory Practice (GLP) 
compliant laboratory. Storage of samples for future bioanalytical research is also assigned to 
York Bioanalytical Solutions Limited.  


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Analysis of neutralizing antibodies (NAbs) is assigned to BioAgilytix, Lademannbogen 10, 
22339 Hamburg, Germany. This is a GLP compliant laboratory.   
The safety laboratory analyses are assigned to BARC USA Inc., 5 Delaware Drive, Lake Success 
NY 11042-1114, U.S.A. This is a GLP and College of American Pathologists (CAP) compliant 
laboratory.  
Analysis of the levels of urinary HS is assigned to Greenwood Genetic Center, 106 Gregor 
Mendel Cir, Greenwood, South Carolina 29646, USA. This is a CAP and Clinical Laboratory 
Improvement Amendments (CLIA) accredited laboratory. 
4.4 
Central MRI reading 
 is assigned to develop a study-specific MRI manual 
applicable for the MRI scans to be used at study sites, validation of test-data from each site, 
quality assurance of completed MRI scans, and determination of the brain and abdominal 
variables from completed MRI assessments, as specified in Section 7.5.3.3.   
4.5 
Data monitoring committee 
A data monitoring committee (DMC), independent from Sobi and Principal Investigators, is 
assigned to monitor all safety and immunogenicity data at intervals specified in Section 7.5.4.8. 
The primary responsibility of the DMC is to provide safety oversight of the study conduct in 
order to protect study participants.  
The DMC employed in the FIH study (SOBI003-001) will continue to monitor safety and 
immunogenicity data in this extension study. 
The DMC is planned to comprise an independent statistician and 2 clinicians that, collectively, 
have experience from DMC, management of pediatric patients with lysosomal storage disease 
(LSD), clinical immunology, and the conduct of clinical studies with enzyme replacement 
therapy (ERT).  
A DMC charter will outline DMC membership, responsibilities, data review meeting details, and 
lines of communication with the study teams at Sobi and INC Research. 
5 
Introduction 
Sobi is developing SOBI003, a chemically modified recombinant human sulfamidase, for 
enzyme replacement in patients with Mucopolysaccharidosis type IIIA (MPS IIIA); Sanfilippo A 
syndrome. MPS IIIA is a rare disease with rapid progression from early childhood, often 
resulting in death during the 2nd or 3rd decade of life. Currently there is no approved treatment 
and to date, therapy is limited to treatment and relief of symptoms. The unmet medical need is 
therefore high.  


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This extension study SOBI003-002 is designed to assess the safety and tolerability of long-term 
SOBI003 treatment and to evaluate the efficacy of SOBI003 in improving neurocognitive 
function and other measures indicative of a favorable outcome of SOBI003 treatment as 
compared to untreated MPS IIIA patients.   
Patients completing the 24-week, open-label treatment period of the FIH study (SOBI003-001) 
with SOBI003 will be offered enrolment into this extension study. The current study will be a 
direct continuation of the FIH study (SOBI003-001), thus commencing with Week 25 and 
ending at Week 104, giving a total SOBI003 treatment duration of 2 years. 
5.1 
Background 
5.1.1 
MPS IIIA 
MPS IIIA or Sanfilippo A, is an inherited LSD that is progressive, life-shortening and rare. 
MPS IIIA is one of 4 distinct subtypes of MPS III (denoted IIIA, IIIB, IIIC and IIID) (3).  
MPS IIIA is an autosomal recessive disorder caused by mutations in the SGSH gene that result in 
absence of or a deficiency in the enzyme sulfamidase (N-sulfoglucosamine sulfohydrolase). 
Lack of sulfamidase activity leads to insufficient degradation of HS and lysosomal accumulation 
of HS and its metabolites in lysosomes throughout the body (4). As of today, 142 mutations have 
been described in the SGSH gene coding for sulfamidase (5). Data suggest a geno- and 
phenotype correlation and that patients homozygous or compound heterozygous for the S298P 
mutation have a slower progression of the disease (6).  
Depending on disease severity, patients have a median life-expectancy of about 15 years. The 
clinical course of MPS IIIA can be divided into 3 phases (7). In the first phase, which usually 
starts between 1 and 4 years of age, a developmental delay becomes apparent after an initial 
normal development during the first 1 to 2 years of life. The most prominent finding in this 
phase is speech delay (6, 7, 8).  
The diagnosis of MPS IIIA is usually established during the second phase, which generally starts 
around 3 to 4 years of age. This phase is characterized by increasing behavioral problems with 
hyperactivity, aggressive and destructive behavior as well as reduced attention span (7), which 
responds poorly to standard medications and behavioral-based interventions (9). A pronounced 
and rapid decline in cognitive skills becomes evident and the sleeping pattern is disturbed with 
extreme difficulty in falling asleep and with frequent awakening (10). 
In the third and final “quiet” phase, behavioral symptoms diminish while motor retardation 
emerges with walking and swallowing difficulties sometimes requiring percutaneous endoscopic 
gastrostomy (PEG) feeding. The progressive neurodegeneration causes spasticity, seizures, loss 
of speech, and severe dementia, which ultimately results in a vegetative state (9).  
Patients usually die from respiratory infections in the end of the second or beginning of the third 
decade of life (11) although patients with a slowly progressing phenotype may live longer (6). 


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5.1.2 
SOBI003 
SOBI003 is a chemically modified variant of recombinant human sulfamidase. SOBI003 is a 
sterile solution for i.v. infusion after dilution. In this extension study, SOBI003 is administered 
once weekly. 
By modification of the sulfamidase glycans, the uptake of SOBI003 systemically is strongly 
reduced. This translates into a reduced serum clearance as demonstrated in mice. SOBI003 
passes the blood-brain barrier (BBB) presumably by passive transcytosis, whereby the increased 
plasma exposure facilitates generation of pharmacological relevant levels of SOBI003 in the 
central nervous system (CNS) compartment. Once SOBI003 enters the target cells and reaches 
the lysosomal compartment, it shows enzymatic activity and stability comparable to that of 
unmodified sulfamidase, as demonstrated in fibroblasts of MPS IIIA patients. 
5.1.3 
SOBI003 nonclinical development 
In a MPS IIIA mouse model with a spontaneous missense mutation of the SGSH gene, disease 
manifestations similar to the human conditions are obtained, including lysosomal storage of HS 
and neurological pathology. In these mice, repeated i.v. administration of SOBI003 resulted in a 
dose and time dependent clearance of HS in brain. The reduction in HS translated into 
improvements in terms of lysosomal size and neuroinflammation as well as beneficial effects on 
behavioral impairments.  
HS reduction in cerebrospinal fluid (CSF) correlated with reduction of HS in whole brain of 
MPS IIIA mice following repeated i.v. administration of SOBI003, thus supporting the use of HS 
reduction in CSF as a biomarker of disease modification. 
In MPS IIIA mice, a relationship between treatment effect and SOBI003 dose level and 
treatment duration was observed. The reduction of HS in brain was related to the accumulated 
active SOBI003 dose. The return to baseline HS biomarker levels after discontinuation of 
treatment was also a gradual process in this mouse model. To quantify and understand the dose, 
time, concentration and effect relationship in MPS IIIA mice, a semi-mechanistic in silico model 
was developed based on mouse PK, distribution of SOBI003 to the brain, SOBI003 entering 
target cells, the intracellular retention of SOBI003 and an intracellular SOBI003 concentration-
effect relationship on HS reduction. Human fibroblasts of an MPS IIIA patient (27) were used 
for in vitro determination of SOBI003 cell entry rate, cell retention, and intracellular 
concentration-effect relationship. Allometric scaling from rat and cynomolgus monkey to human 
was applied to predict clearance and volume of distribution in patients (body weight 20 kg). 
Translating the mouse in silico model to human repeated weekly administration of 3 mg/kg, 
SOBI003 is predicted to gradually achieve a brain HS reduction of ~ 35 % after 3 months and ~ 
45 % after 6 months treatment. Thus, according to model-based simulations using the in silico 
model, the 3 mg/kg dose level is expected to gradually elicit a pharmacological effect in CNS in 
humans. Repeated weekly administration of 10 and 20 mg/kg SOBI003 is predicted to achieve a 
brain HS reduction of ~ 75 % and~ 80 % after 3 months and ~ 80 % and ~ 85 % respectively 
after 6 months treatment relative to baseline. 


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Nonclinical safety assessments have been performed to support the SOBI003 development 
program. The nonclinical safety studies were performed in accordance to international standards 
for drug development and OECD Principles of GLP. A 3-month toxicity study was performed in 
MPS IIIA mice, a disease model to evaluate any potential interactions of the drug and the 
disease. A 1-month toxicity study in healthy non-human primates (cynomolgus monkey) was 
also performed. In addition, to support the clinical development in pediatric patients, juvenile 
rats were treated for one month from 10 days up to 5 weeks of age, which corresponds to a life-
span in humans ranging from neonates up to the age of 6 years. Throughout the nonclinical 
safety program SOBI003 was administered by i.v. infusion every third day following pre-
treatment with anti-histamine to appropriately resemble the clinical treatment regimen.  
In the species tested, the treated animals did not show any signs of adverse effects. Thus, the 
safety evaluation of SOBI003 has shown that it is well-tolerated. In favor of SOBI003 treatment 
was also improvements in the disease state in MPS IIIA mice, such as lower incidences and/or 
severity of microscopic findings and with lower kidney, liver and spleen weights. However, the 
histopathological examinations revealed that the treatment of all three species at higher doses 
were associated with an accumulation of eosinophilic material in the cytoplasm of macrophages 
of various origin; liver, lymph nodes and the heart. The observations were clearly dose 
dependent and did not cause any detected harmful effects or other negative consequences to the 
animals. The observations were partially reversible after 4 weeks withdrawal of treatment. The 
anomalies were judged to be a result of a normal physiological function of tissue macrophages to 
scavenge proteins and the observed accumulation may be due to the high protein load. Thus, 
since these findings were not considered as adverse the NOAEL was set to the highest dose 
administered in the three species tested, i.e., 300 mg/kg in the mice and rats and 150 mg/kg in 
the cynomolgus monkeys.  
The lowest SOBI003 serum exposures at the NOAEL dose levels in these species were observed 
in the mice following the 300 mg/kg dose, where mean Cmax,ss was 86.3 and 163 μmol/L and 
mean AUCτ,ss was 718 and 934 μmol*h/L in in male and female mice, respectively. Based on 
predicted steady state PK in patients (Cmax,ss 0.89, 3.0, and 5.9 μmol/L; AUCτ,ss 11.5, 38.5, and 
77.0 h·μmol/L at dose levels 3, 10 and 20 mg/kg), the margins to SOBI003 exposure in the 
pivotal toxicity studies are thus at least 100-fold for a starting dose of 3 mg/kg and at least 10-
fold for a dose of 20 mg/kg. Further details are presented in the SOBI003 Investigator Brochure). 
5.1.4 
SOBI003 immune mediated reactions 
In an initial explorative study in MPS IIIA mice, where the efficacy of 3 different sulfamidase 
derivatives was assessed (whereof SOBI003 was one), Sobi encountered hypersensitivity 
reactions. Mice were given the test articles at 30 mg/kg every other day as a bolus injection 
without antihistamine pretreatment. The study was terminated due to hypersensitivity reactions 
in connection with the fifth i.v. dose. A second study was performed, where the mice were 
pretreated with the antihistamine chlorpheniramine, and the injection rate was extended to 
approximately 5 to 10 seconds per injection. The same test articles, doses, and dose frequencies 
were applied as in the initial study, and the second study could be finalized as planned without 


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any abnormal observations (a 25-day treatment period with a total of 13 injections). 
Subsequently, antihistamine pretreatment was included in the chronic efficacy studies. 
The nonclinical studies in MPS IIIA mice show that ADAs are generated against SOBI003. In 
the studies performed with anti-histamine pretreatment, including the 3 month toxicity study the 
ADA response does not compromise safety or alter the exposure, as assessed at 24 hours after 
last dose administration. A number of chronic efficacy studies have been performed with 
antihistamine pretreatment in MPS IIIA mice without observing any obvious toxicities or lack of 
efficacy. In cynomolgus monkey a repeated dose paradigm with doses once every third day 
indicated that ADAs had an impact on SOBI003 exposure. ADAs did not appear to impact the 
Cmax in plasma, but possibly the AUC. Apart from these deviations, exposure after the last dose 
was similar to that observed after the first dose. No ADA development was seen in the pivotal 
juvenile rat toxicity study. 
Development of ADAs is a common finding in ERTs and correlates to the degree of endogenous 
enzyme expression (12, 13, 14, 15). Nonclinical assessments of immunogenicity of human 
proteins, applying in silico, in vitro, or animal models have, so far, shown only limited or no 
translatability to the clinical situation.  
The polypeptide sequence of SOBI003 is identical to human sulfamidase. However, as a result of 
use of the CHO expression system and the glycan modifications, through which some peripheral 
carbohydrate ring structures in the glycans are linearized, the overall structure of SOBI003 is not 
identical to human sulfamidase. Therefore, an immune reaction to SOBI003 may be expected in 
analogy to what occurs with other ERTs. ADAs and their impact on safety, PK and PD are 
monitored closely in this extension study. 
5.1.5 
Study rationale 
SOBI003 is being developed for treatment of MPS IIIA. Scientific advice on the nonclinical and 
chemistry, manufacturing and control (CMC) development has been obtained from the FDA on 
16 February 2016 and from EMA in 28 June 2016. A pre-IND meeting was held with the FDA 
on 21 June 2017 to obtain agreement on the conduct of the FIH study (SOBI003-001) with 
SOBI003.  
The FIH study (SOBI003-001) is designed to assess the safety, tolerability, PK, PD and 
immunogenicity of SOBI003 at 3 dose levels to provide knowledge needed to optimize the 
further evaluation of SOBI003 in patients with MPS IIIA. Patients completing the 24-week, 
open-label treatment period of the FIH study will be offered enrolment into the extension study 
SOBI003-002.  
Study SOBI003-002 is designed to assess the safety and tolerability of long-term SOBI003 
treatment and to evaluate the efficacy of SOBI003 in improving neurocognitive function and 
other measures indicative of a favorable outcome of SOBI003 treatment. The follow-up period 
of the extension study is 80 weeks, giving a total SOBI003 treatment duration of 104 weeks to 
allow for a comparison with data from a recent NH study (22). 


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5.2 
Potential risks and benefits 
MPS IIIA is an irreversible, progressive, life-shortening disease with no existing effective 
therapeutic alternative. SOBI003 provides a potential clinical benefit by reducing the levels of 
stored HS and its metabolites, and thereby reducing neuro-inflammation and the clinical 
manifestations of MPS IIIA. 
Apart from ADA development in two species (MPS IIIA mouse and cynomolgus monkey) out of 
the three included in the pivotal toxicity program, which is an expected finding considering the 
foreignness of a human protein to animal species, the nonclinical safety evaluation of SOBI003 
did not show any signs of adverse effects, thus SOBI003 was well-tolerated. 
Given the observed pharmacological and toxicology profile in non-clinical studies, and 
following patient completion of 24 weeks treatment in the FIH study (SOBI003-001), it is judged 
that SOBI003 can be given to patients in a carefully monitored extension study. Adherence to 
study inclusion/exclusion criteria and close clinical monitoring will be applied. 
Although SOBI003 has been given for 24 weeks in the 001-study, hypersensitivity 
reactions/immune-mediated adverse reactions may still occur, including anaphylaxis and 
infusion reactions, are commonly reported for lysosomal ERTs. To reduce the incidence and 
severity of these adverse reactions, slow infusion rates, prolonged infusion duration and 
pretreatment with antihistamines will be applied. Severe and potentially life-threatening adverse 
hypersensitivity/immune-mediated reactions may, however, still occur.  
Close clinical supervision by medical staff that are experienced with ERT treatment will be 
applied during and after the infusions. This will ensure early detection and adequate treatment of 
potential adverse reactions. Potential hypersensitivity reactions including anaphylactic events 
and infusion related reactions will be treated in accordance with the current anaphylactic 
algorithm (17). Further symptomatic treatment with antipyretics and additional antihistamines 
may be administered to manage milder hypersensitivity/immune-mediated reactions. 
Immunosuppressant treatment will be administered in cases of less tolerable reactions. In 
addition, the availability of cardiopulmonary resuscitation equipment and immediate access to 
emergency medical services is secured. 
Potential delayed hypersensitivity reactions may occur outside the hospital setting (refer to Table 
1) for minimum hospitalization periods during study participation). Parents/caregivers will be 
carefully informed of potential signs and symptoms of delayed hypersensitivity reactions and of 
the importance to seek immediate medical attention.  
SOBI003 has the potential to become the first disease modifying therapy in patients with MPS 
IIIA. The disease-modifying effect of SOBI003 is believed to be most beneficial if treatment is 
started in very young patients since they have limited neuronal damage. SOBI003 could possibly 
stop, or reverse, the progress of the neuronal damage and the neurocognitive decline leading to a 
normal or a near normal neurocognitive development. In older patients, that have more 
pronounced neuronal damage, it is likely that already developed neuronal damage is not 
reversible. However, further disease progression might be prevented or at least slowed down.  


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The ultimate effect of the disease modifying effect would be to improve the cognition and 
thereby prolong life, minimize behavioral problems and sleep disturbances, and increase QoL 
including reduction of caregiver burden. The evaluation of the benefits of SOBI003 treatment in 
pediatric patients with MPS IIIA is based on the results in the SOBI003 non-clinical studies 
showing reduced levels of stored HS and its metabolites in brain and CSF, reduction of 
neuroinflammation in brain, reduction of lysosomal swelling and secondary storage products in 
brain as well as trends towards a beneficial effect on behavioral impairment. If translated to 
human these beneficial effects may reduce the devastating clinical manifestations of MPS IIIA. 
Potential study procedural risks include the use of sedation/general anesthesia and use of a 
central venous access port. To minimize study related procedural risks, local hospital routines 
will be applied for the procedures. The selection of anesthetic method will be in accordance with 
local hospital routines and as judged by pediatric anesthesiologist with prior experience from 
MPS patients. The parents/caregivers will be trained in management of the port, in accordance 
with local hospital routines. This includes the actions to take in case an infection is suspected. 
The central venous access port is added as part of the preceding FIH study (SOBI003-001), but 
there may be occasions when a patient may need to replace an existing port.  
In summary, the potential benefits of SOBI003 treatment are considered to outweigh the 
foreseeable risks. 
6 
Study objectives and endpoints 
The efficacy analysis will be based on data 2 years after the start of the FIH study (SOBI003-
001), baseline being baseline assessments in the FIH study. 
6.1 
Primary objective  
The primary objective is: 
• To assess the long-term safety and tolerability of SOBI003  
6.1.1 
Primary endpoint 
The primary endpoint to evaluate the safety and tolerability of SOBI003 is: 
• Treatment Emergent Adverse Events (TEAEs) and Serious Adverse Events (SAEs) 
6.1.2 
Secondary endpoints related to the primary objective 
The secondary endpoints to evaluate the safety and tolerability of SOBI003 are: 
• Vital signs (blood pressure, heart rate, body temperature, respiratory rate and oxygen 
saturation) 


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• Laboratory safety variables (hematology, coagulation, clinical chemistry and urine 
analysis) 
6.2 
Key secondary objectives 
• To evaluate the efficacy of SOBI003 on neurocognitive function, as compared to 
untreated MPS IIIA patients from a NH control 
• To evaluate the effect of SOBI003 on HS levels in CSF  
6.2.1 
Key secondary endpoints 
The endpoints relating to the key secondary objective are: 
Study efficacy evaluation will primarily be based on:  
• Change from baseline at Week 104 in Development Quotient (DQ) as assessed by the 
Bayley Scales of Infant and Toddler Development®, third edition (BSID-III) cognitive 
subtest or the Kaufman Assessment Battery for Children, Second edition (KABC-II) 
• Change from baseline at Week 104 in CSF HS 
 
Additional key secondary endpoints are:  
• Change from baseline at Week 52 in Development Quotient (DQ) as assessed by the 
Bayley Scales of Infant and Toddler Development®, third edition (BSID-III) cognitive 
subtest or the Kaufman Assessment Battery for Children, Second edition (KABC-II) 
• Change from baseline at Weeks 52 and 104 in Age Equivalent (AEq) as assessed by the 
Bayley Scales of Infant and Toddler Development®, third edition (BSID-III) cognitive 
subtest or the Kaufman Assessment Battery for Children, Second edition (KABC-II) 
• Change from baseline at Week 52 in CSF HS 
6.3 
Secondary objectives  
The secondary objectives are: 
1. To assess the effect of SOBI003 on adaptive behavior, as compared to untreated MPS 
IIIA patients from a NH control 
2. To assess the effect of SOBI003 on HS levels in serum and urine  
3. To assess the effect of SOBI003 on brain magnetic resonance imaging (MRI) 
abnormalities  
4. To assess the effect of SOBI003 on liver and spleen volume 
5. To assess the effect of SOBI003 on Quality of Life 
6. To assess the effect of SOBI003 on language 
7. To assess the effect of SOBI003 on motor function 
8. To assess the effect of SOBI003 on sleep pattern  


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9. To assess the immunogenicity of SOBI003 
10. To characterize steady-state pharmacokinetics (PK) of SOBI003 by the use of non-
compartmental analysis (NCA) 
6.3.1 
Secondary endpoints 
The endpoints relating to the 1st secondary objective are: 
• Change from baseline at Weeks 52 and 104 in adaptive behavior age-equivalence score 
(AEq) as assessed by Vineland Adaptive Behavior Scales, Second edition (VABS-II) 
The endpoints relating to the 2nd secondary objective are: 
• Change from baseline at Weeks 52 and 104 in serum HS  
• Change from baseline at Weeks 52 and 104 in urine HS 
The endpoints relating to the 3rd secondary objective are: 
• Change from baseline at Weeks 52 and 104 in gray matter volume as assessed by brain 
volumetric MRI 
• Change from baseline at Weeks 52 and 104 in compound ventricular volume as assessed 
by brain volumetric MRI 
• Change from baseline at Weeks 52 and 104 in fractional anisotropy (FA) and mean 
diffusivity (MD) of corpus callosum as assessed by diffusion tensor imaging MRI 
• Change from baseline at Weeks 52 and 104 in FA and MD of cerebral white matter as 
assessed by diffusion tensor imaging MRI 
• Change from baseline at Weeks 52 and 104 in cerebral white matter as assessed by 
susceptibility weighting imaging (SWI) MRI 
• Change from baseline at Weeks 52 and 104 in basal ganglia as assessed by SWI MRI 
The endpoints relating to the 4th secondary objective are: 
• Change from baseline at Weeks 52 and 104 in liver volume as assessed by abdominal 
MRI 
• Change from baseline at Weeks 52 and 104 in spleen volume as assessed by abdominal 
MRI 
The endpoints relating to the 5th secondary objective are: 
• Change from baseline at Weeks 52 and 104 in Pediatric Quality of Life inventory 
(PedsQL) total score and PedsQL™ Family Impact Module total score 
The endpoints relating to the 6th secondary objective are: 
• Change from baseline at Weeks 52 and 104 in expressive language AEq score as assessed 
by the BSID-III language subtests or the KABC-II Expressive Vocabulary subtest, and 
the VABS-II communication domain 


