A Phase 2 Study of Burosumab for Fibroblast Growth Factor-23 Mediated Hypophosphatemia in Fibrous Dysplasia
Phase: PHASE2
Conditions: Fibrous Dysplasia Of Bone
Sponsor: National Institute of Dental and Craniofacial Research (NIDCR)

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Abbreviated Title: Burosumab for FD 
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Abbreviated Title: Burosumab for FD 
NIH IRB #: 000798 
Version Date: February 20, 2024 
Title: A phase 2 Study of Burosumab For Fibroblast Growth Factor-23 Mediated 
Hypophosphatemia in Fibrous Dysplasia 
NIH Principal Investigator: Alison Boyce, MD 
NIDCR 
Building 30, Room 228 
MSC 4320 
Bethesda, MD 20892 
Phone: 301-221-1933 
E-mail: alison.boyce@nih.gov 
 
 
 
Investigational Agents: 
 
Drug Name: 
Burosumab 
IND Number: 
161576 
Sponsor: 
NIDCR 
Manufacturer: 
Kyowa Kirin Co. Ltd. 

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TABLE OF CONTENTS 
1 
TABLE OF CONTENTS ..................................................................................................... 2 
2 
STATEMENT OF COMPLIANCE ..................................................................................... 4 
3 
PROTOCOL SUMMARY ................................................................................................... 5 
3.1 
Synopsis .................................................................................................................... 5 
3.2 
Schema ...................................................................................................................... 6 
3.3 
Schedule of Activities (SoA)..................................................................................... 8 
4 
INTRODUCTION .............................................................................................................. 10 
4.1 
Study Rationale ....................................................................................................... 10 
4.2 
Background ............................................................................................................. 11 
4.3 
Risk/Benefit Assessment ......................................................................................... 12 
5 
OBJECTIVES AND ENDPOINTS .................................................................................... 18 
6 
STUDY DESIGN ............................................................................................................... 20 
6.1 
Overall Design ........................................................................................................ 20 
6.2 
Scientific Rationale for Study Design ..................................................................... 21 
6.3 
Justification for Dose .............................................................................................. 21 
7 
STUDY POPULATION .................................................................................................... 21 
7.1 
Inclusion Criteria ..................................................................................................... 21 
7.2 
Exclusion Criteria .................................................................................................... 22 
7.3 
Inclusion of Vulnerable Participants ....................................................................... 22 
7.4 
Inclusion of Pregnant Women, fetuses or neonates ................................................ 23 
7.5 
Lifestyle Considerations .......................................................................................... 23 
7.6 
Screen Failures ........................................................................................................ 23 
7.7 
Strategies for Recruitment and Retention ............................................................... 23 
8 
STUDY INTERVENTION ................................................................................................ 24 
8.1 
Study Interventions(s) Administration .................................................................... 24 
8.2 
Preparation/Handling/Storage/Accountability ......................................................... 26 
8.3 
Measures to Minimize Bias: Randomization and Blinding ..................................... 27 
8.4 
Study Intervention Compliance ............................................................................... 27 
8.5 
Concomitant Therapy .............................................................................................. 27 
9 
STUDY INTERVENTION DISCONTINUATION AND PARTICIPANT 
DISCONTINUATION/WITHDRAWAL ................................................................................. 28 

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9.1 
Study Intervention Discontinuation ..........................................................................28 
9.2 
Participant Discontinuation/Withdrawal from the Study .........................................28 
9.3 
Lost to Follow-up .................................................................................................... 29 
10 
STUDY ASSESSMENTS AND PROCEDURES .......................................................... 29 
10.1 
Screening Procedures .............................................................................................. 29 
10.2 
Study Evaluations & Procedures ............................................................................. 30 
10.3 
Safety and Other Assessments ................................................................................ 32 
10.4 
Adverse Events and Serious Adverse Events .......................................................... 33 
10.5 
Unanticipated Problems .......................................................................................... 38 
11 
STATISTICAL CONSIDERATIONS ........................................................................... 38 
11.1 
Statistical Hypothesis .............................................................................................. 38 
11.2 
Sample Size Determination ......................................................................................39 
11.3 
Populations for Analyses ......................................................................................... 39 
11.4 
Statistical Analyses ................................................................................................. 40 
12 
REGULATORY AND OPERATIONAL CONSIDERATIONS ....................................41 
12.1 
Informed Consent Process ........................................................................................41 
12.2 
Study Discontinuation and Closure ..........................................................................44 
12.3 
Confidentiality and Privacy ..................................................................................... 44 
12.4 
Future use of Stored Specimens and Data ................................................................45 
12.5 
Safety Oversight .......................................................................................................46 
12.6 
Clinical Monitoring ................................................................................................. 46 
12.7 
Quality Assurance and Quality Control ...................................................................47 
12.8 
Data Handling and Record Keeping ....................................................................... 47 
12.9 
Protocol Deviations and Non-Compliance ...............................................................47 
12.10 
Publication and Data Sharing Policy ....................................................................... 48 
12.11 
Collaborative Agreements ........................................................................................48 
12.12 
Conflict of Interest Policy ........................................................................................49 
13 
Abbreviations .................................................................................................................. 49 
14 
REFERENCES ............................................................................................................... 50 