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• Change from baseline at Weeks 52 and 104 in receptive language AEq score as assessed 
by the BSID-III language subtests or the KABC-II Expressive Vocabulary subtest, and 
the VABS-II communication domain 
The endpoints relating to the 7th secondary objective are: 
• Change from baseline at Weeks 52 and 104 in gross motor function AEq score as 
assessed by the BSID-III motor subtests and the VABS-II 
• Change from baseline at Weeks 52 and 104 in fine motor function AEq score as assessed 
by the BSID-III motor subtest and the VABS-II 
The endpoints relating to the 8th secondary objective are: 
• Change from baseline at Weeks 52 and 104 in sleep pattern as assessed by the Children´s 
Sleep Habits Questionnaire (CSHQ) score 
• Change from baseline at Weeks 52 and 104 in sleep-related variables as assesses by 
actigraphy (including total sleep time, total day- and night time sleep duration, sleep 
latency, sleep efficiency, number of nocturnal awakenings, and wake after sleep onset) 
The endpoints relating to the 9th secondary objective are: 
• Occurrence of ADAs against SOBI003 in serum at Weeks 38, 52, 78 and 104, and 
adjacent to dose adjustments (seroconversion rate, time to seroconversion, 
transient/persistent). For patients with confirmed ADA positive serum samples, the 
following additional endpoints apply; ADA titers and IgG subclasses in serum, and 
presence of neutralizing antibodies (NAb) in serum. 
• Occurrence of ADAs against SOBI003 in CSF at Weeks 52 and 104 (conversion rate, 
time to occurrence, transient/persistent). For patients with confirmed ADA positive CSF 
samples, the following additional endpoints apply: ADA titers and presence of NAb in 
CSF. 
The endpoints relating to the 10th secondary objective are: 
• Serum SOBI003 multiple-dose PK parameters at Weeks 38, 52, 78 and 104, and adjacent 
to dose adjustments; tEnd of inf, CEnd of inf, CPre-dose, AUC0-168h,  CL 
• SOBI003 concentrations in CSF at Weeks 52 and 104. 
6.4 
Exploratory objectives  
The exploratory objectives are to explore the effect of SOBI003 on: 
1. To assess the effect of SOBI003 on adaptive behavior over time 
2. To characterize the PK properties of SOBI003 following repeated administration by the 
use of population PK analysis 
3. To evaluate the PK/PD relationship between SOBI003 concentrations in serum and effect 
of SOBI003 on HS levels in CSF, serum and urine by the use of population modelling 
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4. To evaluate the PK/PD relationship between SOBI003 concentrations in serum and CSF, 
and the effect of SOBI003 on other biomarkers than HS and neuro-cognitive measures 
eg. DQ, as well as MRI data, by the use of population modelling  
As local regulations permit and provided that additional separate caregiver consent is given, the 
exploratory objectives are also to: 
• Collect and store serum and CSF samples to enable analyses of biomarkers with possible 
relation to safety, tolerability, immunogenicity, PK and PD of SOBI003, as identified in 
future  
Serum and CSF samples for potential future biomarker analyses will be stored for a maximum of 
10 years following study completion. The results of any such analyses will not be included in the 
Clinical Study Report for this study, but reported separately when analyzed, thus enabling 
exploration of any emerging novel disease-related discoveries of e.g., previously unknown 
alleles, inflammatory cytokines, other HS biomarkers (e.g. HS metabolites), components of the 
complement system, and neurodegeneration.  
6.4.1 
Exploratory endpoints 
The endpoints related to the 1st exploratory objective are: 
• Change from baseline at Weeks 52 and 104 in adaptive behavior composite score as 
assessed by Vineland Adaptive Behavior Scales, Second edition (VABS-II) 
The endpoints related to the 2nd exploratory objective are: 
• Population PK model parameter estimates and associated covariates describing intra- and 
inter-individual variability in respective parameter estimate. The results of these analyses 
will not be included in the Clinical Study Report for this study, but reported separately. 
The endpoints related to the 3rd and 4th exploratory objective are: 
• Population PK/PD model parameter estimates and associated covariates describing intra- 
and inter-individual variability in respective parameter estimate. The results of these 
analyses will not be included in the Clinical Study Report for this study, but reported 
separately. 
7 
Investigational plan 
7.1 
Overall study design and plan 
This is an open, single-arm, multicenter extension study to assess the long-term safety, 
tolerability and efficacy of SOBI003 in pediatric MPS IIIA patients who previously participated 
in the FIH study (SOBI003-001) study. Patients completing the 24-week treatment of the 
FIH study will be offered to participate in the continuous 80 week treatment period of the 
extension study. The extension study starts with enrolment at Week 25, giving a total SOBI003 


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treatment duration of 104 weeks for each patient. Please refer to Figure 1 for an overview of the 
study design. A recent NH study is used as external control (22) to enable an evaluation of 
efficacy. Neurocognitive and adaptive behavior data assessed in the extension study at Week 52 
and Week 104 following start of treatment will be compared to available NH data within the 
target study population. The NH population for comparison consists of 14 patients with a rapid 
progressive MPS IIIA disease and a baseline age of 12 to 72 months. 
As the FIH study (SOBI003-001) has a sequential, ascending, multiple-dose design, the first 
patients will enter the extension study before the FIH study is completed. When entering the 
extension study, these patients will receive the highest dose that has been declared safe by the 
SRC in the ongoing FIH study (SOBI003-001) study. Patients enrolled in Cohort 1 of FIH study 
may thus be switched to the dose applied in Cohort 2 or Cohort 3, depending on safety clearance 
by the SRC. If a patient is initially switched to the dose applied in Cohort 2, the patient may 
subsequently later be switched to the dose applied in Cohort 3. Depending on recruitment rate in 
the FIH study (SOBI003-001) study, a patient enrolled in Cohort 1 may be directly switched to 
the dose applied in Cohort 3. Upon completion of the FIH study, an analysis aimed at selecting 
the dose for forthcoming studies will take place. Once the dose has been selected, this dose will 
be applied to all patients enrolled in the extension study. 
SOBI003 is administered as weekly i.v. infusions over a period of time of 1 to 4 hours. Prior to 
initiation of each infusion, the patients are pretreated with a single dose of non-sedative 
antihistamine. If infusion-related reactions occur, then the infusion duration may be expanded up 
to 24 hours and supportive medication may be administered, at the discretion of the investigator.  
The long-term safety, tolerability and immunogenicity of SOBI003 will be assessed throughout 
the extension study whereas measurements of clinical efficacy and disease-related biomarkers 
will be performed at Weeks 52 and 104. The potential of SOBI003 to improve the 
neurocognitive function will be compared to published data from a recent NH study (22).  
The independent DMC employed in the FIH study (SOBI003-001) will continue to monitor 
safety and immunogenicity data in the SOBI003-002 study.  
Following completion of the extension study, depending on demonstrated safety, tolerability and 
benefit-risk evaluation of SOBI003, study patients’ continuous access to SOBI003 treatment 
may be arranged as part of a Sobi-sponsored extension study starting in direct connection to the 
study, or through an alternative ethically and regulatory accepted approach. 
Figure 1 
Overview for study design for study SOBI003-002 
 




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use of natural history data instead of formal comparator groups in clinical studies in MPS 
diseases (24). In the case of treatment of MPS IIIA, no active comparator exists and Sobi does 
not consider it ethical to withhold a potentially efficient treatment in patients with a rapidly 
progressive, and life-shortening condition. Data from a recent NH study (22) will therefore serve 
as control for the studies in the SOBI003 clinical program. 
In order to compare SOBI003 treatment with the NH study, comparable patients will be included 
and the time points for efficacy evaluations and the neurocognitive and behavioral tools used 
will be identical. The efficacy endpoints in the SOBI003 clinical development program have 
been selected based on the recommendations in a position statement by key experts in the field, 
the clinical relevance (24, 25, 26 ) as well as on the endpoints in the NH study (22). The efficacy 
analysis will be based on data 2 years after the start of the FIH study (SOBI003-001), baseline 
being baseline assessments in the FIH study. The choice of treatment duration is based on advice 
from key clinical experts in the area and the availability of NH data. It is considered long enough 
to differentiate efficacy of SOBI003 treatment compared to an untreated control.  
The dose in the SOBI003-002 study will primarily be selected on the basis of safety and 
tolerability results and the magnitude of HS reduction in CSF observed for the dose levels in the 
FIH study (SOBI003-001). At enrolment into the extension study (SOBI003-002), the individual 
dose will be adjusted to the highest tolerable dose level in order to optimize treatment duration 
on an efficacious dose. Upon completion of the FIH study, an analysis aimed at selecting the 
dose for forthcoming studies will take place. Once the dose has been selected, this dose will be 
applied to all patients enrolled in the extension study. 
7.3 
Selection of study population 
7.3.1 
Inclusion criteria 
A patient must fulfill the following criteria in order to be included in the study: 
1. Completion of the FIH study (SOBI003-001) 
2. Informed consent obtained from the patient’s legally authorized representative(s)  
7.3.2 
Exclusion criteria 
The presence of the following criterion excludes a patient from inclusion in the study: 
1. If, in the opinion of the investigator, there are patient specific safety concerns that 
contraindicates further treatment with SOBI003 


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7.3.3 
Withdrawal of patients from treatment or study 
7.3.3.1 
Withdrawal from treatment 
A patient should be withdrawn from the study treatment if, in the opinion of the investigator, it is 
medically necessary, or if it is the wish of the patient’s primary caregiver(s). During the 
informed consent process, the investigator will clarify that it is essential for the patient’s safety 
to be willing to comply with the study protocol requirements, including study safety and 
immunogenicity assessments following a potential withdrawal of study treatment. 
When a patient is withdrawn from study treatment, the date and time of the last SOBI003 
infusion and the date and reason for treatment withdrawal should be clearly described in the 
relevant sections of the case report form (CRF). If a patient is removed from treatment because 
of an AE, the reason for treatment withdrawal should always be stated as ‘AE’ irrespective of 
whether this was the investigator’s or the patient’s primary caregiver(s) decision. 
After treatment withdrawal, efficacy, safety, immunogenicity and PK assessments should be 
completed as soon as possible and repeated 30 to 40 days after the last SOBI003 administration, 
as specified for “Early Termination” in the Schedule of Events (Table 2).   
When possible, study assessments (excluding SOBI003 infusion) of Weeks 38, 52, 78 and 104 
should continue in accordance with the Schedule of Events (Table 2) in order to collect 
continuous immunogenicity, safety and efficacy data for study patients following withdrawn 
treatment. Additional safety assessments will be performed at the discretion of the investigator, 
as warranted by the AE(s) leading to treatment withdrawal.  
A patient that is withdrawn from study treatment due to an AE, should be followed up until the 
AE(s) leading to treatment withdrawal are either resolved or have stabilized even after the 
patient’s participation in the study is over. Each clinically significant abnormal laboratory value 
or other clinically meaningful abnormality should be followed until the abnormality resolves or 
until a decision is made that it is not likely to resolve. Should the 30 to 40-day post last infusion 
be ADA-positive, then the ADA titer will be determined and ADA samplings will continue at 
approximately monthly basis until the ADAs have disappeared or titers have stabilized at a lower 
level. Every time an ADA sample is taken, a corresponding PK assessment is done.  
7.3.3.2 
Withdrawal from study 
The patient’s legally authorized representative is free to withdraw the patient from the study at 
any time.  
A patient that is withdrawn from the study should be examined as soon as possible, whenever 
possible, irrespective of the reason for withdrawal. The efficacy, safety, immunogenicity and PK 
assessments should be completed as soon as possible and repeated 30 to 40 days after the last 
SOBI003 administration, as specified for “Early Termination” in the Schedule of Events (Table 
2). The CRF should be completed to the highest possible extent. 


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7.3.4 
Replacement of withdrawn patients 
Withdrawn patients will not be replaced. 
7.3.5 
Specific restrictions/requirements on patients 
The patients are required to visit the site weekly for the SOBI003 infusions and remain at the site 
for at least 1 hour after the end of the infusion. The hospitalization period may be extended as 
per local routine for admission/discharge and per patient need as determined by the investigator 
(e.g., concurrent illness and travel distance). 
Following a dose adjustment, patients are hospitalized for at least 48 hours after initiation of 
each of the first 3 infusions. If dose adjustment is a decrease in dose as a result of study dose 
selection for forthcoming studies, and there are no safety concerns, the patient may be 
discharged 1 hour or later after the end of each infusion. 
7.4 
Treatments 
7.4.1 
Treatments administered  
In this open-label study, the investigational medicinal product (IMP) is SOBI003. 
SOBI003 is administered as i.v. infusions given once weekly for a duration of 80 weeks (from 
Week 25 until Week 104 following the first 24 weeks of IMP administration in the FIH study 
(SOBI003-001) study. 
SOBI003 solution, 20 mg/mL, is mixed with NaCl 0.9% infusion solution prior to 
administration. For a bodyweight < 25 kg, the total infusion volume is 100 mL. For a 
bodyweight ≥ 25 kg, the total infusion volume is 250 mL.  
Actual materials to be used for mixing SOBI003 solution with NaCl infusion solution (i.e., 
infusion solutions, syringes and needles) and for administering the infusions (i.e., infusion lines, 
syringes, manifolds, venous access ports) must be preapproved by Sobi to secure that all 
materials are compatible with SOBI003. Detailed IMP preparation instructions are provided in a 
separate IMP manual. 
7.4.2 
Identity of investigational medicinal products 
SOBI003 is provided as concentrated solution for i.v. infusion, 20 mg/mL, in 5-mL injection 
vials. Each vial contains 4 mL. Ten vials are packed in one box/outer carton. Vial and outer 
carton labeling will comply with national regulatory requirements. To facilitate accurate drug 
accountability, vial-specific numbers are printed on the vial labels. 
The drug substance is manufactured by 
 
. The drug product is manufactured by 
 


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 Secondary packaging of vials and labeling of cartons is done by 
     
SOBI003 is shipped and stored at frozen conditions. 
Possible deficiencies related to the handling, storage and quality of the IMPs should be reported 
to the study monitor and also directly to complaints@sobi.com. 
7.4.3 
Method of assigning patients to a treatment group 
This is a single-arm study. 
7.4.4 
Selection of doses 
Initially, the patients enrolled into the extension study will receive the highest dose that has been 
declared safe by the Safety Review Committee (SRC) in the at the time ongoing FIH study 
(SOBI003-001) study. The planned dosage range for the FIH study is 3 to 20 mg/kg. 
Patients enrolled in Cohort 1 of the FIH study (SOBI003-001) study may thus be switched to the 
dose applied in Cohort 2 or Cohort 3, depending on safety clearance by the SRC. If a patient is 
initially switched to the dose applied in Cohort 2, the patient may subsequently be switched to 
the dose applied in Cohort 3. Depending on recruitment rate in the FIH study, a patient enrolled 
in Cohort 1 may be directly switched to the dose applied in Cohort 3.  
Upon completion of the FIH study (SOBI003-001) study, an analysis aimed at selecting the dose 
for forthcoming studies will take place. The analysis is conducted by Sobi and will be based on 
risk-benefit observed for the doses applied during the FIH study. Once the dose has been 
selected, this dose will be applied to all patients enrolled in the extension study. This may result 
in a decrease or increase of all current patient doses in the extension study.  
Dose adjustments will be avoided during the 4-week period prior to Week 52 and 104 in order to 
avoid interference with study efficacy assessments. Any requested dose adjustment during this 
time should be postponed, if not considered medically justified by the investigator. Patients will 
be extensively monitored during dose adjustments as described in Section 7.5.1.7.   
7.4.5 
Selection and timing of doses for each patient 
SOBI003 is administered as weekly i.v. infusions. The infusions are administered by qualified 
health care professionals. Every effort should be made to have the infusions administered every 
7th day. A +/- 1-day window is applied i.e., if the first infusion in study FIH study (SOBI003-
001) was administered on a Wednesday, then the infusions in the extension study can be 
administered on Tuesdays, Wednesdays or Thursdays.  
In case of signs and/or symptoms of ongoing infection at subsequent infusion occasions, infusion 
may be postponed, as judged by the investigator. If the infusion needs to be postponed more than 


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3 days, then the investigator should discuss with the Sponsor’s MD to determine the timing of 
the next infusion (i.e., whether to await the next scheduled infusion). 
Within 30 to 60 minutes prior to each infusion, a single dose of a non-sedative antihistamine 
should be administered. The antihistamine can either be e.g., cetirizine, levo-cetirizine, 
loratadine, des-loratadine or fexofenadine, and the administered doses will be in compliance with 
locally approved labeling. The antihistamine agent is selected at the discretion of the 
investigator. Antipyretic medication may also be administered, at the discretion of the 
investigator. 
The actual doses of SOBI003 to be administered should be based on the patient’s body weight at 
4-week intervals (i.e., the actual dose administered at Weeks 25 to 28 is based on the body 
weight obtained pre-infusion at Week 25, the actual dose administered at Weeks 29 to 32 is 
based on the body weight obtained pre-infusion at Week 29, etc.). The body weight is obtained 
either on the day prior to the infusion or the day of infusion. For a body weight < 25 kg, the 
targeted total infusion volume is 100 mL. For a body weight ≥ 25 kg, the targeted total infusion 
volume is 250 mL. If the infusion bag contains an overfill volume, the infusion should continue 
until the infusion bag is emptied. 
The final concentration of SOBI003 in the infusion bag will be calculated based on the added 
volume of SOBI003 to the infusion bag, and the total volume in the infusion bag. 
The SOBI003 infusions are initially given over a period of 4 hours. When no more dose 
increases are expected, and the intensified study assessments associated with dose adjustments 
are completed (Section 7.5.1.7), the infusion period in individual patients may step-wise be 
decreased at the discretion of the investigator. The minimal infusion period is 1 hour. 
Infusion rate schedules are provided in a separate IMP manual. 
The drug accountability records will capture sufficient details to verify the amount of SOBI003 
administered at each infusion occasion. 
In case of occurrence of infusion reactions, the infusion duration may be prolonged up to 
24 hours at the discretion of the investigator. 
For individual study patients there may be situations, due to safety or infusion related reactions 
observed at a higher dose level, where it is judged by investigator that it is in the patient’s best 
interest to reduce the treatment dose. In such situations investigator should discuss with Sobi MD 
regarding an individual patient dose adjustment.  
7.4.6 
Prior and concomitant therapy 
Other therapies considered necessary for the patient’s welfare including melatonin for sleep 
disorder may be given at the discretion of the investigator. Patients on low dose genistein 
(<10 mg/kg/day) may continue treatment on the same dose throughout the study. All such 
therapy that is administered or used from the time of enrolment until completion of the study 
must be recorded in the CRF. This includes prescription drugs, herbal products, vitamins, 
minerals, and over-the-counter medications and the anesthetic drugs administered during study 


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procedures (oxygen is not captured). Preferably, the treatment regimen should be unaltered 
during the study and thus only adjusting dose or medication(s) when medically warranted.  
No other medicinal product under investigation may be used concomitantly with the IMP in this 
study.  
As described in Section 7.4.5, a single dose of a non-sedative antihistamine should be 
administered prior to start of each SOBI003 infusion. Each administration is recorded in the 
CRF. 
In case of identified infusion-related reactions, immediate treatment is given at the discretion of 
the investigator. Depending on symptoms, this may e.g., be antipyretics such as acetaminophen 
(paracetamol), corticosteroids or additional antihistamines. Anaphylactic reactions will be treated 
in accordance with current anaphylaxis algorithm “Hypersensitivity to Biological Agents - 
Updated Diagnosis, Management, and Treatment” issued by the AAAI (17). Necessary 
equipment for resuscitation must be available during study drug infusion. 
If clinically justified, patients who develop high titer antibodies that affect PK/PD and/or safety 
may benefit from the use of an immune tolerizing regimen. As there is no proven immune 
tolerizing approach established for ERTs in MPS IIIA, immune tolerizing approaches used in 
other LSDs (22) may be applied at the discretion of the investigator after discussion with Sobi 
Medical Director.  
7.4.7 
 Treatment compliance 
Product accountability records will be kept. The pharmacy and investigator must maintain 
accurate records demonstrating date and amount of IMP received, to whom and by whom 
administered (patient-by-patient accounting), and accounts of returned IMP and any IMP 
accidentally or deliberately destroyed. 
All unused IMP will be counted. At the end of the study, any remaining IMP will be returned to 
Almac for destruction, or destroyed locally. In either case, a certificate of destruction must be 
issued. 
7.5 
Efficacy, safety, pharmacokinetic, and pharmacodynamic 
assessments 
7.5.1 
Study schedule 
7.5.1.1 
Schedule of events 
The following schedule of events provides an overview of extension study assessments (Table 
2), as well as the following detailed schedules of events: 
Table 3: Detailed Schedule of events – Enrolment and treatment weeks with weight assessment 
Table 4: Detailed Schedule of events – Treatment weeks without weight assessment 


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Table 5: Detailed Schedule of events – Weeks 38 and 78 
Table 6: Detailed schedule of events – Weeks 52 and 104 –Day 1 
Table 7: Detailed schedule of events – Weeks 52 and 104 – Days 2 to 7 
Table 8: Detailed schedule of events – Following a SOBI003 dose adjustment - first 3 weeks 
Table 9: Detailed schedule of events – Following a SOBI003 dose adjustment – Weeks 4 and 8 
 




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examination (general appearance, skin (including potential reactions around the infusion site), eyes, ears, nose, 
neck, nymph nodes, throat, heart, lungs, abdomen, musculoskeletal system and extremities) is conducted.  
c  During the treatment period, body weight is assessed at approximately 4-week intervals to determine the 
actual SOBI003 dose to be administered. Weight is therefore obtained prior to preparation of the SOBI003 
infusions solution at Enrolment (Week 25) and every 4th week during the study. The weight is obtained either the 
day prior to the infusion or the day of infusion. 
d  Vital signs includes blood pressure, heart rate, body temperature, respiratory rate and oxygen saturation 
measured by pulse oximetry. At each infusion, assessments are done pre-infusion, mid-infusion and within 1 
hour after end of infusion. If dose is adjusted, vital signs are measured according to 7.5.5.4. 
e.  Within 30 to 60 minutes prior to each SOBI003 infusion, a single dose of a non-sedative antihistamine should 
be administered.  
f.  SOBI003 is administered as weekly infusions; +/- 1-day window is applied. 
g   Use of general anesthesia or sedation as well as selection of anesthetic/sedative agents is per local hospital 
routine and anesthesiologist judgement. 
h   Only applicable when separate informed consent has been provided for future research.  
i  Sleep pattern is assessed by actigraph recordings for 7 consecutive days at Weeks 51-52 and 103-104, i.e., the 
recordings start Weeks 51 and 103, and will cease in the morning of the Week 52 and 104 infusions. An 
actigraph log is completed during the days of actigraphy. Parents should complete the CSHQ upon completion of 
each actigraph assessment (i.e., at Weeks 52 and 104 this will be during the infusion days). 
j  In case both BSID-III and KABC-II are to be administered, the BSID-III should be administered first, and 
there should be at least 2 days between the BSID-III and KABC-II assessments. 
 








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c. Within 30 to 60 minutes prior to each SOBI003 infusion, a single dose of a non-sedative antihistamine should be administered. 
d. PK sample should be collected as soon as possible following end of infusion.  
e. 168 hour PK sample for weeks 38 and 78 is collected pre-infusion on weeks 39 and 79 respectively.  
 








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c. In case both BSID-III and KABC-II should be assessed, the BSID-III should be administered first, and there should be at least 2 days between the BSID-III and KABC-II 
assessments. If only BSID-III or KABC-II is to be assessed this should be done on Day 7. 
 






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Table 10 
Detailed PK blood sampling schedule 
Week 
Time 
No of samplesa 
Week 38 
Pre-infusion 
1 
4h / End of Infusion 
2 
168h 
1 
Week 52 
Pre-infusion 
1 
4h / End of Infusion 
2 
Day 2c  
1 
168h 
1 
Week 78 
Pre-infusion 
1 
4h / End of Infusion 
2 
168h 
1 
Week 104 
Pre-infusion 
1 
4h / End of Infusion 
2 
Day 2c  
1 
168h 
1 
At week of dose 
adjustmentb 
Pre-infusion 
1 
4h / End of Infusion 
2 
168h 
1 
3 weeks after 
dose adjustment 
Pre-infusion 
1 
4 weeks after 
dose adjustmentb 
Pre-infusion 
1 
4h / End of Infusion 
2 
168h 
1 
8 weeks after 
dose adjustmentb 
Pre-infusion 
1 
4h / End of Infusion 
2 
168h 
1 
At early 
treatment/study 
termination 
Early Termination visit – time point same as 
immunology sample  
1 
30-40 days post Early Termination visit - time point 
same as immunology sample 
1 
If additional immunogenicity samples as part of 
follow-up- number of samples per time point 
1 
a  If Number = 1; PK blood sample is collected from central venous access port. If Number =2; One PK sample 
will be collected from the central venous access port and one PK sample will be collected from a peripheral 
venous line. The PK samples from a peripheral venous line for the End of infusion sample can be excluded if it 
has been confirmed in the FIH study (SOBI003-001) that the SOBI003 i.v. infusion does not interfere with the 
PK blood sampling.. 
b  If the dose of SOBI003 is adjusted in a patient, PK blood samples will be collected before infusion, at the end 
of infusion and 168 hours after start of the infusion at the week of dose adjustment and 4 and 8 weeks after the 
dose adjustment. 
c  At the time of CSF sample collection Day 2, a PK blood sample will also be collected. In case the time point 
for the CSF sample is deviating from the planned time point, the blood samples should be adjusted accordingly. 


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7.5.1.2 
Week 25 / Enrolment  
The patient is admitted to the hospital the day prior to or on the day of the SOBI003 infusion. 
This week will be continue directly following last study visit (Week 24) in the FIH study 
(SOBI003-001) without any break in treatment. Baseline information collected during the first 
study will be used for the extension study. Patient demography information will only be 
collected at Week 25 if there are any changes to the already collected data.  
The informed consent process, including the provision of signed consent for study 
participation, is completed and the patient eligibility is confirmed. 
AEs and concomitant medications are captured continuously from Day 1 of Week 25 until 
study completion. This includes all events observed/diagnosed or reported since the last visit 
of the FIH study (SOBI003-001) study (Week 24 / End of study). 
Prior to start of the infusion, the following is performed: 
• Body weight is obtained either the day prior to the infusion or the day of infusion 
• General appearance and skin are assessed (part of physical examination) 
• Vital signs are assessed 
Within 30 to 60 minutes prior to start of the SOBI003 infusion, a single dose of a non-
sedative antihistamine is administered. SOBI003 is administered in accordance with Section 
7.4.5. 
Vital signs are assessed approximately 2 hours after start of infusion. Within an hour of 
completion of the infusion, vital signs, general appearance and skin are assessed.  
The patient may be discharged from the hospital 1 hour or more after the end of the infusion.   
7.5.1.3 
Weeks 26 to 37, Weeks 39 to 51, Weeks 53 to 77 and Weeks 79 to 103 
SOBI003 is administered as weekly infusions; a +/- 1-day window is applied. The patients 
will return to the hospital the day prior to or on the day of each infusion. AEs and use of 
concomitant medications during non-hospital stay are captured.  
Prior to start of each infusion, weekly vital signs and general appearance and skin are 
assessed.  
At Weeks 29, 33, 37, 41, 45, 49, 53, 57, 61, 65, 69, 73, 77, 81, 85, 89, 93, 97 and 101, body 
weight is also assessed to determine the SOBI003 dose to be administered during a 
forthcoming 4-week interval, respectively. The body weight is obtained either on the day prior 
to the infusion or the day of infusion.  
At Weeks 39 and 79, a pre-infusion PK sample with be collected as part of the PK collection 
from previous visits (Weeks 38 and 78 respectively). 
Within 30 to 60 minutes prior to start of each SOBI003 infusion, a single dose of a non-
sedative antihistamine is administered. SOBI003 is administered in accordance with Section 
7.4.5.  
Vital signs are assessed approximately mid-infusion as described in Section 7.5.5.4. Within an 
hour of completion of the infusion, vital signs and general appearance and skin are assessed. 


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Prior to discharge at Weeks 51 and 103, the parent/caregiver is given the actigraph and the 
accompanying actigraph log. The parent/caregiver is instructed to start the sleep assessment 7 
days prior to attendance for the 52th and 104th infusion.  
The patient may be discharged from the hospital 1 hour or more after the end of each infusion.   
7.5.1.4 
Weeks 38 and 78 
SOBI003 is administered as weekly infusions; a +/- 1-day window is applied. The patients 
will return to the hospital the day prior to or on the day of each infusion. AEs and use of 
concomitant medications during non-hospital stay are captured.  
Prior to start of each infusion, vital signs and general appearance and skin are assessed. Blood 
and urine are collected for safety laboratory and HS assessments, and blood samples are also 
collected for assessment of immunogenicity and PK.  
Within 30 to 60 minutes prior to start of each SOBI003 infusion, a single dose of a non-
sedative antihistamine is administered. SOBI003 is administered in accordance with Section 
7.4.5.  
Vital signs are assessed approximately mid-infusion as described in Section 7.5.4.4. As soon 
as possible following end of infusion a blood sample is collected for PK evaluation. Vital 
signs and general appearance and skin are assessed within an hour of completing the infusion.  
The patient may be discharged from the hospital 1 hour or later after the end of each infusion.   
On Day 7, prior to the next weekly infusion, a blood sample is collected for PK evaluation.  
7.5.1.5 
Week 52 
SOBI003 is administered as weekly infusions; a +/- 1-day window is applied. The patients 
will return to the hospital the day prior to or on the day of the last infusion. AEs and use of 
concomitant medications during non-hospital stay are captured. The actigraph and 
accompanying actigraph log are collected. 
 
Week 52, Day 1 Assessments 
Prior to start of the infusion, the following is performed: 
• Vital signs are assessed 
• General appearance and skin are assessed 
• Blood and urine is obtained for safety laboratory 
• Blood and urine is obtained for HS assessment 
• Blood is obtained for immunogenicity and PK assessments 
• When separate consent for future research has been provided, serum samples will also 
be collected for storage at the central laboratory. 
Within 30 to 60 minutes prior to start of each SOBI003 infusion, a single dose of a non-
sedative antihistamine is administered. SOBI003 is administered in accordance with Section 
7.4.5.  


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Vital signs are assessed approximately mid-infusion as described in Section 7.5.4.4. As soon 
as possible following end of infusion, a blood sample is collected for PK evaluation. Vital 
signs and general appearance and skin are assessed within an hour of completing the infusion.  
The parent/caregiver completes the CSHQ questionnaires, preferably during Day 1.  
 
Week 52, Day 2 to 7 Assessments 
On day 2, general anesthesia is applied in accordance with local routines at the study site. 
CSF sampling for PK, ADA, and HS assessments and MRI scanning of brain, liver and spleen 
are completed while the patient is anesthetized. The order of the procedures should preferably 
be as stated. Should this not be feasible for an individual patient, then effort should be made 
to have the assessments performed in the same order as they were performed in the FIH study 
(SOBI003-001). When separate consent for future research has been provided, CSF will also 
be collected for storage at the central laboratory.  
At the time of CSF sample collection Day 2, a PK blood sample will also be collected. In case 
the time point for the CSF sample is deviating from the planned time point, the blood samples 
should be adjusted accordingly. 
On Day 3, the VABS-II is assessed by parent/caregiver (refer to Section 7.5.3.2). 
The parent/caregiver completes the PedsQL questionnaire, preferably during Day 4. 
Based on the patient’s developmental age, as determined by the VABS-II score, the BSID-III 
and/or KABC-II tests are conducted for assessment of neurocognition, language and motor 
function (see Sections 7.5.3.1, 7.5.3.2, and 7.5.3.6, respectively). If only BSID-III or only 
KABC-II is to be assessed, then this should be done on Day 7. If both BSID-III and KABC-II 
should be assessed, then the BSID-III should be administered on Day 4 or 5 and the KABC-II 
on Day 7.  
On Day 7, a neurological and a complete physical examination are performed, an ECG is 
conducted and height, weight and head circumference are obtained. In addition, blood is 
collected on Day 8 (approximately 168h after start of SOBI003 infusion) for PK analyses as 
specified in Section 7.5.5.1. 
The patient may be discharged from the hospital 1 hour or later after start of the infusion. The 
patient will then return to the hospital for study assessments as detailed in Schedule of Events 
(Table 7). 
 
7.5.1.6 
Week 104 / End of Study 
SOBI003 is administered as weekly infusions; a +/- 1-day window is applied. The patients 
will return to the hospital the day prior to or on the day of the last infusion. AEs and use of 
concomitant medications during non-hospital stay are captured. The actigraph and 
accompanying actigraph log are collected. 
 
Week 104, Day 1 Assessments 
Prior to start of the infusion, the following is performed: 
• Vital signs are assessed 


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• General appearance and skin are assessed 
• Blood and urine is obtained for safety laboratory 
• Blood and urine is obtained for HS assessment 
• Blood is obtained for immunogenicity and PK assessments 
• When separate consent for future research has been provided, serum samples will also 
be collected for storage at the central laboratory. 
Within 30 to 60 minutes prior to start of each SOBI003 infusion, a single dose of a non-
sedative antihistamine is administered. SOBI003 is administered in accordance with Section 
7.4.5.  
Vital signs are assessed approximately mid-infusion as described in Section 7.5.5.4. As soon 
as possible following end of infusion, a blood sample is collected for PK evaluation. Vital 
signs and general appearance and skin are assessed within an hour of completing the infusion.  
The parent/caregiver completes the CSHQ questionnaires, preferably during Day 1.  
 
Week 104, Day 2 to 7 Assessments 
General anesthesia is applied in accordance with local routines at the study site. CSF sampling 
for PK, ADA, and HS assessments and MRI scanning of brain, liver and spleen are completed 
while the patient is anesthetized. The order of the procedures should preferably be as stated. 
Should this not be feasible for an individual patient, then effort should be made to have the 
assessments performed in the same order as they were performed in the FIH study 
(SOBI003-001). When separate consent for future research has been provided, CSF will also 
be collected for storage at the central laboratory.  
At the time of CSF sample collection Day 2, a PK blood sample will also be collected. In case 
the time point for the CSF sample is deviating from the planned time point, the blood samples 
should be adjusted accordingly. 
On Day 3, the VABS-II is assessed by parent/caregiver (refer to Section 7.5.3.2). 
The parent/caregiver completes the PedsQL questionnaire, preferably during Day 4. 
Based on the patient’s developmental age, as determined by the VABS-II score, the BSID-III 
and/or KABC-II tests are conducted for assessment of neurocognition, language and motor 
function (see Sections 7.5.3.1, 7.5.3.2, and 7.5.3.6, respectively). If only BSID-III or only 
KABC-II is to be assessed, then this should be done on Day 7. If both BSID-III and KABC-II 
should be assessed, then the BSID-III should be administered on Day 4 or 5 and the KABC-II 
on Day 7.  
On Day 7, a neurological and a complete physical examination are performed, an ECG is 
conducted and height, weight and head circumference are obtained. In addition, blood is 
collected on Day 8 (approximately 168h after start of SOBI003 infusion) for PK analyses as 
specified in Section 7.5.5.1. 
The patient may be discharged from the hospital 1 hour or later after start of the infusion. The 
patient will then return to the hospital for study assessments as detailed in Schedule of Events 
(Table 7). 


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For patients that are permanently discontinuing SOBI003 treatment, serum samples for PK 
and ADA analyses should be obtained 30 to 40 days after last SOBI003 infusion. Patients 
with ADA-positive samples should continue to be followed in accordance with Sections 
7.5.4.3 and 7.5.5.1.  
7.5.1.7 
Weeks of dose adjustments 
During the study there may be situations where individual patients or all study patients will 
increase or reduce their treatment dose, please refer to 7.4.4 and 7.4.5 for more details. In 
such situations, a more extensive initial schedule of assessments will follow.  
Dose adjustments will be avoided during Weeks 48 to 52 and 100 to 104, in order not to 
interfere with study efficacy assessments on Week 52 and 104, respectively. Any requested 
dose adjustment during this time should be postponed until after these assessments have been 
completed, if not considered medically justified by the investigator.  
 
First 3 weeks following a SOBI003 dose adjustment 
SOBI003 is administered as weekly infusions; a +/- 1-day window is applied. The patients 
will return to the hospital the day prior to or on the day of the last infusion. AEs and use of 
concomitant medications during non-hospital stay are captured.  
Prior to start of the infusion, the following is performed: 
• Vital signs are assessed 
• General appearance and skin are assessed 
• Blood and urine is obtained for safety laboratory 
• Blood and urine is obtained for HS assessment 
• Blood is obtained for immunogenicity (only on week 3) and PK assessments (on 
weeks 1 and 3) 
• A pulse-oximeter is applied 
Within 30 to 60 minutes prior to start of each SOBI003 infusion, a single dose of a non-
sedative antihistamine is administered. SOBI003 is administered in accordance with Section 
7.4.5.  
At hourly intervals during the infusion, (i.e. at approximately 1, 2 and 3 hours after start of 
infusion) vital signs, general appearance and skin are assessed. As soon as possible following 
end of infusion, a blood sample is collected for PK evaluation (only on week 1). Vital signs 
and general appearance and skin are assessed within an hour of completing the infusion, and 
the continuous pulse oximetry is discontinued.  
Vital signs, general appearance and skin are assessed within 6-7 hours after start of infusion, 
and also within 8 to 12 hours after start of infusion, as well as on Day 2 and 3.  
On Day 8 (only on week 1) a blood sample for PK evaluation is collected (pre-infusion the 
following weekly dose).  
The patient may be discharged from the hospital 48 hours after start of the infusion. The 
patient will then return to the hospital for study assessments on Days 3 and 8.  


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If dose adjustment is a decrease in dose as a result of study dose selection for forthcoming 
studies, and there are no safety concerns, the patient may be discharged 1 hour or more after 
the end of each infusion. In such situations the assessments should follow the schedule with 
the exemption that the vital signs, general appearance and skin assessments within 6-7 hours 
after start of infusion, and also within 8 to 12 hours after start of infusion, as well as on Day 2 
and 3 may be excluded as per investigator decision.  
 
On Weeks 4 and 8 following a SOBI003 dose adjustment 
SOBI003 is administered as weekly infusions; a +/- 1-day window is applied. The patients 
will return to the hospital the day prior to or on the day of the last infusion. AEs and use of 
concomitant medications during non-hospital stay are captured.  
Prior to start of the infusion, the following is performed: 
• Vital signs are assessed 
• General appearance and skin are assessed 
• Blood is obtained for PK assessments  
Within 30 to 60 minutes prior to start of each SOBI003 infusion, a single dose of a non-
sedative antihistamine is administered. SOBI003 is administered in accordance with Section 
7.4.5.  
Vital signs are assessed approximately mid-infusion as described in Section 7.5.4.4. As soon 
as possible following end of infusion, a blood sample is collected for PK evaluation. Vital 
signs and general appearance and skin are assessed within an hour of completing the infusion.  
On Day 8 a blood sample for PK evaluation is collected (pre-infusion the following weekly 
dose).  
The patient may be discharged from the hospital 1 hour or more after the end of each infusion. 
7.5.1.8 
Early withdrawal from treatment/study 
If the patient is withdrawn from study treatment, the patient should be examined as soon as 
possible after making the withdrawal decision. AEs and use of concomitant medications are 
captured. Blood is collected for safety laboratory, HS, immunogenicity and PK assessments. 
Urine is collected for safety laboratory and HS assessments.  
Vital signs are assessed, and a neurological and a physical examination are performed. An 
ECG is conducted, and height, weight and head circumference are obtained.    
The VABS-II is assessed by parent/caregiver (refer to Section 7.5.3.2). The parent/caregiver 
completes the PedsQL questionnaire. 
Based on the patient’s developmental age, as determined by the VABS-II score, the BSID-III 
and/or KABC-II tests are conducted for assessment of neurocognition, language and motor 
function (see Sections 7.5.3.1, 7.5.3.2, and 7.5.3.6, respectively). If both BSID-III and KABC-
II should be assessed, then the BSID-III should be administered 2 days prior to the completion 
of KABC-II.  
When possible, study assessments (excluding SOBI003 infusion) of Weeks 38, 52, 78 and 
104 should continue in accordance with the Schedule of Events. At minimum, the Early 


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Termination assessments should be repeated 30 to 40 days after the last SOBI003 
administration. Patients with ADA-positive samples should continue to be followed in 
accordance with Sections 7.5.4.3 and 7.5.5.1.  
7.5.1.9 
Estimated blood sampling volumes and sampling priority list  
Applying the European Commission guidance (18), 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.  
Local and/or regional guidelines regarding blood draw volumes may also apply. 
Information of blood volumes per assessment type and sampling occasion are provided in a 
separate central laboratory manual.  The total blood volume will not exceed 8 mL at a single 
time.  
Blood sampling necessary for the clinical management of the patient will prevail over any 
study specific sampling. 
Should the blood volume be restricted at any of the sampling time points, then the analyses 
should be prioritized in the following order: 
1. Immunogenicity (ADA) 
2. Coagulation 
3. PK 
4. Hematology 
5. Blood chemistry 
6. HS 
7. Serum collection for future biomarker analyses 
 
7.5.2 
Demography 
The following demographic data are captured in the FIH study (SOBI003-001); date of birth 
(month and year), gestational age at birth, gender, ethnicity, race, country of residence and 
native language. In addition, information on the patient’s sibling(s) is captured, including age 
and MPS IIIA diagnostic status (confirmed as non-affected/confirmed as affected/under 
current investigation). For sibling(s) with confirmed diagnosis, the sibling’s age at diagnosis 
and genotype are also captured, when known. 
Any changes to the patient´s demographic data (i.e., country of residence) or information on 
the patient´s siblings are recorded at Week 25 / Enrolment. 
7.5.3 
Efficacy assessments 
7.5.3.1 
Neurocognition 
Neurocognition is assessed at Weeks 52 and 104, and during Early Termination, by use of the 
neurocognition domain of the BSID-III and/or the KABC-II Nonverbal Index (NVI).  


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The selection of neurocognitive assessment method is done at the baseline assessment of the 
FIH study (SOBI003-001) based on the algorithm presented in Table 11. The neurocognitive 
test(s) applied in the FIH study should also be used in the extension study. 
Table 11 
Selection of neurocognitive assessment method  
Chronological age at the 
assessment time point 
Development age-equivalence as 
established by VABS-II adaptive 
behavior composite  
Neurocognitive test to apply 
<42 months 
Any age-equivalence 
BSID-III 
≥42 months 
<36 months 
BSID-III 
≥42 months 
36 to 42 months 
BSID-III + KABC-II* 
≥42 months  
>42 months 
KABC-II 
* The BSID-III should be administered first, and there should be at least 2 days until the KABC-II assessment in 
order to reduce KABC-II outcome bias of patient tiredness. 
The neurocognitive developmental age (months) is derived on the basis of the BSID-III 
cognitive total raw score and BSID-III age-normative data. 
The neurocognitive developmental age (months) is derived from the mean AEq scores on the 
NVI of the KABC-II, where an AEq scores is the average score for a particular age. 
The Development Quotient (DQ) is obtained by dividing the neurocognitive developmental 
age with chronological age. 
For patients completing an assessment of both BSID-III and KABC-II, the BSID-III score 
will be used as a basis for calculating the DQ of neurocognitive development at baseline. A 
calibration of overlapping AEq scores between BDID-III and KABC-II will be done to assess 
if a patient outgrows the BSID-III test during the duration of the study. If confirmed, 
assessments of KABC-II will form the basis for calculating DQ of neurocognitive 
development for remaining study assessments.  
Neurocognition assessments are performed by child development specialists/psychologists 
with prior experience of MPS IIIA patients. Each patient should preferably have the same 
assessor throughout the study in order to reduce potential variability. When practically 
feasible, the aim should be to have the assessments performed in rested children early during 
the day, i.e., prior to 1 pm. The aim should also be to roughly keep the same assessment time 
point for an individual child, i.e., morning/afternoon.   
To ensure that the BSID-III and KABC-II assessments are performed in accordance with the 
study instructions, completed assessment forms will be sent to a central reader (NeuroCog 
Trials) for data quality assurance, calculation of final scores and determination of Age 
Equivalence scores.  
7.5.3.2 
Adaptive behavior 
Adaptive behavior is assessed at Weeks 52 and 104, and during Early Termination. 
The patients’ ability to cope with changes, to demonstrate independence and to learn new 
skills are assessed by use of the Parent/Caregiver Rating Form of the VABS-II. This measures 
five competence domains: communication, socialization, daily living skills, motor skills and 
an adaptive behavior composite of the first four domains.  


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The VABS-II is assessed by parent/caregiver. Every effort will be made to have the same 
parent/caregiver completing the form at each assessment time point.  
The adaptive behavior age-equivalent score is determined as the mean of the subdomain age-
equivalent scores including the communication, socialization, and daily living skills (thus 
excluding the motor skills domain). 
Completed assessment forms will be sent to a central reader (NeuroCog Trials), for data 
quality assurance of completed assessment forms, calculation of final scores and 
determination of Age Equivalence scores, and data management. 
7.5.3.3 
Magnetic resonance imaging 
Brain and abdominal MRI are performed under general anesthesia at Weeks 52 and 104. 
MRI scanning protocols including details on sequence parameters and scanning guidelines are 
provided to the clinical sites under the coordination of the central MRI reader. MRI field 
strength should be a minimum of 1.5, preferable, 3.0 tesla.  
Preferably, the same MRI technician should perform all study related scans. The separate 
MRI assessment protocol provided prior to the study start should be followed for each scan. 
MRI data are sent to the central reader for quantitative analyses. 
The brain MRI assessment protocol includes: 
1. 
3D T1-weighted MPRAGE (~6 min) for volumetric analysis 
2. 
DTI and gre fieldmap (~10 min) for white matter analysis 
3. 
3D FLAIR and T2 (~8 min) for volumetric analysis 
4. 
4.SWI (~10 min) for iron content analysis 
The abdominal MRI assessment protocol includes: 
1. 
T1 3D VIBE (~2 min.) 
2. 
T2 HASTE (~2 min.) 
Liver/spleen volumes are evaluated by MRI using a standard MRI protocol. 
7.5.3.4 
Quality of life and caregiver burden 
The parent proxy-report format of the PedsQL questionnaire (Version 4.0) (29) will be used to 
assess the child’s quality of life. The Family impact Module of the PedsQL (Version 2.0) will 
be used to assess the caregiver burden. The PedsQL will be completed at Baseline and at 
Weeks 52 and 104 and at early termination.  Every effort should be made to have the same 
parent/caregiver responding to the PedsQL questions at each assessment time point. 
The PedsQL version (i.e., infant/toddler/young children) will be selected on the basis of the 
chronological age of the patient.  
 


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7.5.3.5 
Language 
Expressive and receptive language are assessed at Weeks 52 and 104, and during Early 
Termination, by the BSID-III language module and the VABS-II communication domain. In 
addition, written language is assessed by the VABS-II communication domain. 
For those patients taking the KABC-II for cognitive assessment, the Expressive Vocabulary 
from the KABC-II is applied to assess language development.  
7.5.3.6 
Motor function 
Fine and gross motor skills are assessed at Weeks 52 and 104, and during Early Termination, 
by the BSID-III motor function module and the VABS-II motor skills domain. 
7.5.3.7 
Sleep pattern  
The patients’ sleep pattern is evaluated using the CSHQ and by use of actigraphy.  
Two additional items are added to the original CSHQ questionnaire to further characterize 
common MPS IIIA specific issues with sleep i.e. disruptive behavior at night and dangerous 
behavior at night. The CSHQ is completed by the primary caregiver prior to the infusions at 
Weeks 52 and 104. This CSHQ will capture the child’s sleep habits during the past week. 
Every effort will be made to have the same caregiver completing the CSHQ at each 
assessment time point. 
An actigraph will be applied to the non-dominant wrist and recordings will be made for 7 
consecutive days and nights before the Weeks 52 and 104 assessments. 
The wrist or ankle placement should be used consistently throughout the study period and be 
the same as used during the FIH (SOBI003-001) study. The device will be worn constantly 
during the recording periods only allowing removal for washing and bathing. The aim is to 
ensure that at least 5 days of evaluable recordings are obtained on each occasion. A daily wear 
time of 20 hours per day will be regarded as a compliant recording. The recording will be 
supported by an actigraph log. Recorded actigraph data will be evaluated using the 
accompanying software developed by the manufacturer. A subset of the actigraphy data is 
coded to be analyzed in a subsequent separate blinded analysis of the manually edited dataset.   
The following parameters will be determined on the basis of recordings in the actigraph log: 
• Bedtime (clock time child is put to bed) 
• Wake time (clock time child is taken out of bed) 
• Time in bed (time between Bedtime and Wake time) 
The following variables are derived as obtained from the actigraph software:  
• Sleep onset (clock time for ﬁrst appearance of a predetermined number of consecutive 
min of sleep) 
• Sleep offset (clock time for last of a predetermined number of consecutive min of 
sleep) 
• Sleep period (time between sleep onset and sleep offset) 
• Total sleep time (TST, duration of sleep in sleep period) 
• Wake after sleep onset (WASO, number of minutes scored as wake during sleep 
period) 


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• Sleep efﬁciency (percentage sleep: TST/time in bed) 
• Night waking frequency (number of night wakings) 
• Night waking duration (sum of minutes scored as night waking) 
24 h sleep duration (amount of sleep in a 24-hour period) Sleep onset latency is determined as 
Time between bedtime (as recorded on the actigraph log) and sleep onset (as captured by the 
actigraph software). 
The Sadeh algorithm (28) is used for determining which epochs (1-minute recordings) are 
marked as “sleep” versus which are marked as “awake”. The Tudor-Locke method is applied 
to determine sleep periods, where 5 consecutive minutes of recorded “sleep” defines Sleep 
onset and where 10 consecutive minutes of “awake” time defines Sleep offset. 
7.5.4 
Safety assessments 
7.5.4.1 
Adverse events 
 
Definitions 
Adverse event 
An AE is any untoward medical occurrence in a patient or trial subject administered a 
pharmaceutical product; the event does not necessarily have a causal relationship with the 
treatment or usage. 
AEs include the following: 
• Abnormal test findings, as specified below. 
• Clinically significant signs and symptoms. 
• Changes in physical examination findings. 
• Unexpected progression/worsening of underlying disease. 
In addition, signs and symptoms resulting from the following should also be handled 
according to the same principles as AEs: 
• Overdose. 
• Withdrawal of treatment. 
• Interactions. 
• Abuse. 
• Misuse. 
Abnormal test findings 
An abnormal test finding, e.g. abnormal laboratory analysis results, vital signs or ECG, should 
be recorded as an AE in any of the following situations: 
• The test is associated with accompanying symptoms. Note, that the symptom, not the 
test result, should be recorded as an AE. 


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• The test result leads to a medical/surgical intervention including withdrawal of IMP(s) 
or discontinuation from the study. Repeat/confirmatory testing is not considered a 
medical intervention. 
• The investigator considers the test result to be clinically significant. 
Preexisting conditions  
A preexisting condition (i.e., a disorder present before the AE reporting period started and 
noted on the pretreatment medical history/physical examination form of the FIH study 
(SOBI003-001) should not be reported as an AE unless the condition worsens or episodes 
increase in frequency during the AE reporting period.  
Procedures 
Diagnostic and therapeutic non-invasive and invasive procedures, such as surgery, should not 
be reported as AE. However, the medical condition for which the procedure was performed 
should be reported if it meets the definition of an AE. For example, an acute appendicitis that 
begins during the AE reporting period should be reported as the AE and the resulting 
appendectomy entered in the comments section of the CRF. 
Serious adverse event (SAE) 
An AE that meets one or more of the following criteria/outcomes is classified as serious: 
• Results in death. 
• Is life-threatening (i.e., at immediate risk of death). 
• Requires in-patient hospitalization or prolongation of existing hospitalization. 
• Results in persistent or significant disability/incapacity. 
• Is a congenital anomaly/birth defect (i.e., in an offspring to the study subject). 
Other medically important AE that may not result in death, be life threatening, or require 
hospitalization may be considered serious when, based upon appropriate medical judgment, 
they may jeopardize the patient or subject or may require medical or surgical intervention to 
prevent one of the outcomes listed above. Examples of such events are intensive treatment in 
an emergency room or at home for allergic bronchospasm, blood dyscrasias or convulsions 
that do not result in hospitalization or development of dependency or abuse. 
Serious also includes any other event that the investigator or company judges to be serious. 
Any suspected transmission of an infectious agent via IMP shall also be considered serious. 
Hospitalization 
Hospitalization includes transfers within a hospital (e.g. from the hospital ward to the 
intensive care unit) and also includes admissions less than 24 hours. The following situations 
are not considered hospitalizations (although other SAE criteria may still apply): 
• Outpatient procedures / ambulatory care. 
• Emergency department visits. 


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Hospitalization in the absence of an AE occurring during the study should not be considered 
an SAE. This includes: 
• Hospitalization due to a pre-existing condition not associated with a worsening of the 
pre-existing condition. 
• Protocol specified admission. 
• Elective admission, e.g. due to cosmetic surgery. 
• Pre-planned admission for a condition specified at Baseline for the patient. 
Treatment-emergent adverse event (TEAE) 
TEAE is any AE with onset or worsening reported from the time that the first dose of IMP is 
administered until completion of or early termination from the study. 
 
Adverse event reporting period 
The period for recording AE, including SAEs, on the CRF begins Day 1 upon signing of the 
study ICF on Week 25 and ends at Day 8 of Week 104 (End of Study). This includes all 
events observed/diagnosed or reported since the last visit of the FIH study (SOBI003-001) 
(Week 24 / End of study). 
In addition, SAEs should be reported, from the time the ICF is signed until 28 days past the 
last dose of IMP, unless the patient will continue SOBI003 treatment in a Sobi-sponsored 
extension study starting in direct connection to the study, collecting these events. 
 
 
Eliciting and recording adverse event information 
The investigator is to record all directly observed AE, and all AEs spontaneously reported by 
the parent/patient, in the CRF using concise medical terminology.   
When possible and appropriate, a diagnosis rather than individual signs and symptoms shall 
be recorded. The investigator is responsible for obtaining sufficient information to determine 
seriousness, causality and outcome of each AE. 
Severity assessment 
For the purpose of consistency, the investigator will use the grading provided in Table 12 to 
describe the maximum intensity of the AE. The grading is based on the NCI CTCAE (version 
4.03).  
Table 12 
Severity grade definitions according to NCI CTCAE (version 
4.03) 
Grade I 
Mild; asymptomatic or mild symptoms; clinical or diagnostic observations 
only; intervention not indicated 
Grade II 
Moderate; minimal, local or non-invasive intervention indicated; limiting 
age-appropriate instrumental Activities of Daily Living (ADL) 


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Grade III 
Severe or medically significant but not immediately life-threatening; 
hospitalization or prolongation of hospitalization indicated; disabling; 
limiting self-care ADL 
Grade IV 
Life-threatening consequences; urgent intervention indicated 
 
Note the distinction between the seriousness (serious/non-serious) and the intensity (severity) 
of an AE. Severe is a measure of intensity; thus, a severe reaction is not necessarily a serious 
reaction. For example, a headache may be severe in intensity, but would not be classified as 
serious unless it met one of the criteria for serious events listed above. 
Causality assessment 
For each AE, the investigator or sub-investigator must make a causality assessment on the 
basis of his/her clinical judgment to determine if there is a reasonable possibility that the 
IMP(s) caused the AE. The AE is assessed as related or not related to the IMP(s) with the 
following definitions: 
Related 
The AE follows a reasonable temporal sequence from the study product 
administration, 
and cannot be reasonably explained by the subject’s clinical state or other factors 
(e.g., disease under study, concurrent diseases, or concomitant medications). 
 
Not Related 
The AE does not follow a reasonable temporal sequence from study product 
administration, or can be reasonably explained by the subject’s clinical state or other 
factors (e.g., disease under study, concurrent diseases, and concomitant medications).  
 
Serious adverse event reporting 
Both serious and non-serious AEs are to be reported on the AE page of the CRF as specified 
in the CRF instructions. The form for collection of SAE information is not the same as the 
general AE CRF page. Where the same data are collected, the forms must be completed in a 
consistent manner. For example, the same AE term should be used on both forms. 
Any SAE must be reported by the investigator if it occurs during the clinical study whether or not 
the SAE is considered to be related to the investigational product. An SAE report consists of the 
SAE form including medical history and concomitant medications. A copy of these forms must be 
emailed or faxed within 24 hours at:  
• SAE reporting email address: INCDrugsafety@INCResearch.com  
• SAE reporting toll fax number: +1 877 464 7787  
• SAE reporting country specific toll-free fax numbers  
In addition, to the SAE reporting to INC, the investigator must via email notify the 
Sobi Medical Director and Drugsafety@sobi.com. 


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The investigator shall provide INC Research with sufficient information to enable a complete 
medical assessment of the reported event. Best efforts shall be made by the investigator to 
provide INC Research with additional information related to any SAE as requested.  
The investigator should not wait to receive additional information to document fully the event 
before notification of a SAE, though additional information may be requested. Where 
applicable, information from relevant laboratory results, hospital case records, and autopsy 
reports should be obtained. All new information obtained, relevant to an SAE report, should 
be forwarded to INC Research within the same timeframe as the initial information. 
Instances of death, congenital abnormality, or an event that is of such clinical concern as to 
influence the overall assessment of safety, if brought to the attention of the investigator at any 
time after cessation of study drug administration and linked by the investigator to this study, 
should be reported to the study monitor.  
Sobi and/or INC Research will promptly notify all relevant investigators and the regulatory 
authorities of findings that could adversely affect the safety of subjects, impact on the conduct 
of the study or alter the independent ethics committee (IEC)/institutional review board (IRB) 
approval/favorable opinion of the study. In addition, INC Research, on behalf of Sobi, will 
expedite the reporting to all concerned investigators, to the IECs/IRBs, where required, and to 
the regulatory authorities of all adverse reactions that are both serious and unexpected. The 
expedited reporting to the regulatory authority in the U.S.A. will however be managed by 
Sobi. 
 
Follow-up of unresolved adverse events 
All AEs should be followed until they are resolved or the investigator assesses them as 
chronic or stable, or the patient’s participation in the study ends, i.e., until Day 7 of Week 104 
(End of Study). How to report changes in an ongoing AE during a patient's participation in the 
study is described in the CRF instructions.  
In addition, all serious and non-serious AEs assessed by the investigator as related to 
SOBI003 should continue to be followed until they resolve or until the investigator assesses 
them as “chronic” or “stable”, even after the patient's participation in the study is over.  
7.5.4.2 
Laboratory safety assessments 
Biochemistry, hematology, coagulation and urine analyses are conducted at a central 
laboratory (BARC). The time points for sample collection are summarized in Table 13 as well 
as the analyses performed at each sampling occasion. 
At the discretion of site personnel, urine collection bags will be used as needed. 
In case of acute infusion reaction or anaphylactic reaction (taken at an AE grade III or greater 
but may also include grade II at the discretion of the investigator, central laboratory analyses): 
C-reactive protein (hsCRP), IL-1ra, TNFα, IgE, and tryptase.  
Depending on the severity of the reaction and at the discretion of the investigator additional 
analyses may be performed at local laboratory to better understand the mechanism of the 
reaction. 
Clinically significant laboratory values should be reported as AEs (see Section 7.5.4.1.1 for 
details).  


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Sampling details are provided separately in the Study laboratory manual. 
Table 13 
Safety laboratory assessment time points 
Analyses 
Study visit 
Sampling time point(s) 
Biochemistry (1.5 mL blood): Aspartate 
aminotransferase (AST), Alanine 
aminotransferase (ALT), Total bilirubin (if 
>upper limit of normal [ULN] then also 
direct and indirect bilirubin), Creatinine, 
Albumin, Potassium (K), Sodium (Na), 
Calcium (Ca), non-fasting Glucose, and C-
reactive protein (CRP). 
Hematology (0.5 mL blood): Hemoglobin 
(Hb), Erythrocytes, White blood cell count 
(WBC), Differential blood count and 
Platelet count. 
Coagulation (1.7 mL): PT/INR, APTT, 
and Fibrinogen. 
Urinalysis (dip-stick analyses, central 
laboratory): pH, Glucose, Proteins, and 
Blood 
Weeks 38, 52, 78 and 104 
Pre-infusion (Day 1) 
In case of SOBI003 dose 
adjustment 
For the first 3 infusions following dose 
adjustment: Pre-infusion  (Day 1) 
 
 
C-reactive protein (hsCRP), IL-1ra, TNFα, 
IgE, and tryptase (6.4 mL blood) 
In case of 
infusion/anaphylactic reaction 
 
7.5.4.3 
Immunogenicity 
Serum and CSF samples are collected for central laboratory analysis of SOBI003 ADAs by a 
validated immunoassay method (York Bioanalytical Solutions Limited, York, UK). Assays 
are being developed for assessment of neutralizing antibodies, both for antibodies inhibiting 
cellular uptake and for enzyme activity inhibiting antibodies (BioAgilytix, Hamburg, 
Germany). At each sampling occasion, a blood volume of 1.5 mL will be collected.  
Serum samples are collected prior to start of SOBI003 infusion at Weeks 38, 52, 78 and 104, 
and during Early Termination. Triplicate aliquots are required for each sampling time point. 
CSF samples (0.5 mL) are collected at Weeks 52 and 104. 
If the dose of SOBI003 is adjusted in a patient, serum samples are collected prior to start of 
the first adjusted infusion and then prior to the 3rd adjusted infusion i.e., at 2 occasions per 
dose adjustment.   
For patients with an ADA-positive serum sample, the following will also be determined in 
serum: ADA titer, IgG subclasses, and presence of NAb. 
For patients with an ADA-positive CSF sample, the following will also be determined in 
CSF: ADA titer and presence of NAb. 
Should any patient permanently discontinue SOBI003 treatment, then a serum sample will be 
collected 30 to 40 days after the last SOBI003 administration for ADA assessment. Should the 
sample be ADA-positive, then the ADA titer will be determined and ADA samplings will 
continue at approximately monthly basis until the ADA has disappeared or titers have 
stabilized at a lower level. 


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The impact of ADAs on the safety, tolerability, and PK of SOBI003 will be explored, as well 
as the potential impact on HS levels in CSF, serum and urine. 
Sampling details are provided separately in the Study laboratory manual. 
7.5.4.4 
Vital signs 
Vital signs (blood pressure, heart rate, body temperature, respiratory rate, and oxygen 
saturation) are measured at each SOBI003 infusion.  
At Weeks 25 to 104, vital signs are measured pre-infusion, mid- infusion and within 1 hour 
after end of each infusion. Vital signs are also measured at Early Termination.  
If the dose of SOBI003 is adjusted in a patient, vital signs are measured pre-infusion, 1, 2 and 
3 hours after start of infusion, within 1 hour after end of infusion, within 6-7 hours after start 
of infusion, within 8-12 hours after start of infusion, 24 hours after start of infusion and 48 
hours following infusion for the first 3 infusions. During these weeks, continuous pulse 
oximetry is assessed from pre-infusion until completion of SOBI003 infusion.  
Blood pressure and heart rate are measured in accordance to each clinic´s standard 
procedures. When the clinical situation allows, the assessments should preferably be done in 
supine position after the patient has rested comfortably for at least 5 minutes. Body 
temperature is measured in degrees Celsius using a tympanic thermometer according to each 
clinic´s standard procedures. The pulse oximetry sensor device is placed on a fingertip or 
earlobe (according to standard routines at the study site). In case of need to prolong infusions 
(i.e., > 4 hours) at any time during the study, pulse oximetry monitoring will be applied, as 
judged by the investigator. 
Clinically significant abnormal vital signs values should be reported as AEs (see Section 
7.5.4.1.1 for details).   
7.5.4.5 
Electrocardiograms 
12-lead ECGs are obtained at Weeks 52 and 104, and during Early Termination. ECG 
machines Mortara ELI 250c with VERITASTM resting ECG interpretation algorithm will be 
provided to the sites.  
Any ECG that is auto-interpreted as abnormal should be assessed for clinical significance by a 
health care professional with sufficient competence and experience of interpreting pediatric 
ECGs. If a patient shows an abnormal ECG, additional safety recordings may be made and the 
abnormality followed to resolution if required.  
If the clinical situation allows, attempts should be made to have the 12-lead ECG recordings 
obtained after the patients have been resting in a supine position for at least 5 minutes. The 
patients should preferably avoid any postural changes during the ECG recordings and clinical 
staff will ensure patients are awake during the ECG recording. 
Paper printouts of ECGs are to be stored as source documents to allow the possibility of 
retrospectively analyzing the ECGs. A study ECG manual will be provided.  
Clinically significant ECG findings should be reported as AEs (see Section 7.5.4.1.1 for 
details).  


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7.5.4.6 
Other safety assessments 
 
Physical examination and anthropometry 
The complete physical examination performed on Day 7 of Weeks 52 and 104, as well as 
during Early Termination, includes an assessment of the following: general appearance, skin 
(including potential reactions around the infusion site), eyes, ears, nose, neck, nymph nodes, 
throat, heart, lungs, abdomen, musculoskeletal system and extremities.   
At Weeks 25 to 104, general appearance and skin at the infusion site are examined prior to 
start of each infusion and within 1 hour after end of infusion. 
Height and head circumference are assessed at Weeks 52 and 104.  
Weight is assessed every 4 weeks during the treatment period in order to determine the actual 
SOBI003 dose to be administered (Section 7.4.5). The body weight is obtained either on the 
day prior to the infusion or the day of infusion. 
Height and head circumference are recorded in centimeters and weight in kilograms. For all 
weight assessments, a scale with at least 100-g accuracy should be used. 
 
Neurological examination  
At Weeks 52 and 104, and during Early Termination, a pediatric neurologist conducts an 
applicable age-related neurological examination including: 
• Cranial Nerves 
• Cerebellar function 
• Sensory function 
• Reflexes 
• Motor function   
Normal/abnormal status will be captured, and any abnormalities will be specified. 
7.5.4.7 
Appropriateness of measurements 
The safety assessments in this study are widely used and generally recognized as reliable, 
accurate, and relevant. 
7.5.4.8 
Data safety monitoring board 
A DMC is assigned to monitor safety and immunogenicity data. In addition, selected PD and 
efficacy data will be provider in order to facilitate a risk benefit review of study data. The 
primary responsibility of the DMC is to provide additional safety oversight of the study 
conduct in order to further protect study participants.   
The DMC is planned to comprise an independent statistician and two clinicians that, 
collectively, have experience from DMC, management of pediatric patients with LSD, clinical 
immunology, and the conduct of clinical trials with ERT. The DMC members must not be 
investigators in the study or otherwise associated with the sponsor.  
A DMC charter will specify the operating procedures including DMC membership, 
responsibilities, data review meeting details, and lines of communication with the study teams 
at Sobi and INC Research.  


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There are 2 scheduled DMC review meetings, one upon all patients’ completion of Week 52 
and one upon all patients’ completion of Week 104.  
7.5.5 
Pharmacokinetic assessments 
7.5.5.1 
Sampling procedures 
The sampling procedures are briefly described below and are described in more detail in the 
Study laboratory manual. Blood samples are obtained through the central venous access port 
to characterize SOBI003 PK in serum. For the PK samples collected at the end of infusion a 
PK sample will also be collected from a peripheral venous line, as described in more details 
below. A blood volume of 0.3 mL will be collected from the central venous access port and an 
additional 0.3 mL blood will be collected from the peripheral venous line, as applicable.  
PK blood samples will be collected before start of infusion, at the end of infusion and 168h 
after start of infusion at Weeks 38, 52, 78 and 104.  
If the dose is adjusted in a patient, PK blood samples will also be collected before, at the end 
of infusion and 168 h after start of the infusion for the adjusted dose. In addition, PK blood 
samples will be collected before, at the end of infusion and 168 h after start of the infusion 4 
weeks and 8 weeks after adjusting the dose. A PK blood sample will also be collected before 
the 3rd adjusted dose, as reference for ADA (see Section 7.5.4.3 for more details).  
Acceptable deviations from these planned sampling time points are the following: 4 h (end of 
infusion) (+0.5h), and 168h (- 1h).  
Details on PK blood sampling are presented in Section 7.5.1.1. and ysummarized in Table 10. 
Duplicate aliquots are required for each sampling time point. Separate blood samples from a 
peripheral venous line are collected in parallel for samples collected at the end of infusion in 
order to compare serum SOBI003 concentrations in samples collected from a peripheral line 
with samples from the central venous access port line, which is used also for the i.v. 
administration of SOBI003. The purpose of these parallel samples is to confirm that the 
SOBI003 i.v. infusion does not interfere with the blood sampling. The PK samples from a 
peripheral venous line for the End of infusion sample can be excluded if it has been confirmed 
in the FIH study (SOBI003-001) that the SOBI003 i.v. infusion does not interfere with the PK 
blood sampling. 
In addition, at each time point a sample is collected for immunogenicity, a blood sample is 
obtained for determination of SOBI003 in serum. In case of a time deviation for the 
immunogenicity sample, the time for the PK sample should be adjusted accordingly, or an 
additional PK sample may have to be collected. Therefore, in case the SOBI003 treatment is 
terminated prior to Week 104, then a PK and immunogenicity sample should be obtained as 
soon as possible after the decision of early treatment termination, as well as 30 to 40 days 
after the final SOBI003 infusion.  
For patients with confirmed ADA levels, blood samples for PK and immunogenicity analysis 
should continue in accordance with Section 7.5.4.3. 
CSF samples (0.5 mL) are collected during general anesthesia at Day 2 on Weeks 52 and 104 
for determination of SOBI003. Triplicate aliquots are required for each sampling time point. 
At the time of CSF sample collection, a blood sample will also be collected for determination 


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of SOBI003 in serum. In case the time point for the CSF sample is deviating from the planned 
time point, the blood samples should be adjusted accordingly.  
The exact time of the SOBI003 infusion start and completion as well as of each PK sampling 
are recorded in the CRF for each patient. 
Sampling, storage and shipment details are provided separately in the Study laboratory 
manual. 
7.5.5.2 
Bioanalytical method 
SOBI003 concentrations in serum and CSF are determined at a central laboratory (York 
Bioanalytical Solutions Limited, York YO26 6QR, United Kingdom) by the use of a validated 
immunoassay. The bioanalytical method may not be specific for SOBI003 and may cross-
react with endogenous sulphamidase. Potential endogenous pre-dose sulphamidase 
concentrations are taken into consideration in the PK analysis e.g. by subtracting these levels 
from post-dose SOBI003 concentrations 
7.5.5.3 
Non-compartmental pharmacokinetic analysis 
PK calculations, based on serum concentrations, are performed in Phoenix WinNonlin by 
means of NCA. Individual serum concentration data from each patient and the exact time 
points for blood sampling will be used throughout the analyses. The following multiple-dose 
PK parameters will be determined for SOBI003 at Weeks 39, 52, 78 and 104, and during 
dose-adjustments:  
• The time of the end of the infusion of SOBI003, tEnd of inf  
• The observed serum concentration at the end of infusion of SOBI003, CEnd of inf 
• The observed serum concentration immediately before the start of infusion of 
SOBI003, CPre-dose 
• The area under the plasma concentration-time curve from time 0 to last sample, 
AUC168hClearance, CL 
The area under the plasma concentration-time curve from time 0 to last sample, AUC168h 
calculated according to the linear log trapezoidal method. Other PK parameters may be 
calculated as applicable. 
7.5.5.4 
Population PK analysis 
All SOBI003 serum concentration data will be included in the population PK analysis. The 
objective is to explore the PK and the impact of covariates (e.g. body weight, age and dose 
level) on the PK of SOBI003. 
7.5.5.5 
Population PK/PD analysis   
SOBI003 serum concentration data and SOBI003 CSF concentration data are planned to be 
included in the population PK/PD analysis. The objective of this analysis is to explore the 
relationship between SOBI003 exposure and selected biomarkers e.g. HS in serum and CSF. 


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7.5.6 
Pharmacodynamic assessments 
7.5.6.1 
Heparan sulfate  
Serum and urine are collected pre-infusion at Weeks 38, 52, 78 and 104 for analyses of HS. 
The blood sampling volume is a 0.3 mL at each sampling occasion. 
CSF samples (200 µL) are collected at Weeks 52 and 104 for analyses of HS.  
The serum and CSF HS analyses are performed at a central laboratory (York Bioanalytical 
Solutions Limited, York YO26 6QR, United Kingdom). Urine HS analysis is performed at 
another laboratory (Greenwood Genetic Center, 106 Gregor Mendel Cir, Greenwood, South 
Carolina 29646, USA).  
HS storage in serum and CSF is assessed using liquid chromatography tandem mass 
spectrometry (LC-MS/MS). The HS polymer itself is highly heterogeneous and therefore it is 
not possible to analyze at the intact molecule level. Therefore, the total level of HS is 
measured by analyzing selected disaccharides derived from enzymatic digestion (adaptation 
of method described in Naimy et al. 2016) (20).  
Sampling, storage and shipment details are provided separately in the Study laboratory 
manual. 
7.5.6.2 
Future bioanalytical research 
As local regulations permit and provided that additional separate caregiver consent is given, 
blood (2 mL) and CSF (1 mL) samples are collected for future biomarker analyses at Weeks 
52 and 104.  
The samples will be stored at a central laboratory (York Bioanalytical Solutions Limited) for 
a maximum of 10 years following study completion (i.e. last patient’s last visit in this study).  
MPS IIIA is a very rare and severe disease for which there is a lot of research ongoing to 
further increase the understanding of disease pathology as well as diagnosis. The purpose of 
the sample storage is to allow future exploration/confirmation of new research findings. This 
includes:  
• Biomarkers in serum and/or CSF with possible relation to the safety, tolerability, 
immunogenicity, PK and PD of SOBI003  
The results of any such analyses will not be included in the Clinical Study Report for this 
study, but reported separately when analyzed, thus enabling exploration of any emerging 
novel disease-related discoveries of e.g., previously unknown disease alleles, inflammatory 
cytokines (e.g., IL1Ra, TNFα, calprotectin, neopterin), other HS biomarkers (e.g. HS 
metabolites), components of the complement system, and neurodegeneration (e.g., T-tau, 
hepatocyte growth factor, calbindin D).  
Sampling details are provided separately in the Study laboratory manual. 
7.5.6.3 
Appropriateness of measurements 
Storage of HS in brain lysosomes causes pathological changes such as neuroinflammation and 
inhibition of autophagy in the MPS IIIA mouse model (21). As demonstrated in nonclinical 
studies, SOBI003 treatment reduces blood and brain HS levels, has favorable effects on 


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pathophysiological parameters such as neuroinflammation and lysosomal size and shows 
trends towards normalization of behavior in mice. Furthermore, the levels of HS derivatives in 
brain homogenate and CSF are strongly correlated, and the HS reduction at different dose 
levels of SOBI003 is paralleled in these two compartments.  
Patients with MPS IIIA have elevated CSF HS levels in CSF as compared to healthy 
individuals (22). Also in humans, a reduction of HS in CSF is expected to mirror the 
reduction in brain and thus be a useful PD tool for dose selection. 
8 
Quality control and quality assurance 
This study will be conducted in compliance with this protocol, study specific procedures, INC 
Research SOPs, the ICH Guideline for Good Clinical Practice, and applicable regulatory 
requirements. 
Monitoring visits to the study site are performed periodically during the study, to help ensure 
compliance with the protocol, study specific procedures and applicable regulatory 
requirements. Source documents are reviewed for verification of agreement with data in 
CRFs. All patient informed consent forms are reviewed. The investigator or institution 
guarantees access to source documents by Sobi, its representatives, and appropriate regulatory 
agencies. 
The study site may be subject to a quality assurance audit by Sobi or its representatives, as 
well as inspection by appropriate regulatory agencies. 
It is important that the investigator(s) and the(ir) relevant personnel are available during the 
monitoring visits and possible audits and that sufficient time is devoted to the process. 
9 
Statistical plan 
9.1 
Determination of sample size 
All patients completing the FIH study (SOBI003-001) will be offered to continue into this 
extension study and the number of patients in the extension study is thus not based on 
statistical grounds. 
However, the 14 patients in the NH study that will be used as an external control group had a 
mean baseline DQ of 58.9 points and declined with a mean of 30.4 (SD=12.1) DQ points 
during 24 months. Therefore, assuming very high likelihood of showing significant decrease 
in HS (with baseline mean of 5.2, std 1.8, correlation of 0.1 and a decrease of 80% the power 
is 99%), with 9 patients treated with SOBI003, the power to demonstrate an improvement in 
cognitive function is at least 80% if the decline is 9.8 DQ points for patients treated with 
SOBI003 as compared to a decline of 30.4 DQ points for untreated control patients (SD=13.0) 
and the reduction is homogeneous across age.   
9.2 
Definition of study populations 
The following analysis sets will be used in the statistical analyses.  


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Safety analysis set (SAF): The SAF will consist of all patients who received at least 1 dose of 
IMP.  
The full-analysis set (FAS) is the efficacy analysis set which will consist of all patients 
enrolled in this extension study, and all patients in the NH study with a rapid progressive 
disease having a baseline age of 12-72 months (in the DQ analyses). 
PK analysis set (PK): The PK set will consist of all patients where at least one SOBI003 dose 
has been administered correctly and where SOBI003 serum or CSF concentration data is 
available without any protocol deviation interfering with these results. 
Immunogenicity analysis set (IAS): The IAS will consist of those subjects in the safety 
analysis set who have sufficient blood samples taken for ADA testing at baseline (screening 
visit) and at least one post-dose time-point 
The SAF is used for the safety analysis, the FAS is used for the secondary and explorative 
efficacy variables. 
A subpopulation of the FAS patients who are up to 30 months of age and in the FIH 
(SOBI003-001) study was initially assigned a dose at least as high as the dose selected for a 
planned phase III study will be included in future primary analysis population for 
demonstrating efficacy using combined data from the FIH study and the extension study, the 
Phase III trial and the corresponding patients in the NH study (control patients), consisting of 
the 14 patients with a rapid progressive MPS IIIA disease and a baseline age of 12 to 72 
months. 
9.3 
Estimands 
There will be a de facto estimand in the study, which is the primary estimand for the 
evaluation of efficacy. The estimand is the change in  
• cognitive decline in all the patients from the population captured by the inclusion and 
exclusion criteria (see Sections 4.2.1 and Section 4.2.2) and the part of the NH 
population with a rapid progressive disease having a baseline age of 12-72 months, 
irrespectively of other medications used and adherence to treatment, and estimated by 
a repeated measures model of the change from baseline in DQ as described in Section 
14.1.  
• decline in HS levels in CSF in all the patients from the population captured by the 
inclusion and exclusion criteria (see Sections 4.2.1 and Section 4.2.2) irrespectively of 
other medications used and adherence to treatment, and estimated by a repeated 
measures model of the change from baseline in HS as described in Section 14.1.     
To address foreseeable inter-current events, such as drop-outs, all missing values will be 
imputed (see Section 9.4.4) in accordance with the treatment policy principle. A sensitivity 
analysis will be performed where no imputations are performed, but all values are used: If a 
patient has a missing value in any assessment, then the same patient’s non-missing scores will 
be used in the repeated measures model. The repeated measures model (see Section 9.4.4) 
handles missing values based on the missing at random (MAR) assumption. One further 
sensitivity analysis for DQ will address this assumption based on zero imputations, the 
rational being that the patients not assessed are those expected to have a severe DQ decline. 
Other sensitivity analyses for this purpose will be tipping point analyses. 


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9.4 
Overall statistical and analytical plan 
9.4.1 
General statistical issues 
A detailed description of the statistical analyses to be performed will be documented in a 
statistical analysis plan to be completed prior to database lock. 
9.4.2 
Demographics and baseline characteristics 
Demographic and other baseline characteristics are listed and summarized with descriptive 
statistics. 
9.4.3 
Analysis related to primary objective 
Safety tabulations of AE data, vital signs data, and laboratory data are performed. Continuous 
variables are summarized using the number of patients, the mean, the standard deviation, the 
median, the minimum value, and the maximum value. Categorical variables are summarized 
using frequency counts and percentages. 
9.4.4 
Analysis related to secondary objectives  
9.4.4.1 
Key secondary endpoints at Week 104 
The first key efficacy endpoint related to the first key secondary objective is the change from 
baseline in Development Quotient (DQ) of neurocognitive development at Week 104 after 
start of SOBI003 treatment in the FIH study (SOBI003-001). Since this is a single-arm study 
without an internal control group, efficacy relating to neurocognition will be evaluated 
through a comparison to an external historical control group consisting of the available natural 
history data within the target study population, i.e. 14 patients with a rapid progressive disease 
and a baseline age of 12 to 72 months followed for 24 months (22).  
The Bayley Scales of Infant and Toddler Development, Third Edition (BSID-III) or the 
Kaufman Assessment Battery for Children, Second Edition (KABC-II) will be used to assess 
neurodevelopment using the same approach as in the NH study (22). For each patient, an age-
equivalent score (AEq) is determined using published normative data for the US population. 
An AEq score is the average score for a particular age. The Development Quotient is 
calculated as the AEq divided by the chronological age of the child multiplied with 100, i.e. 
DQ = 100*AEq / Age. 
For patients completing an assessment of both BSID-III and KABC-II, the BSID-III score 
will be used as a basis for calculating the DQ of neurocognitive development at baseline. A 
calibration of overlapping AEq scores between BDID-III and KABC-II will be done to assess 
if a patient outgrows the BSID-III test during the duration of the study. If confirmed, 
assessments of KABC-II will form the basis for calculating DQ of neurocognitive 
development for remaining study assessments.  
DQ of neurocognitive development will be evaluated using a repeated measures analysis with 
the DQ measurements at baseline, Week 52, and Week 104 as response, and visit and visit-


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treatment interaction as fixed factors, baseline age as covariate and an unstructured covariance 
matrix will be used to estimate the covariance pattern. The primary efficacy analysis set will 
thus consist of all patients included in this extension study (patients treated with SOBI003) 
and 14 patients from the NH study (untreated patients). The null hypothesis of no treatment 
effect will be tested with a significance test for the treatment*time-effect, in the second step 
of the multiple testing procedure (see Section 9.4.5) The difference between 104 weeks and 
baseline will be used as the contrast of interest for the test. 
All missing DQ values will be imputed. For a patient who stops treatment, let tp denote the 
turning point, i.e. the time point when the patient stops treatment. The patient’s assessments 
as well as the time points for prediction are classified as being on either side of the turning 
point or at the turning point: prior to tp, at tp, or after tp. For patients who does not stop 
treatment, let tp = ∞, i.e. every time point is considered as prior to the tp. Let v denote a 
missing value to be imputed for a patient. The imputations will be based on two categories of 
predictions.  
1)  If the patient has two or more observations on the same side of tp as v (including a 
possible observation at tp), then v is considered as exclusively patient-predictable (p1), i.e. it 
can be predicted by simple linear regression based only on the patient’s data (intra -or extra-
polation). On the other hand, if only one or zero observations exists on the same side of tp 
(from the particular patient) as v (including a possible observation at tp), then it is considered 
as non-predictable exclusively from the patient’s data.  
2) The other type of prediction (p2), will be calculated by the use of a population derived 
slope, estimated based on the repeated measures model in Section 9.4.4 (without imputations), 
and a patient observation. There will be two cases; If the patient has one or more observations 
on the same side of tp as v (including a possible observation at tp), then the nearest 
observation will be used together with a slope, which is based on the population (treated or 
untreated) of the same status as the side of tp where the prediction time point is situated, as 
well as the interval relative the visits which contain the prediction time point. The other case 
is when there is no observation on the same side of tp as v (and no observation at tp). In this 
case, a prediction at tp will first be calculated, based on the same method as described above 
(under 2) but on the other side of tp, i.e. the nearest observation relative tp on the other side of 
tp will be used together with a slope based on the population (treated or untreated) of the same 
status as the side of tp where this nearest observation time point is situated, as well as the 
interval relative the visits which contain the tp. This prediction at the tp is in then used to 
predict v as described under the first case (under 2). 
For each missing value v, the following algorithm is used to impute v by i: 
If p1 does not exists, then p2 is used, i.e., i = p2. 
Otherwise, a weighted average will be used for the imputation: i = w1 p1 + w2 p2, where 
w1 = exp(-λln(2)/3) and w2 = 1 - exp(-λln(2)/3) and λ is the distance in months between the 
time point for prediction and the nearest available non-missing patient assessment time point. 
The exponential function is motivated by an exponential decrease of relevance of individual 
patient data relative to population data with increasing time, and the coefficient ln(2)/3 is 
chosen such that population data reach the same weight as individual patient data after 75 % 
of the distance between 2 visits, i.e. 3 months. When individual patient data is available near a 
missed visit, the patient data weight is near 100 %, and when the distance is near one year on 
the other hand, the individual patient data weight has decreased to nearly 6 %. 


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The second key efficacy endpoint related to the second key secondary objective is the change 
from baseline in HS levels in CSF at Week 104 after start of SOBI003 treatment in the FIH 
study (SOBI003-001). 
For the purpose of the multiple testing procedure (see Section 14.3), the linear repeated 
measures analysis with untransformed HS levels in CSF will be used, identical to the DQ 
analysis with the exception of the treatment factors. 
The time effect is used to judge the HS level change in CSF. The null hypothesis of no change 
will be tested with a significance test for the time-effect in the first step of the multiple testing 
procedure (see Section 9.4.5). The difference between 104 weeks and baseline will be used as 
the contrast of interest for the test. Missing HS values will be imputed according to the same 
methodology as for the missing DQ values. 
9.4.4.2 
Secondary endpoints and additional key secondary endpoints 
To assess the PD effect of SOBI003 on HS levels in CSF, serum and urine, linear models are 
used to model the change from baseline in HS levels as dependent variable, for both logged 
HS levels and untransformed HS levels, and baseline level and age as continuous covariates, 
and accumulated dose as covariate and sex as factor. The analyses are conducted for each 
assessment time point. In addition, linear analyses with HS levels, both logged HS levels and 
untransformed HS levels, in CSF, serum and urine, as dependent variable, and baseline level 
and age as continuous covariates, and dose and sex as factors will be performed across all 
assessments, with assessment as a repeated factor. 
Adaptive behavior will be analyzed with the same repeated measures model as DQ, but 
adapted for one group (i.e. no treatment*visit interaction term), the SOBI003 group. 
PK results are presented by dose level using descriptive statistics. In addition, results are 
presented by demographic characteristics, e.g., age-group and bodyweight, as applicable. 
Immunogenicity is summarized using frequency counts and percentages by dose level.To 
assess the PD effect of SOBI003 on MRI, linear models are used to model the change from 
baseline in MRI as dependent variable, for both logged MRI and untransformed MRI, and 
baseline level and age as continuous covariates, and accumulated dose (including the FIH 
study) as covariate and sex as factor. The analyses are conducted for each assessment time 
point i.e. Weeks 52 and 104. 
In addition, linear analyses with MRI levels, both logged MRI levels and untransformed MRI 
levels, as dependent variable, and baseline level and age as continuous covariates, and 
accumulated dose as covariate and sex as factor will be performed across all assessments 
(including the FIH study), with assessment as a repeated factor. 
Endpoints relating to the neurocognition, adaptive behavior, liver and spleen volume, QoL, 
language, motor function and sleep pattern are summarized using descriptive statistics.  
 
9.4.5 
Multiple comparison procedure 
A hierarchical approach will be used for the key secondary co-endpoints.  


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The primary analysis will be based on a 2-sided test using a significance level of 0.05. A 
stepwise sequential testing procedure will be used to ensure a multiple level of significance of 
0.05.  
• 1st step: The null hypothesis of no difference between the treatments with respect to 
the reduction from baseline HS in CSF at 24 months will be tested using a significance 
level of 0.05. If the null hypothesis is rejected, then it will be concluded that SOBI003 
reduces HS. Furthermore, the 2nd step of the sequential testing procedure will be 
performed. 
• 2nd step: The null hypothesis of no difference between the treatments with respect to 
the change in DQ score at 24 months will be tested using a significance level of 0.05. 
If the null hypothesis is rejected, it will be concluded that SOBI003 improves 
cognitive function as compared to untreated patients.  
This multiple comparison procedure controls that the multiple level of significance is no more 
than 5%. 
Formally, the second confirmatory step will only be valid after the 1st step has been 
successfully met.  
 
9.4.6 
Analysis related to exploratory objectives 
Continuous variables are summarized using the number of patients, the mean, the standard 
deviation, the median, the minimum value, and the maximum value. Categorical variables are 
summarized using frequency counts and percentages. 
9.4.7 
Analysis of safety and tolerability data 
9.4.7.1 
Adverse events 
Reported AE(s) during the study are coded using MedDRA and severity of AEs is graded 
using NCI CTCAE v.03. The number of patients with any AE are is summarized in frequency 
tables by treatment dose level, body system, preferred term, relation to IMP and maximum 
severity. Listings of AE subgroups such as SAE(s) and AEs leading to discontinuation are 
also presented. 
9.4.7.2 
Physical examination 
All physical examination records will be listed. 
9.4.7.3 
Neurological examination 
All neurological examination records will be listed. 
9.4.7.4 
Laboratory variables 
Laboratory test results will be compared to laboratory reference ranges, and values outside of 
the applicable range will be flagged as high (H) or low (L). The laboratory test results will be 
listed for each subject and summarized by descriptive statistics. 


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9.4.7.5 
Vital signs 
Vital sign results will be compared to reference ranges, and values outside the applicable 
range (including clinically important change and orthostatic change values) will be flagged as 
high (H) or low (L). The vital sign results will be listed for each subject and summarized by 
descriptive statistics. 
9.4.7.6 
ECG 
12-lead ECGs are obtained at Weeks 52 and 104, and during Early Termination. ECG 
machines Mortara ELI 250c with VERITASTM resting ECG interpretation algorithm will be 
provided to the sites. The ECGs will be listed for each subject. 
9.4.8 
Interim analysis 
No interim analysis is planned for this study. 
9.4.9 
Multiple comparison/multiplicity 
Since no multiple hypothesis tests will be performed, there will be no adjustments for 
multiplicity.  
9.4.10 
Handling of missing data 
All missing DQ values will be imputed. A sensitivity analysis will be performed where no 
imputations are performed, but all values are used: If a patient has a missing DQ score in any 
assessment, then the same patient’s non-missing scores will be used in the repeated measures 
model (see Section 9.4.4). The repeated measures model handles missing values based on the 
MAR assumption. One further sensitivity analysis will address this assumption based on zero 
imputations. Another sensitivity analysis for this purpose will be a tipping point analysis. 
10 
Data collection, handling and record keeping 
10.1 
Data standards 
Collection of data should be performed in the Clinical Data Acquisition Standards 
Harmonization (CDASH) format, according to the Clinical Data Interchange Standards 
Consortium (CDISC). The standards should be used to the extent possible and/or required for 
the specific study/project. The minimum requirement of the CDISC standard is to collect all 
core variables specified as ‘Required’ in the Study Data Tabulation Model (SDTM) format.  
10.2 
Case report form 
A CRF is required and should be completed for each included patient. In this study an 
electronic CRF will be used. The completed original CRFs are the sole property of Sobi and 


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should not be made available in any form to third parties, except for authorized 
representatives of appropriate regulatory authorities, without written permission from Sobi. 
It is the responsibility of the investigator to ensure completion and to review and approve all 
CRFs. CRFs must be signed electronically by the investigator. These signatures serve to attest 
that the information contained on these CRFs is correct. At all times, the investigator has final 
responsibility for the accuracy and authenticity of all clinical and laboratory data entered on 
the CRFs.  
10.3 
Source data 
Patient source documents are the physician’s patient records maintained at the study site. In 
most cases, the source documents will be the hospital’s or the physician’s chart. In those 
cases, the information collected on the CRFs must match those charts. For the MRIs and 
actigraph assessments, the digital files are the source. For ECG the print-outs are the source. 
For the VABS-II, BSID-III and the KABC-II, the completed test forms and the central 
reader’s confirmation of total scores and age-equivalence scores are the source. 
10.4 
Database closure 
Prior to database closure, all tasks or criteria defined in the data management plan must be 
completed and documented. The study database must be locked before generation of any final 
results. The database lock will be approved by relevant study personnel and all edit accesses 
will be removed. The study database can only be unlocked in case critical errors, affecting the 
main conclusions of the study, are discovered. 
10.5 
Record retention 
To enable evaluations and/or audits from Health Authorities and/or Sobi (or delegates), the 
investigator agrees to keep records in accordance with the essential documents defined in the 
ICH GCP Guidelines (1), including the identity of all participating patients (sufficient 
information to link records, e.g., CRFs and hospital records), all original signed informed 
consent forms, copies of all paper CRFs (i.e., completed paper questionnaires and BSID-
III/KABC-II assessments forms), an archival copy on compact disc of the electronic CRFs 
provided by INC Research and detailed records of IMP accountability. The records should be 
retained by the investigator according to local regulations or as specified in the Clinical Trial 
Agreement. 
If the investigator relocates, retires, or for any reason withdraws from the study, the study 
records may be transferred to an acceptable designee, such as another investigator, another 
institution, or to Sobi. The investigator must obtain Sobi’s written permission before 
disposing of any records. 
11 
End of study 
The end of this study is defined as the date of last patient out, i.e., the last patient’s last visit. 


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12 
Sponsor’s discontinuation criteria 
Sobi reserves the right to discontinue the study prior to inclusion of the intended number of 
patients, but intends only to exercise this right for valid scientific or administrative reasons. 
After such a decision, the investigator must contact all participating patients within 2 weeks. 
All study materials must be collected and all the CRFs completed to the greatest extent 
possible. 
13 
Dissemination and publication of results 
Sobi will register the study and post study results regardless of outcome on a publicly 
accessible website in accordance with applicable laws and regulations, e.g. on 
www.clinicaltrials.gov and EudraCT.  
Sobi follows the principles of the International committee of medical journal editor’s 
recommendations for the conduct, reporting, editing, and publication of scholarly work in 
medical journals (23). After completion of this study, the data may be considered for 
reporting at a scientific meeting or for publication in a scientific journal. The sponsor will be 
responsible for these activities and will work with the investigators to determine how the 
publication is written, the number and order of authors, the journal or scientific meeting to 
which it will be submitted, and other related issues. The results of the study, or any part 
thereof, shall not be published without the prior written consent and approval of Sobi, such 
consent and approval not to be unreasonably withheld. 
 


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14 
References 
1 
ICH Harmonised Tripartite Guideline: Guideline for Good Clinical Practice E6(R2) 
Current Step 5 version dated 15 December 2016. Available from: 
http://www.ich.org/products/guidelines/efficacy/article/efficacy-guidelines.html  
2 
World Medical Association Declaration of Helsinki; Ethical Principles for Medical 
Research Involving Human Subjects. Adopted by the 18th WMA General Assembly, 
Helsinki, Finland, June 1964, latest amendment at the 59th WMA General Assembly, 
Seoul, South Korea, October 2008. Available from: 
http://www.wma.net/en/30publications/10policies/b3/ 
3  
Van de Kamp JJP, Niermeijer MF, von Figura K and Giesberts MAH. Genetic 
heterrogeneity and clinical variability in the Sanfilippo syndrome (types A, B and C). 
Clinical Genetics 1981; 20:152-60. 
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Valstar MJ, Ruijter GJ, van Diggelen OP, Poorthuis BJ, Wijburg FA. Sanfilippo 
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Jakobkiewicz-Banecka J, Gabig-Ciminska M, Kloska A, Malinowska M, Piotrowska 
E, Banecka-Majkutewicz Z, et al. Glycosaminoglycans and mucopolysaccharidosis 
type III. Front Biosci (Landmark Ed). 2016;21:1393-409. 
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Valstar MJ, Neijs S, Bruggenwirth HT, Olmer R, Ruijter GJ, Wevers RA, et al. 
Mucopolysaccharidosis type IIIA: clinical spectrum and genotype-phenotype 
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Cleary MA, Wraith JE. Management of mucopolysaccharidosis type III. Arch Dis 
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Buhrman D, Thakkar K, Poe M, Escolar ML. Natural history of Sanfilippo syndrome 
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Wijburg FA, Wegrzyn G, Burton BK, Tylki-Szymanska A. Mucopolysaccharidosis 
type III (Sanfilippo syndrome) and misdiagnosis of idiopathic developmental delay, 
attention deficit hyperactivity disorder or autism spectrum disorder. Acta Paediart. 
2013;102(5):462-70. 
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Fraser J, Wraith JE, Delatycki MB. Sleep disturbance in mucopolysaccharidosis type 
III (Sanfilippo syndrome): a survey of managing clinicians. Clin Genet. 
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Delgadillo V, O'Callaghan Mdel M, Gort L, Coll MJ, Pineda M. Natural history of 
Sanfilippo syndrome in Spain. Orphanet J Rare Dis. 2013;8:189. 
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Brooks DA. Immune response to enzyme replacement therapy in lysosomal storage 
disorder patients and animal models. Mol Genet Metab. 1999;68(2):268-75. 
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Kakavanos R, Turner CT, Hopwood JJ, Kakkis ED, Brooks DA. Immune tolerance 
after long-term enzyme-replacement therapy among patients who have 
mucopolysaccharidosis I. Lancet 2003;361:1608–13. 
14  
Kishnania PS, Goldenberga PC, DeArmeya SL, Hellerb J, Benjaminc D, Younga S, et 
al.  Cross-reactive immunologic material status affects treatment outcomes in Pompe 
disease infants. Mol Genet Metab. 2010;99(1):26–33. 
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Barbier AJ, Bielefeld, B, Whiteman DAH, Natarajan M, Pano A, Amato DA. The 
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in attenuated mucopolysaccharidosis II patients aged 5 years and older treated with 
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Neufeld E, Muenzer J. The mucopolysaccharidoses. In: Scriver CR, Beaudet AL, Sly 
WS, Valle D, Childs B, Kinzler KW, et al. The Metabolic and Molecular Basis of 
Inherited Disease. 8 edition. New York: McGraw-Hill; 2001:3421-52. 
17 
Galvão VR, Castells MC. Hypersensitivity to biological agents - updated diagnosis, 
management, and treatment J Allergy Clin Immunol Pract. 2015;3(2):175-185.    
18  
European Commission 2017. Ethical considerations for clinical trials on medicinal 
products conducted with the paediatric population. 
https://ec.europa.eu/health/documents/eudralex/vol-10 en  
19  
Crawley AC, Gliddon BL, Auclair D, Brodie SL, Hirte C, King BM, et al. 
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IIIA. Brain Res. 2006;1104(1):1-17. 
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Naimy H, Powell KD, Moriarity JR, Wu J, McCauley TG, Haslett PAJ, et al. A novel 
LC–MS/MS assay for heparan sulfate screening in the cerebrospinal fluid of 
mucopolysaccharidosis IIIA patients. Bioanalysis. 2016;8(4):285–295. 
21 
Archer LD, Langford-Smith KJ, Bigger BW and Fildes JE. Mucopolysaccharide 
diseases: A complex interplay between neuroinflammation, microglial activation and 
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Shapiro EG, Nestrasil I, Delaney KA, Rudser K, Kovac V, Nair N, et al. A prospective 
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23 
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conduct, reporting, editing, and publication of scholarly work in medical journals: 
updated December 2016 [Internet]. International Committee of Medical Journal 
Editors (ICMJE); 2016. [cited 2017 Jan 12]. Available from: 
http://www.icmje.org/recommendations/ 
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Ghosh A, Shapiro EG, Rust S, Delaney K, Parker S, Shaywitz AJ, et al. 
Recommendations on clinical trial design for treatment of mucopolysaccharidosis. 
Orphanet J Rare Dis. 2017;12(117):1-15. 
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Janzen D, Delaney KA and Shapiro EG. Cognitive and adaptive measurement 
endpoints for clinical trials in mucopolysaccharidoses types i, ii, and iii: A review of 
the literature. Mol Genet Metab. 2017;121(2):57-69. 
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Van der Lee JH, Morton J, Adams HR, Clarke L, Ebbink BJ, Escolar ML, et al. 
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SAP_001.pdf: 


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Table of contents 
1 
Abbreviations and definition of terms ................................................................................... 5 
2 
Introduction ............................................................................................................................ 6 
3 
Study objectives and endpoints .............................................................................................. 6 
3.1 
Primary objective .............................................................................................................. 6 
3.2 
Key secondary objectives .................................................................................................. 6 
3.3 
Secondary objectives ......................................................................................................... 6 
3.4 
Exploratory objectives ...................................................................................................... 7 
3.5 
Study endpoints ................................................................................................................. 7 
3.5.1 Primary endpoint ........................................................................................................ 7 
3.5.2 Secondary endpoints related to the primary objective ............................................... 7 
3.5.3 Key secondary endpoints ........................................................................................... 8 
3.5.4 Secondary endpoints .................................................................................................. 8 
3.5.5 Exploratory endpoints .............................................................................................. 10 
4 
Study methods ...................................................................................................................... 10 
4.1 
Overall study design and plan ......................................................................................... 10 
4.2 
Selection of study population .......................................................................................... 11 
4.2.1 Inclusion criteria ...................................................................................................... 11 
4.2.2 Exclusion criteria ..................................................................................................... 11 
4.3 
Method of treatment assignment ..................................................................................... 12 
4.3.1 Control group ........................................................................................................... 12 
4.3.2 SOBI003................................................................................................................... 12 
5 
Sequence of Planned analyses ............................................................................................. 12 
5.1 
Interim Analyses ............................................................................................................. 12 
5.2 
Analyses and reporting .................................................................................................... 12 
6 
Estimands ............................................................................................................................. 12 
7 
Sample size determination ................................................................................................... 13 
7.1 
Change from baseline in DQ score and in HS levels in CSF at 104 weeks .................... 13 
8 
Analysis sets ........................................................................................................................ 13 
8.1 
Safety analysis set ........................................................................................................... 14 
8.2 
Full-analysis set ............................................................................................................... 14 
8.3 
PK analysis set ................................................................................................................ 14 
8.4 
Immunogenicity analysis set ........................................................................................... 14 
9 
General issues for statistical analysis ................................................................................... 14 
9.1 
Handling of missing data ................................................................................................ 15 


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9.2 
Multicenter studies .......................................................................................................... 16 
9.3 
Derived and computed variables ..................................................................................... 16 
10 
Patient disposition ................................................................................................................ 17 
11 
Demographics and baseline characteristics ......................................................................... 17 
11.1 Demographics ................................................................................................................. 17 
11.2 Baseline characteristics ................................................................................................... 18 
11.3 Medical history................................................................................................................ 18 
12 
Prior and concomitant medication ....................................................................................... 18 
13 
Treatment compliance .......................................................................................................... 18 
14 
Efficacy analyses ................................................................................................................. 18 
14.1 The DQ endpoint ............................................................................................................. 18 
14.1.1 Sensitivity analyses of the DQ endpoint .................................................................. 20 
14.2 The HS endpoint ............................................................................................................. 20 
14.2.1 Sensitivity analyses of the HS endpoint ................................................................... 21 
14.3 Multiple comparison procedure ...................................................................................... 21 
14.4 Adaptive Behavior .......................................................................................................... 22 
14.5 The MRI endpoints ......................................................................................................... 22 
14.6 Exploratory endpoints ..................................................................................................... 23 
14.7 Other efficacy endpoints ................................................................................................. 23 
14.8 Subgroup Analyses ......................................................................................................... 23 
14.9 Analysis of the subpopulation to be included in the future primary analysis population
 ......................................................................................................................................... 23 
15 
Safety analyses ..................................................................................................................... 24 
15.1 Drug exposure ................................................................................................................. 24 
15.2 Adverse events ................................................................................................................ 24 
15.2.1 Adverse Events ........................................................................................................ 24 
15.2.2 Serious adverse events ............................................................................................. 25 
15.2.3 Adverse Events leading to study discontinuation .................................................... 25 
15.2.4 Adverse Events by Severity ..................................................................................... 25 
15.2.5 Adverse Events by Relationship to Study Drug ....................................................... 26 
15.2.6 Deaths....................................................................................................................... 26 
15.3 Laboratory data ............................................................................................................... 26 
15.4 Vital signs ....................................................................................................................... 26 
16 
Pharmacokinetics and Immunogenicity ............................................................................... 27 
16.1 Pharmacokinetic Parameters ........................................................................................... 27 
16.2 Immunogenicity .............................................................................................................. 28 


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17 
The primary analysis for the pivotal phase 3 study ............................................................. 29 
18 
References ............................................................................................................................ 30 
 
Table of figures 
Figure 1 Overview for study design for study SOBI003-002 ....................................................... 11 
 
Table of tables 
Table 1 Partial date derivation ...................................................................................................... 15 
Table 2 Selection of neurocognitive assessment method .............................................................. 16 
 
 


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1 
Abbreviations and definition of terms 
 
 
ADA 
Anti-drug antibody 
AE 
Adverse event 
AEq 
Age-equivalent score 
AUC 
Area under curve 
BSID-III 
Bayleys Scales of Infant and Toddler Development®, third edition 
CL 
Clearance 
CNS 
Central nervous system 
CSR 
Clinical study report 
DQ 
Development quotient 
FAS 
Full analysis set 
FIH 
First time in human 
HS 
Heparan sulfate 
IMP 
Investigational medicinal product 
KABC-II 
Kaufman assessment battery for children, second edition 
MPS IIIA 
Mucopolysaccharidosis type IIIA 
MAR 
Missing at random 
MRI 
Magnetic resonance imaging 
NH 
Natural history 
NVI 
Nonverbal index 
SAE 
Serious adverse event 
SAP 
Statistical Analysis Plan 
SRC 
Safety review committee 
Sobi 
Swedish Orphan Biovitrum 
TEAE 
Treatment emergent adverse event 
PPS 
Per Protocol Set 
VABS-II 
Vineland adaptive behavior scales, second edition 


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2 
Introduction 
This Statistical Analysis Plan (SAP) describes the planned analysis and reporting for Sobi 
protocol SOBI003-002 (An open, single-arm, multicenter extension study to assess the safety, 
tolerability and efficacy of long-term SOBI003 treatment in pediatric MPS IIIA patients).  
This extension study is being completed to assess the efficacy and safety of SOBI003 for the 
treatment of MPS IIIA in pediatric patients. 
The purpose of this SAP is to outline the planned analyses to be completed to support the 
Clinical Study Report (CSR) for protocol SOBI003-002. The planned analyses identified in this 
SAP will be included in regulatory submissions and/or future manuscripts. Also, exploratory 
analyses not necessarily identified in this SAP may be performed to support the clinical 
development program. Any post-hoc, or unplanned, analyses not identified in this SAP will be 
clearly identified in the respective CSR. This SAP also includes a description of upcoming Phase 
III analyses, see Section 17. 
The structure and content of this SAP provides sufficient detail to meet the requirements 
identified by the FDA and International Conference on Harmonization of Technical 
Requirements for Registration of Pharmaceuticals for Human Use (ICH): Guidance on Statistical 
Principles in Clinical Trials. All work planned and reported for this SAP will follow 
internationally accepted guidelines, published by the American Statistical Association and the 
Royal Statistical Society, for statistical practice.  
3 
Study objectives and endpoints 
3.1 
Primary objective 
The primary objective is: 
• To assess the long-term safety and tolerability of SOBI003  
3.2 
Key secondary objectives 
• To evaluate the efficacy of SOBI003 on neurocognitive function, as compared to 
untreated MPS IIIA patients from a NH control. 
• To evaluate the effect of SOBI003 on HS levels in CSF 
3.3 
Secondary objectives 
The secondary objectives are: 
1. To assess the effect of SOBI003 on adaptive behavior, as compared to untreated MPS 
IIIA patients from a NH control 
2. To assess the effect of SOBI003 on HS levels in serum and urine  


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3. To assess the effect of SOBI003 on brain magnetic resonance imaging (MRI) 
abnormalities  
4. To assess the effect of SOBI003 on liver and spleen volume 
5. To assess the effect of SOBI003 on Quality of Life 
6. To assess the effect of SOBI003 on language 
7. To assess the effect of SOBI003 on motor function 
8. To assess the effect of SOBI003 on sleep pattern  
9. To assess the immunogenicity of SOBI003 
10. To characterize steady-state pharmacokinetics (PK) of SOBI003 by the use of non-
compartmental analysis (NCA) 
3.4 
Exploratory objectives 
The exploratory objectives are: 
1. To assess the effect of SOBI003 on adaptive behavior over time 
2. To characterize the PK properties of SOBI003 following repeated administration by the 
use of population PK analysis 
3. To evaluate the PK/PD relationship between SOBI003 concentrations in serum and effect 
of SOBI003 on HS levels in CSF, serum and urine by the use of population modelling 
analysis  
4. To evaluate the PK/PD relationship between SOBI003 concentrations in serum and CSF, 
and the effect of SOBI003 on other biomarkers than HS and neuro-cognitive measures 
eg. DQ, as well as MRI data, by the use of population modelling 
As local regulations permit and provided that additional separate caregiver consent is given, the 
exploratory objectives are also to: 
• Collect and store serum and CSF samples to enable analyses of biomarkers with possible 
relation to safety, tolerability, immunogenicity, PK and PD of SOBI003, as identified in 
future  
3.5 
Study endpoints 
3.5.1 
Primary endpoint 
The primary endpoint to evaluate the safety and tolerability of SOBI003 is: 
• Treatment Emergent Adverse Events (TEAEs) and Serious Adverse Events (SAEs) 
3.5.2 
Secondary endpoints related to the primary objective 
The secondary endpoints to evaluate the safety and tolerability of SOBI003 are: 


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• Vital signs (blood pressure, heart rate, body temperature, respiratory rate and pulse 
oximetry) 
• Laboratory safety variables (hematology, coagulation, clinical chemistry and urine 
analysis) 
3.5.3 
Key secondary endpoints 
Study efficacy evaluation will primarily be based on:  
• Change from baseline at Week 104 in Development Quotient (DQ) as assessed by the 
Bayley Scales of Infant and Toddler Development®, third edition (BSID-III) cognitive 
subtest or the Kaufman Assessment Battery for Children, Second edition (KABC-II) 
• Change from baseline at Week 104 in CSF HS 
 
Additional key secondary endpoints are: 
• Change from baseline at Week 52 in Development Quotient (DQ) as assessed by the 
Bayley Scales of Infant and Toddler Development®, third edition (BSID-III) cognitive 
subtest or the Kaufman Assessment Battery for Children, Second edition (KABC-II) 
• Change from baseline at Weeks 52 and 104 in Age Equivalent (AEq) as assessed by the 
Bayley Scales of Infant and Toddler Development®, third edition (BSID-III) cognitive 
subtest or the Kaufman Assessment Battery for Children, Second edition (KABC-II) 
• Change from baseline at Week 52 in CSF HS 
3.5.4 
Secondary endpoints 
The endpoints relating to the 1nd secondary objective are: 
• Change from baseline at Weeks 52 and 104 in adaptive behavior age-equivalence score 
(AEq) as assessed by Vineland Adaptive Behavior Scales, Second edition (VABS-II) 
• Change from baseline at Weeks 52 and 104 in adaptive behavior composite score as 
assessed by Vineland Adaptive Behavior Scales, Second edition (VABS-II) 
The endpoints relating to the 2rd secondary objective are: 
• Change from baseline at Weeks 52 and 104 in serum HS  
• Change from baseline at Weeks 52 and 104 in urine HS 
The endpoints relating to the 3th secondary objective are: 
• Change from baseline at Weeks 52 and 104 in gray matter volume as assessed by brain 
volumetric MRI 
• Change from baseline at Weeks 52 and 104 in compound ventricular volume as assessed 
by brain volumetric MRI 
• Change from baseline at Weeks 52 and 104 in fractional anisotropy (FA) and mean 
diffusivity (MD) of corpus callosum as assessed by diffusion tensor imaging MRI 


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• Change from baseline at Weeks 52 and 104 in FA and MD of cerebral white matter as 
assessed by diffusion tensor imaging MRI 
• Change from baseline at Weeks 52 and 104 in cerebral white matter as assessed by 
susceptibility weighting imaging (SWI) MRI 
• Change from baseline at Weeks 52 and 104 in basal ganglia as assessed by SWI MRI 
The endpoints relating to the 4th secondary objective are: 
• Change from baseline at Weeks 52 and 104 in liver volume as assessed by abdominal 
MRI 
• Change from baseline at Weeks 52 and 104 in spleen volume as assessed by abdominal 
MRI 
The endpoints relating to the 5th secondary objective are: 
• Change from baseline at Weeks 52 and 104 in Pediatric Quality of Life inventory 
(PedsQL) total score  
The endpoints relating to the 6th secondary objective are: 
• Change from baseline at Weeks 52 and 104 in expressive language AEq score as assessed 
by the BSID-III language subtests or the KABC-II Expressive Vocabulary subtest, and 
the VABS-II communication domain 
• Change from baseline at Weeks 52 and 104 in receptive language AEq score as assessed 
by the BSID-III language subtests or the KABC-II Expressive Vocabulary subtest, and 
the VABS-II communication domain 
The endpoints relating to the 7th secondary objective are: 
• Change from baseline at Weeks 52 and 104 in gross motor function AEq score as 
assessed by the BSID-III motor subtests and the VABS II 
• Change from baseline at Weeks 52 and 104 in fine motor function AEq score as assessed 
by the BSID-III motor subtest and the VABS-II 
The endpoints relating to the 8th secondary objective are: 
• Change from baseline at Weeks 52 and 104 in sleep pattern as assessed by the Children´s 
Sleep Habits Questionnaire (CSHQ) score 
• Change from baseline at Weeks 52 and 104 in sleep-related variables as assesses by 
actigraphy (including total sleep time, total day- and night time sleep duration, sleep 
latency, sleep efficiency, number of nocturnal awakenings, and wake after sleep onset) 
The endpoints relating to the 9th secondary objective are: 
• Occurrence of Anti-drug antibody (ADA) against SOBI003 in serum at Weeks 39, 52, 78 
and 104, and adjacent to dose adjustments (seroconversion rate, time to seroconversion, 
transient/persistent). For patients with confirmed ADA positive serum samples, the 
following additional endpoints apply; ADA titers and IgG subclasses in serum, and 
presence of neutralizing antibodies (NAb) in serum. 
• Occurrence of ADAs against SOBI003 in CSF at Weeks 39, 52, 78 and 104 (conversion 
rate, time to occurrence, transient/persistent). For patients with confirmed ADA positive 


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CSF samples, the following additional endpoints apply: ADA titers and presence of NAb 
in CSF. 
The endpoints relating to the 10th secondary objective are: 
• Serum SOBI003 PK parameters at Weeks 38, 52, 78 and 104, and adjacent to dose 
adjustments; tEnd of inf, CEnd of inf, CPre-dose, CL, AUC0-168h 
• SOBI003 concentrations in CSF pre-dose at Weeks 52 and 104. 
3.5.5 
Exploratory endpoints 
The endpoints related to the 1st exploratory objective are: 
• Change from baseline at Weeks 52 and 104 in adaptive behavior composite score as 
assessed by Vineland Adaptive Behavior Scales, Second edition (VABS-II) 
The endpoints related to the 2nd exploratory objective are: 
• Population PK model parameter estimates and associated covariates describing intra- and 
inter-individual variability in respective parameter estimate. The results of these analyses 
will not be included in the Clinical Study Report for this study, but reported separately. 
The endpoints related to the 3rd exploratory objective are: 
• Population PK/PD model parameter estimates and associated covariates describing intra- 
and inter-individual variability in respective parameter estimate. The results of these 
analyses will not be included in the Clinical Study Report for this study, but reported 
separately. 
4 
Study methods 
4.1 
Overall study design and plan 
This is an open, single-arm, multicenter extension study to assess the long-term safety, 
tolerability and efficacy of SOBI003 in pediatric MPS IIIA patients who previously participated 
in the (FIH) SOBI003-001 study. Patients completing the FIH study will be offered to participate 
in the extension study. Please refer to Figure 1 for an overview of the study design. A published 
natural history study (referred to as the NH study in the present document) is used as external 
control (Error! Reference source not found.). Neurocognitive and adaptive behavior data 
assessed in the extension study at Week 52 and Week 104 following start of treatment will be 
compared to available natural history data within the target study population. The natural history 
population for comparison consists of 14 patients with a rapid progressive MPS IIIA disease and 
a baseline age of 12 to 72 months. 
As the FIH study has a sequential, ascending, multiple-dose design, the first patients will enter 
the extension study (SOBI003-002) before finalization of the FIH study. When entering the 
extension study, these patients will receive the highest dose that has been declared safe by the 


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SRC in the ongoing FIH study. Patients enrolled in Cohort 1 of FIH may thus be switched to the 
dose applied in Cohort 2 or Cohort 3, depending on safety clearance by the SRC. If a patient is 
initially switched to the dose applied in Cohort 2, the patient may subsequently later be switched 
to the dose applied in Cohort 3. Depending on recruitment rate in the FIH study, a patient 
enrolled in Cohort 1 may be directly switched to the dose applied in Cohort 3. Upon completion 
of the FIH study, an analysis aimed at selecting the dose for forthcoming studies will take place. 
Once the dose has been selected, this dose will be applied to all patients enrolled in the extension 
study. The Baseline in SOBI003-001 will be used as the baseline for SOBI003-002 (Figure 1). 
SOBI003 is administered as weekly i.v. infusions over a period of time of 1 to 4 hours. Prior to 
initiation of each infusion, the patients are pretreated with a single dose of non-sedative 
antihistamine. If infusion-related reactions occur, then the infusion duration may be expanded up 
to 24 hours and supportive medication may be administered, at the discretion of the investigator.  
The long-term safety, tolerability and immunogenicity of SOBI003 will be assessed throughout 
the extension study whereas measurements of clinical efficacy and disease-related biomarkers 
will be performed at Weeks 52 and 104. The potential of SOBI003 to improve the 
neurocognitive function will be compared to published data from the NH study. 
Figure 1 Overview for study design for study SOBI003-002 
 
4.2 
Selection of study population 
The primary aim is to select a study population as close as possible to the NH study.  
4.2.1 
Inclusion criteria 
A patient must fulfill the following criteria in order to be included in the study: 
1. Completion of study FIH 
2. Informed consent obtained from the patient’s legally authorized representative(s)  
4.2.2 
Exclusion criteria 
The presence of the following excludes a patient from inclusion in the study: 
1. If, in the opinion of the investigator, there are patient specific safety concerns that 
contraindicates further treatment with SOBI003 


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4.3 
Method of treatment assignment  
4.3.1 
Control group 
The control group used for the statistical analysis of the DQ endpoint is formed by the 14 
patients in the Shapiro Natural History Study with a rapid progressive disease who have a 
baseline age of 12 to 72 months (Shapiro et al 2016).   
4.3.2 
SOBI003 
All patients in this extension study will receive SOBI003 until 104 weeks after start of treatment 
unless withdrawn. 
5 
Sequence of Planned analyses 
5.1 
Interim Analyses 
There is no planned interim analysis for this extension study. 
5.2 
Analyses and reporting 
All final, planned, analyses identified in the protocol and in this SAP will be performed only 
after the last patient has completed the study.  
Any post-hoc analyses included in the CSR, which were not identified in this SAP, will be 
clearly identified as such in the relevant section of the CSR. 
For each patient in the study, all the associated safety and efficacy data in the SOBI003-001 
study will be pooled and presented together with the SOBI003-002 study. Thus the SOIB003-
001 study and the SOBI003-002 study are considered as a single, unified entity. 
6 
Estimands 
There will be a de facto estimand in the study, which is the primary estimand for the evaluation 
of efficacy. The estimand is the change in  
• cognitive decline in all the patients from the population captured by the inclusion and 
exclusion criteria (see Section 4.2.1 and Section 4.2.2) and the part of the NH population 
with a rapid progressive disease having a baseline age of 12 to 72 months, irrespectively 
of other medications used and adherence to treatment, and estimated by a repeated 
measures model of the change from baseline in DQ as described in Section 14.1.  


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• decline in HS levels in CSF in all the patients from the population captured by the 
inclusion and exclusion criteria (see Section 4.2.1 and Section 4.2.2) irrespectively of 
other medications used and adherence to treatment, and estimated by a repeated measures 
model of the change from baseline in HS as described in Section 14.1.  
To address foreseeable inter-current events, such as drop-outs, all missing values will be imputed 
(see Section 14.1) in accordance with the treatment policy principle. A sensitivity analysis will 
be performed where no imputations are performed, but all values are used: If a patient has a 
missing value in any assessment, then the same patient’s non-missing scores will be used in the 
repeated measures model. The repeated measures model (see Section 14.1) handles missing 
values based on the missing at random (MAR) assumption. One further sensitivity analysis for 
DQ will address this assumption based on zero imputations (see Section 14.1.1), the rational 
being that the patients not assessed are those expected to have a severe DQ decline. Other 
sensitivity analyses for this purpose will be tipping point analyses, see Section 14.1.1. 
Furthermore, a principal strata analysis will be performed where only patients without protocol 
violations will be analyzed according (see Section14.1.2). In particular patients who did not 
comply with the dosing scheme but continued the study will be excluded from the analysis. Thus 
the principal strata will be approximated by the clinical per protocol subset of FAS.  
7 
Sample size determination 
7.1 
Change from baseline in DQ score and in HS levels in CSF at 104 
weeks 
All patients completing the FIH study will be offered to continue into this extension study and 
the number of patients in the extension study is thus not based on statistical grounds. 
However, the 14 patients in the natural history study that will be used as an external control 
group had a mean baseline DQ of 58.9 points and declined with a mean of 30.4 (SD=12.1) DQ 
points during 104 weeks. Therefore, assuming very high likelihood of showing significant 
decrease in HS (with baseline mean of 5.2, std 1.8, correlation of 0.1 and a decrease of 80 % the 
power is 99 %), with 9 patients treated with SOBI003, the power to demonstrate an improvement 
in cognitive function is at least 80 % if the decline is reduced from 30.4 to 9.8 DQ points 
(SD=13.0) and the reduction is homogeneous across age.  
8 
Analysis sets 
The following analysis sets will be used in the statistical analyses and exploration of data. 


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8.1 
Safety analysis set 
The Safety analysis set will consist of all patients in the study. For each patient in the study, all 
the associated safety and efficacy data in the SOBI003-001 study will be pooled and presented 
together with the SOBI003-002 study. The safety set will be used for the safety presentations. 
8.2 
Full-analysis set 
The full-analysis set (FAS) is the efficacy analysis set which will consist of all patients enrolled 
in this extension study, and all patients in the NH study with a rapid progressive disease having a 
baseline age of 12-72 months (in the DQ analyses). 
All patients enrolled in this extension study and the FIH study will be treated as having received 
active treatment and patients from the NH study will be treated as having received no treatment. 
For each patient in the study, all the associated safety and efficacy data in the SOBI003-001 
study will be pooled and presented together with the SOBI003-002 study.  
8.3 
PK analysis set 
The PK analysis set will consist of those patients in the safety analysis set who have at least one 
SOBI003 serum concentration value, without any protocol deviation jeopardizing the PK 
evaluation. For each patient in the study, all the associated safety and efficacy data in the 
SOBI003-001 study will be pooled and presented together with the SOBI003-002 study.  
The PK analysis set will be used for the PK analyses.  
8.4 
Immunogenicity analysis set 
The immunogenicity set will consist of those patients in the safety set who have sufficient blood 
samples taken for ADA testing at baseline (screening visit) and at least one post-dose time-point. 
For each patient in the study, all the associated safety and efficacy data in the SOBI003-001 
study will be pooled and presented together with the SOBI003-002 study.  
The immunogenicity set will be used for the immunogenicity analyses. 
9 
General issues for statistical analysis 
All statistical tests will be two-sided and performed using a 5 % significance level, if not stated 
otherwise. Results will be presented as the estimated mean value for each treatment group, the 
estimated difference between groups, the associated 95 % two-sided confidence interval and 
P-value. P-values from statistical analyses will be presented to three decimal places with values 
below 0.001 displayed as <0.001 and confidence intervals will be presented to one more decimal 
places than the raw data. 


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Continuous data will be summarized using descriptive statistics: n, mean, standard deviation 
(SD), standard error of the mean (SE), median, minimum and maximum, unless otherwise 
indicated. Minimum and maximum will be presented to the same number of decimal places as 
the raw data and mean, standard deviation, standard error of the mean and median will be 
presented to one more decimal place than the raw data.  
Categorical data will be summarized using counts and percentages. Percentages will be 
suppressed when the count is zero, however the category will still be displayed. The denominator 
for all percentages will be the number of patients within the treatment group for the population 
of interest, unless otherwise indicated. Percentages will be presented to one decimal place. 
All data will be tabulated in individual patient data listings. 
Statistical analyses will be performed using SAS software (SAS Institute Inc, Cary, North 
Carolina, United States).  
9.1 
Handling of missing data 
All missing DQ values and HS in CSF values will be imputed. The procedure is fully described 
in Section 14.1. A sensitivity analysis will be performed where no imputations are performed, 
but all values are used: If a patient has a missing DQ score in any assessment, then the same 
patient’s non-missing scores will be used in the repeated measures model. The repeated 
measures model (see Section 14.1) handles missing values based on the MAR assumption. One 
further sensitivity analysis will address this assumption based on zero imputations (see Section 
14.1.1), the rational being that the patients not assessed are those expected to have a severe DQ 
decline. Another sensitivity analysis for this purpose will be a tipping point analysis, see Section 
14.1.1. 
If an adverse event (AE) has a completely missing onset date, then the AE will be considered a 
TEAE, unless the (partial) stop date indicates differently. A medication with a completely 
missing start date is considered a prior medication. A medication with a completely missing stop 
date is considered a concomitant medication. If an AE or a medication has a partial missing start 
or stop date, the following rules will be used to impute the date. The imputed date will be used to 
determine whether it is a TEAE for adverse event, or a prior or concomitant medication. 
 
Table 1 Partial date derivation 
Partial Missing Start or 
Stop Date 
Derived Start Date 
Derived Stop Date 
Missing month and day, and 
the year is present 
January 1st of that year or first dose 
date if the year is the same as the 
year of first dose date 
December 31st of that 
year 


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Partial Missing Start or 
Stop Date 
Derived Start Date 
Derived Stop Date 
Missing day, but year and 
month are present 
First day of that month or first 
dose date if the year and month are 
the same as the year and month of 
first dose date 
Last day of that month 
Missing month, but year 
and day are present 
Missing month derived as January 
or same as first dose month if the 
year is the same as the year of first 
dose 
Missing month derived 
as December 
 
9.2 
Multicenter studies 
In order to examine the uniformity of the treatment effect across centers, additional statistical 
analyses will be performed on the DQ endpoint, consisting of descriptive, summary statistics 
presented by center in the treatment group.  
9.3 
Derived and computed variables 
Scores (AEq and DQ) for neurocognitive development  
Neurocognition is assessed at Weeks 52 and 104, and during Early Termination, by use of the 
neurocognition domain of the BSID-III and/or the KABC-II Nonverbal Index (NVI).  
The selection of neurocognitive assessment method is done at the baseline assessment of the 
FIH study (SOBI003-001) based on the algorithm presented in Error! Reference source not 
found.. The neurocognitive test(s) applied in the FIH study should also be used in the extension 
study. 
 
Table 2 Selection of neurocognitive assessment method 
Chronological age at the 
assessment time point 
Development age-equivalence as 
established by VABS-II adaptive 
behavior composite  
Neurocognitive test to apply 
<42 months 
Any age-equivalence 
BSID-III 
≥42 months 
<36 months 
BSID-III 
≥42 months 
36 to 42 months 
BSID-III + KABC-II* 
≥42 months  
>42 months 
KABC-II 
* The BSID-III should be administered first, and there should be at least 2 days until the KABC-II assessment in 
order to reduce KABC-II outcome bias of patient tiredness. 


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The neurocognitive developmental age (months) is derived on the basis of the BSID-III cognitive 
total raw score and BSID-III age-normative data. 
The neurocognitive developmental age (months) is derived from the mean AEq scores on the 
NVI of the KABC-II, where an AEq scores is the average score for a particular age. 
Development Quotient  
DQ is calculated as the AEQ for cognitive development divided by the chronological age of the 
child multiplied with 100, i.e.  
DQ = 100*AEQ / Age 
For patients completing an assessment of both BSID-III and KABC-II, the BSID-III score will 
be used as a basis for calculating the DQ of neurocognitive development at baseline. A 
calibration of overlapping AEq scores between BDID-III and KABC-II will be done to assess if 
a patient outgrows the BSID-III test during the duration of the study. If confirmed, assessments 
of KABC-II will form the basis for calculating DQ of neurocognitive development for remaining 
study assessments.  
10 
Patient disposition 
The following patient disposition details will be summarized and will include the number and 
percentage of patients: 
• 
Included in the each study population (Safety analysis set, efficacy analysis set, 
immunogenicity analysis set, PK analysis set and PD analysis set) 
• 
Completed the study 
• 
Prematurely withdrew (including a breakdown of the primary reasons for withdrawal) 
These data will be listed. Individual reasons for withdrawal and protocol deviations will be 
presented in listings for all randomised patients.  
11 
Demographics and baseline characteristics 
11.1 
Demographics 
Individual patient demographics (age, gender and race) and body measurement data (height, 
weight, body mass index and head circumference) at study start will be listed.  
Age will be counted in months. Height will be measured in centimetres and weight in kilograms. 
BMI (kg/m2) will be calculated from the height and weight.  
These demographic characteristics and body measurements will be summarized for the total 
safety analysis set and the pivotal sub group. 


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11.2 
Baseline characteristics 
Other baseline measurements that will be listed include DQ, AEQ and genotype. The listing will 
include the NH study as well. 
11.3 
Medical history 
Medical and surgical history will be coded using the Medical Dictionary for Regulatory 
Activities (MedDRA) (version 16.1 or higher). All medical history events will be listed by 
system organ class (SOC) and preferred term. Surgical history will be presented in a separate 
listing.  
12 
Prior and concomitant medication 
All prior and concomitant medication will be coded using the latest version of World Health 
Organization drug dictionary (WHO Drug) version June 1 2013. 
Prior medications are defined as those for which the end date is prior to Day 1. Concomitant 
medications are defined as those which are indicated as ‘Ongoing’ on Day 1, those which start 
on or after Day 1 and those which start prior to Day 1 and have an end date on or after Day 1.  
If medication dates are incomplete and it is not clear whether the medication was concomitant, it 
will be assumed to be concomitant. 
The number and percentage of patients who took any concomitant medications will be presented 
by medication class and standardized medication names sorted alphabetically. 
All prior and concomitant medications will be listed by reported name, medication class, 
standardized medication name, indication, dose, dose unit, frequency, route of administration, 
start date and end date or ‘ongoing’ flag and duration of use. Concomitant medications will be 
flagged. 
13 
Treatment compliance 
There will be no measurement of, or analysis of, treatment compliance, nor does it affect 
population assignment (patients must be exposed to IMP to qualify for the analysis sets). 
14 
Efficacy analyses 
14.1 
The DQ endpoint 
One of the key secondary objectives is to assess the effect of SOBI003 on neurocognition, as 
compared to untreated MPS IIIA patients from a NH control. The key endpoint related to this 


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objective is the change from baseline in DQ of neurocognitive development at 104 weeks of 
treatment, and will be estimated by a model based contrast.  
To address the efficacy objective, a repeated measure analysis will be utilized where DQ is the 
response variable and time, baseline age, time*baseline age and treatment*time are fixed effects 
and the dependency between observations within the same patient is represented by an 
unstructured variance-covariance matrix. 
The time window is two weeks, i.e., if the assessment is more than two weeks too early or more 
than two weeks too late, then the DQ is set to missing for that assessment. 
In the NH study, a simple linear regression model was used, i.e. with DQ as the response 
variable and the age of the child as dependent variable (Shapiro et al 2016). As the aim in this 
clinical development program is to demonstrate that treatment with SOBI003 is efficacious and 
the effect of treatment is dependent on the time the patient has been treated, this model needs to 
be adopted so that time and baseline age are factors rather than the actual age of the child (which 
is the sum of the baseline age and the time in study). The results from the NH study suggest that 
the decline in DQ is not linear across all ages, and an interaction term time*baseline age is 
planned to be included in the model to allow for such a non-linearity. Also an unstructured 
variance-covariance matrix is planned to be used to account for the dependency between 
observations within the same patient. As a further justification for the model, it should be noted 
that time, baseline age and time*baseline age are all significant factors in the NH study. 
To represent the treatment effect without constraint to a specific relation across visits, a term 
treatment*time is planned to be included in the model. This effect is used to judge the treatment 
effect. The null hypothesis of no treatment effect will be tested with a significance test for the 
treatment*time-effect in the second step of the multiple testing procedure (see Section 14.3). The 
difference between 104 weeks and baseline will be used as the contrast of interest for the test. 
All missing values will be imputed. For a patients who stops treatment, let tp denote the turning 
point, i.e., the time point when the patient stops treatment. The patient’s assessments as well as 
the time points for prediction are classified as being on either side of the turning point or at the 
turning point: prior to tp, at tp, or after tp. For patients who does not stop treatment, let tp = ∞, 
i.e., every time point is considered as prior to the tp. Let v denote a missing value to be imputed 
for a patient. The imputations will be based on two categories of predictions. 
1). If the patient has two or more observations on the same side of tp as v (including a possible 
observation at tp), then v is considered as exclusively patient-predictable (p1), i.e., it can be 
predicted by simple linear regression based only on the patient’s data (intra-or extrapolation). On 
the other hand, if only one or zero observations exists on the same side of tp (from the particular 
patient) as v (including a possible observation at tp), then it is considered as non-predictable 
exclusively from the patient’s data.  
2) The other type of prediction (p2), will be calculated by the use of a population derived slope, 
estimated based on the repeated measures model in Section 14.1 (without imputations), and a 
patient observation. There will be two cases: If the patient has one or more observations on the 
same side of tp as v (including a possible observation at tp), then the nearest observation will be 
used together with a slope, which is based on the population (treated or untreated) of the same 


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status as the side of tp where the prediction time point is situated, as well as the interval relative 
the visits which contain the prediction time point. The other case is when there is no observation 
on the same side of tp as v (and no observation at tp). In this case, a prediction at tp will first be 
calculated, based on the same method as described above (under 2) but on the other side of tp, 
i.e., the nearest observation relative tp on the other side of tp will be used together with a slope 
based on the population (treated or untreated) of the same status as the side of tp where this 
nearest observation time point is situated, as well as the interval relative the visits which contain 
the tp. This prediction at the tp is in then used to predict v as described under the first case (under 
2). 
For each missing value v, the following algorithm is used to impute v by i. 
If p1 does not exists, then p2 is used, i.e., i = p2. 
Otherwise, a weighted average will be used for the imputation: i = w1 p1 + w2 p2, where  
w1 = exp(-λln(2)/3) and w2 = 1 - exp(-λln(2)/3) and λ is the distance in months between the time 
point for prediction and the nearest available non-missing patient assessment time point. The 
exponential function is motivated by an exponential decrease of relevance of individual patient 
data relative to population data with increasing time, and the coefficient ln(2)/3 is chosen such 
that population data reach the same weight as individual patient data after 75 % of the distance 
between two visits, i.e., three months. When individual patient data is available near a missed 
visit, the patient data weight is near 100 %, and when the distance is near one year on the other 
hand, the individual patient data weight has decreased to nearly 6 %. 
14.1.1 
Sensitivity analyses of the DQ endpoint 
In order to assess the sensitivity of the model, the DQ model described in Section 14.1 will  
• Only use non-missing values, i.e., no imputations will be performed 
• Be extended with a triple interaction factor time*treatment*baseline age 
• Use DQ = 0 for missing DQ values 
An addition sensitivity analysis will be a tipping point analysis: All combinations of DQ values 
(nUN , nT) where nUN, nT ∈ {0,1,2,…,100} are substituted for missings in the untreated arm and the 
treated arm respectively. P-values will be calculated for each combination. 
14.1.2 
Pincipal strata analysis 
A principal strata analysis will be performed where only patients without protocol violations will 
be analyzed according to Section 14.1.1. In particular patients who did not comply with the 
dosing scheme but continued the study will excluded from the analysis. 
14.2 
The HS endpoint 
One of the key secondary objectives is to evaluate the effect of SOBI003 on HS levels in CSF. 


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To evaluate the effect of SOBI003 on HS levels in CSF linear models are used to model the 
change from baseline in HS levels as dependent variable, for both logged HS levels and 
untransformed HS levels, and baseline level and age as continuous covariates, and accumulated 
dose (including the FIH study) as covariate and sex as factor. The analyses are conducted for 
each assessment time point: baseline, week 52 and 104. 
In addition, linear analyses with HS levels, both logged HS levels and untransformed HS levels, 
in CSF, serum and urine, as dependent variable, and baseline level and age as continuous 
covariates, and accumulated dose as covariate and sex as factor will be performed across all 
assessments (including the FIH study), with assessment as a repeated factor. 
For the purpose of the multiple testing procedure (see Section 14.3), the linear repeated measures 
analysis with untransformed HS in CSF levels will be used, identical to the DQ analysis with the 
exception of the treatment factors. 
The time effect is used to judge the HS level change in CSF. The null hypothesis of no change 
will be tested with a significance test for the time-effect in the first step of the multiple testing 
procedure (see Section 14.3). The difference between 104 weeks and baseline will be used as the 
contrast of interest for the test. 
The evaluation of the effect of SOBI003 on HS levels in serum and urine will utilize the same 
models as mentioned above for HS levels in CSF. 
 
The HS levels including change from baseline will also be summarized using descriptive 
statistics: n, mean, standard deviation (SD), standard error of the mean (SE), median, minimum 
and maximum. The HS change from baseline will also be presented as percentages. In addition, 
HS levels, change from baseline in HS levels and change from baseline in HS levels expressed as 
percentages will be presented in figures: by subject as well as mean graphs. 
14.2.1 
Sensitivity analyses of the HS endpoint 
In order to assess the sensitivity of the model, the HS model described in 14.2 will  
• Only use non-missing values, i.e., no imputations will be performed 
An addition sensitivity analysis will be a tipping point analysis: All observed HS values in the 
study are substituted for missings. 
14.3 
Multiple comparison procedure 
A hierarchical approach will be used for the key secondary co-endpoints.  
The primary analysis will be based on a 2-sided test using a significance level of 0.05. A 
stepwise sequential testing procedure will be used to ensure a multiple level of significance of 
0.05.  


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• 1st step: The null hypothesis of no difference between the treatments with respect to the 
reduction from baseline HS in CSF at 24 months will be tested using a significance level 
of 0.05. If the null hypothesis is rejected, then it will be concluded that SOBI003 reduces 
HS. Furthermore, the 2nd step of the sequential testing procedure will be performed. 
• 2nd step: The null hypothesis of no difference between the treatments with respect to the 
change in DQ score at 24 months will be tested using a significance level of 0.05. If the 
null hypothesis is rejected, it will be concluded that Sobi 003 improves cognitive function 
as compared to untreated patients.  
This multiple comparison procedure controls that the multiple level of significance is no more 
than 5 %. 
Formally, the second confirmatory step will only be valid after the 1st step has been successfully 
met.  
14.4 
Adaptive Behavior 
The adaptive behavior age-equivalent score is determined as the mean of the subdomain age-
equivalent scores including the communication, socialization, and daily living skills (thus 
excluding the motor skills domain). 
Adaptive behavior will be analyzed with the same repeated measures model as DQ and described 
in Section 14.1, but adapted for one group (i.e., no treatment*visit interaction term). 
14.5 
The MRI endpoints  
As listed in Section 3.5.4, the MRI endpoints refers to changes in gray matter volume, compound 
ventricular volume, FA and MD in corpus callosum and cerebral white matter, SWI in cerebral 
white matter and basal ganglia. 
To assess the PD effect of SOBI003 on MRI, linear models are used to model the change from 
baseline in MRI as dependent variable, for both logged MRI and untransformed MRI, and 
baseline level and age as continuous covariates, and accumulated dose (including the FIH study) 
as covariate and sex as factor. The analyses are conducted for each assessment time point: week 
52 and 104. 
In addition, linear analyses with MRI levels, both logged MRI levels and untransformed MRI 
levels, as dependent variable, and baseline level and age as continuous covariates, and 
accumulated dose as covariate and sex as factor will be performed across all assessments 
(including the FIH study), with assessment as a repeated factor. 


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14.6 
Exploratory endpoints 
Continuous variables are summarized using the number of patients, the mean, the standard 
deviation, the median, the minimum value, and the maximum value. Categorical variables are 
summarized using frequency counts and percentages. 
14.7 
Other efficacy endpoints 
Endpoints relating to the neurocognition, liver and spleen volume, QoL, language, motor 
function and sleep pattern are summarized using descriptive statistics.  
14.8 
Subgroup Analyses 
In order to examine the uniformity of the treatment effect across subgroups, additional 
exploratory statistical analyses will be performed on the DQ. The subgroups will be categorized 
according to: 
• Baseline DQ 
• Baseline AEq 
• Sex (male, female) 
The corresponding factors and treatment interactions will be included in the model, one at a time 
due to the small sample size. 
No formal hypothesis tests will be performed. 
14.9 
Analysis of the subpopulation to be included in the future primary 
analysis population 
The primary analysis will be repeated for the subgroup of subjects that will be included in the 
Phase III study (see Section 17), i.e., the subpopulation of the FAS patients who are up to 30 
months of age and in the FIH study was initially assigned a dose at least as high as the dose 
selected for the phase III study, and the NH study patients who are up to 30 months of age. In the 
case the model does not converge due to few number of patients, only descriptive statistics will 
be presented. 


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15 
Safety analyses 
15.1 
Drug exposure 
The scope of the drug exposure will include the preceding FIH study as well as the present study. 
The presentations will be based both on the extension study separately, and pooled with the 
preceding study.  
For each patient, graphs will be produced displaying dose by time and accumulated substance 
over time.  
Duration of exposure will be calculated for each patient. It is defined as the total number of days 
a patient is exposed to study drug, and will be calculated using the following formula: 
Time on treatment (days) = [(Treatment end date) – (Treatment start date) + 1]. 
The duration (days) and amount (mg) of exposure as well as the area under exposure curve will 
be summarized in a table using summary statistics, including the number of patients, the mean, 
standard deviation, median, minimum and maximum.  
15.2 
Adverse events 
An adverse event (AE) is defined as any untoward medical occurrence, including a clinically 
significant laboratory finding, symptom, or disease in a patient enrolled into this study regardless 
of its causal relationship to study drug.  
A treatment-emergent AE (TEAE) is defined as any event not present before exposure to study 
drug or any event already present that worsens in either severity or frequency after start of 
treatment. 
Adverse events will be coded using the latest version of Medical Dictionary for Regulatory 
Activities (MedDRA). 
An overview table will present the following information. 
• Number and percentage of patients reporting TEAEs 
• Number and percentage of patients reporting serious TEAEs 
• Number and percentage of patients reporting TEAEs leading to death 
• Number and percentage of patients reporting TEAEs leading to study discontinuation 
• Number and percentage of patients reporting TEAEs related to study drug 
The number of events will also be displayed in this summary table. 
15.2.1 
Adverse Events 
Treatment emergent AEs will be summarized by system organ class, preferred term and ADA-
status (positive, negative, boosted, unknown; each AE is classified according to the patients 


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ADA-status at the time of the AE occurrence;) displaying the number and percentage of patients 
with at least one AE recorded at each level of summarization. The total number of events and the 
number and percentage of patients with at least one TEAE will also be displayed. The 
summarization will be performed for the total safety analysis set and for the pivotal sub group. In 
addition, figures will be presented for each patient, displaying an overlay of drug exposure over 
time and adverse events marked out on the exposure curve. There will be two variants of this 
figure: one with dose by time, and the other with accumulated substance by time. 
15.2.2 
Serious adverse events 
A serious adverse event (SAE) is defined as any event that: 
• Results in death. 
• Is life-threatening (i.e., at immediate risk of death). 
• Requires in-patient hospitalization or prolongation of existing hospitalization. 
• Results in persistent or significant disability/incapacity. 
• Is a congenital anomaly/birth defect (i.e., in an offspring to the study patient). 
SAEs will be summarized by system organ class and preferred term displaying the number and 
percentage of patients with at least one SAE recorded at each level of summarization. The total 
number of events and number and percentage of patients with at least one treatment emergent 
SAE will also be displayed.  
15.2.3 
Adverse Events leading to study discontinuation 
Treatment emergent AEs leading to study discontinuation will be summarized by system organ 
class and preferred term displaying the number and percentage of patients with at least one AE 
recorded at each level of summarization. The total number of events leading to study 
discontinuation and the number and percentage of patients with at least one treatment emergent 
AE leading to study discontinuation will also be displayed.  
15.2.4 
Adverse Events by Severity 
Treatment emergent AEs will be summarized by system organ class, preferred term and severity 
(mild, moderate, severe). The summarization will be performed for the total safety analysis set 
and for the pivotal sub group. The table will display the number and percentage of patients with 
at least one TEAE recorded at each level of summarization within the preferred term. The total 
number of events along with the number and percentage of patients with at least one treatment 
emergent AE will also be displayed by severity. In the event of missing severity information, the 
severity will be displayed as ‘Missing’.  
The same presentation will be displayed for treatment emergent SAEs. 


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15.2.5 
Adverse Events by Relationship to Study Drug 
Treatment emergent AEs will be summarized by system organ class, preferred term and 
relationship to study drug (related, unrelated). The summarization will be performed for the total 
safety analysis set and for the pivotal sub group. The table will display the number and 
percentage of patients with at least one drug-related TEAE recorded at each level of 
summarization. The total number of events along with the number and percentage of patients 
with at least one drug-related treatment emergent AE will also be displayed.  
Treatment emergent adverse events as judged by investigator as possible, probable or definite 
will be classed as related. Those recorded as not related or unlikely will be classed as unrelated. 
In the event of missing relationship information, the relationship will be imputed as related.   
SAEs will be summarized in the same way.  
15.2.6 
Deaths 
Information on the number and percentage of patients reporting TEAEs leading to death will be 
included in the overview table described in Section 15.2. Information on each death will be 
summarized in individual patient narratives.  
15.3 
Laboratory data 
Laboratory test results will be compared to reference ranges, and values outside of the applicable 
reference range will be flagged as high (H) or low (L). In the data listing clinically significant 
values will also be indicated. 
Laboratory data will be summarized by parameter and visit with descriptive statistics for the total 
safety analysis set and the pivotal sub group. This summary will be repeated within baseline 
ADA positive and baseline ADA negative subgroups. 
Laboratory test results categorized as in or outside of the applicable range will be summarized 
using shift tables and shift plots i.e. shift from Baseline. 
The concentration/value for each laboratory parameter will be plotted against time using a 
spaghetti plot for each patient.  
Laboratory data will be listed in full. 
15.4 
Vital signs 
Vital signs (blood pressure, heart rate, body temperature, respiratory rate and pulse oximetry)) 
are measured at the time points specified in the study schedule of events.  
Observed and changes from baseline in vital signs will be summarized by visit with descriptive 
statistics for the total safety analysis set and the pivotal sub group. 


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The vital signs will be plotted using spaghetti plots as described for the laboratory data except 
without boundaries for normal ranges. 
Vital signs results will be listed in full. 
16 
Pharmacokinetics and Immunogenicity 
Blood sampling for PK, PD and immunogenicity is undertaken at the time-points specified in the 
study schedule of assessments. 
16.1 
Pharmacokinetic Parameters 
The PK analysis will be based on the PK analysis set. 
Serum concentrations will be listed and summarised by time point. Individual serum 
concentration profiles will be plotted both on the original scale and on the log scale. Mean (±SD) 
and median serum concentration profiles will be plotted for each dose both on the original scale 
and on the log scale. The individual serum concentration data, and the actual time for IMP 
administration and blood sampling will be used in the derivation of the PK parameters.  
PK calculations, based on serum concentrations, will be performed in Phoenix WinNonlin by 
means of NCA. The following multiple-dose PK parameters will be determined for SOBI003 at 
Weeks 39, 52, 78 and 104, and during dose-adjustments: 
• The time of the end of the infusion of SOBI003, tEnd of inf 
 • The observed serum concentration at the end of infusion of SOBI003, CEnd of inf  
• The observed serum concentration immediately before the start of infusion of SOBI003, CPre-
dose 
• The area under the plasma concentration-time curve from time 0 to last sample, AUC168h 
• Clearance, CL  
AUC168h will be calculated according to the linear log trapezoidal method. Other PK 
parameters may be calculated as applicable. 
In addition to evaluating SOBI003 PK based on SOBI003-002 data only, PK of SOBI003 will 
also be evaluated based on study SOBI003-002 together with PK data obtained from study 
SOBI003-001, since administration of SOBI003 have been started in study SOBI003-001 for all 
patients.  
Pre-dose SOBI003 concentrations in study SOBI003-002 will be used to explore if steady-state 
is maintained or if SOBI003 serum concentrations decrease or increase following totally 2 years 
administration of SOBI003. The extent of accumulation of SOBI003 serum concentrations 
during 2 years treatment will be explored by calculating accumulation ratio (Rac) based on PK 
data from both study SOBI003-001 and study SOBI003-002. Rac will be calculated as AUC0-
168h week n/AUC0-168h week 1, where n is 38, 52, 78 and 104.     


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The ratio of peripheral/central serum concentrations of SOBI003 may be explored in study 
SOBI003-002, in case SOBI003 serum concentrations have been determined in this study, 
depending on the outcome of study SOBI003-001.    
The effect of eg. dose-level, age or body-weight on SOBI003 PK will be explored eg. by plotting 
PK parameters versus dose, age, body-weight.     
The PK parameters will be listed for each patient and summarized for each IMP dose using 
descriptive statistics (the number of patients, arithmetic mean, standard deviation, standard error, 
coefficient of variation (CV) expressed as a percentage, geometric mean, geometric CV%, 
median, minimum, maximum). This summary will be repeated for PK parameters within 
baseline ADA positive and baseline ADA negative subgroups, within ADA positive at any 
postbaseline visit and ADA negative at all postbaseline visits. 
16.2 
Immunogenicity 
The analysis of immunogenicity will in general be based on the immunogenicity analysis set. 
However, exceptions are the analyses of PK by ADA status at baseline, which will be based on 
the PK analysis set, and the AE analysis with ADA-categorized AEs in section 15.2.1. 
For immunogenicity, baseline ADA (pre-existing ADA) from the previous study will be used. 
The following definitions will apply as defined in the harmonised terminology for 
immunogenicity (Shankar et al., 2014, “Assessment and Reporting of the Clinical 
Immunogenicity of Therapeutic Proteins and Peptides—Harmonized Terminology and Tactical 
Recommendations”, The AAPS Journal, DoI:10.1208/s12248-014-9599-2): 
• Evaluable patient: A patients with at least one sample taken after IMP administration that 
is appropriate for ADA testing (with reportable result). 
• ADA-positive sample: When ADA is detected in a sample, the sample is considered 
positive. 
• Baseline ADA: pre-existing antibodies detected at baseline. 
• Treatment induced ADA: de novo development following administration of IMP (i.e., 
formation of ADA any time after the initial IMP administration in a patient without pre-
existing ADA). 
• Treatment boosted ADA: Baseline ADA boosted to higher level following IMP 
administration (i.e., at any time after the initial IMP administration the ADA titer is 
greater than the baseline titer by a factor of four). 
• ADA-positive patient: A patient with at least one treatment-induced or treatment-boosted 
ADA-positive sample at any time during the treatment or follow-up observation period. 
• ADA-negative patient: A patient without a treatment induced or treatment-boosted ADA-
positive sample during the treatment or follow-up observation period. 
• Baseline ADA Positive Patient: Patient with ADA at baseline. Such patient can have 
treatment boosted ADA after dosing. 


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Note that the requirement for inclusion in the immunogenicity set of at least one post-dose ADA 
assessment means that all patients in the immunogenicity set are “evaluable patients”. 
The immunogenicity data will be listed for each patient and individual patient plots of titer 
measurement over time presented. Titer measurements will be summarized by visit and time 
point using descriptive statistics by IMP dose and overall. Immunogenicity will be evaluated in 
regards antibody prevalence (pre-existing antibodies), antibody incidence, titer and boosting 
following dosing, impact on pharmacokinetics responses. 
A summary of ADA positive patients over time will be presented. For each time-point this will 
summarize the number of patients who were ADA positive (treatment induced or treatment 
boosted ADA). A summary of ADA change from baseline immune response will be presented, 
summarizing the overall ADA incidence (number of ADA positive patients) as well as the 
numbers of patients for whom this was treatment induced ADA and treatment boosted ADA, 
together with summaries of titer. 
For the summary of treatment emergent AEs according to system organ class, preferred term and 
ADA-status, refer to section 15.2.1. 
Figures for each patient will be produced with titer and AEs plotted against time with ADA 
status (positive, negative, boosted) will be marked as well. 
The interval [0 TiterMax] that bounds the Titer values will be partitioned into up to four equal 
length intervals, where TiterMax is the maximal observed titer value. For each patient, each AE 
belonging to that patient will be classified according to which subinterval the nearest, previous 
titer belongs to when the AE occurred. For each titer-subinterval an AE summary for the SAF 
will be produced according to the analysis in 15.2.1 but without ADA-status. If one or more of 
the four subintervals are empty of corresponding AEs, then only three intervals will be used. If 
one or more subintervals of those three intervals are empty of corresponding AEs, only two 
subintervals will be used.  
The same analysis will be performed for logged titers, where the interval [0 log(TiterMax)] that 
bounds the log(Titer) values will similarly be partitioned into up to four equal lengths intervals, 
where log(TiterMax) is the maximal observed titer value.  
17 
The primary analysis for the pivotal phase 3 study 
In the Phase III study, patients up to 30 months are planned to be included. Therefore a 
subpopulation of the FAS patients who are up to 30 months of age and in the FIH study was 
initially assigned a dose at least as high as the dose selected for the phase III study will be 
included in the primary analysis population for demonstrating efficacy using combined data from 
the FIH study and the extension study, the Phase III trial and the corresponding patients in the 
NH study (control patients), consisting of the 5 patients with a rapid progressive MPS IIIA 
disease and a baseline age of 12 to 30 months. The primary analysis methods for DQ and HS and 
the estimand for the pivotal phase 3 study is planned to be identical to the corresponding analysis 
and estimand as described in the present SAP. 


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18 
References 
1 
Shapiro EG, Nestrasil I, Delaney KA, Rudser K, Kovac V, Nair N, et al. A prospective 
natural history study of mucopolysaccharidosis type IIIA. J Pediatr, 2016; 170: 278-287 
e271-274.