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Abbreviated Title: Burosumab for FD 
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STATEMENT OF COMPLIANCE 
The trial will be carried out in accordance with International Conference on Harmonisation Good 
Clinical Practice (ICH GCP) and the following: 
• United States (US) Code of Federal Regulations (CFR) applicable to clinical studies (45 
CFR Part 46, 21 CFR Part 50, 21 CFR Part 56, 21 CFR Part 312, and/or 21 CFR Part 812) 
National Institutes of Health (NIH)-funded investigators and clinical trial site staff who are 
responsible for the conduct, management, or oversight of NIH-funded clinical trials have 
completed Human Subjects Protection and ICH GCP Training. 
The protocol, informed consent form(s), recruitment materials, and all participant materials will 
be submitted to the Institutional Review Board (IRB) for review and approval. Approval of both 
the protocol and the consent form must be obtained before any participant is enrolled. Any 
amendment to the protocol will require review and approval by the IRB before the changes are 
implemented to the study. In addition, all changes to the consent form will be IRB-approved; an 
IRB determination will be made regarding whether a new consent needs to be obtained from 
participants who provided consent, using a previously approved consent form. 

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Abbreviated Title: Burosumab for FD 
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1 
PROTOCOL SUMMARY 
1.1 
Synopsis 
Title: 
A Phase 2 Study of Burosumab For Fibroblast Growth Factor-23 Mediated 
Hypophosphatemia in Fibrous Dysplasia 
Study Description: 
This will be a phase 2, open-label, single-arm study to evaluate the safety 
and efficacy of burosumab to normalize serum phosphate levels in subjects 
with fibrous dysplasia (FD) and fibroblast growth factor 23 (FGF23)- 
mediated hypophosphatemia. 
Objectives: 
Primary Objective: 
• 
Evaluate the efficacy of burosumab to normalize serum phosphate 
levels in subjects with FD and FGF23-mediated hypophosphatemia at 
48 weeks. 
Secondary Objectives: 
• 
Evaluate the efficacy of burosumab to normalize serum phosphate 
levels in subjects with FD and FGF23-mediated hypophosphatemia at 
24 weeks. 
• 
Evaluate the safety and tolerability of burosumab in patients with FD. 
• 
Evaluate the effect of burosumab on increasing serum phosphate and 
additional mineral markers. 
• 
Evaluate the impact of burosumab on FD lesion activity. 
• 
Evaluate the effect of burosumab on functional parameters. 
• 
Evalua9te the effect of burosumab on pain and health-related quality of 
life. 
Endpoints: 
Primary Endpoint: 
• 
The proportion of subjects achieving serum phosphate levels within the 
target range (Z-score -1 to +2) at Week 48. 
Secondary Endpoints: 
• 
Proportion of subjects achieving serum phosphate levels within the 
target range (Z-score -1 to +2) at Week 24. 
• 
Adverse events and clinical safety laboratory tests for up to 4 weeks 
after the final burosumab dose (48 weeks for adult subjects, 50 weeks 
for pediatric subjects). 
• 
Change and percent change from baseline to post-baseline visits in 
serum phosphate, serum 1,25(OH)2D, ratio of renal tubular maximum 
reabsorption rate of phosphate to glomerular filtration rate (TmP/GFR). 
• 
Change in FD lesion activity using 18F-NaF PET/CT total lesion 
activity from baseline to 48 weeks 
• 
Change and percent change in serum bone turnover markers, including 
procollagen 1 N-terminal propeptide (P1NP), beta crosslaps C- 
telopeptides (CTX), osteocalcin, and bone-specific alkaline 
phosphatase from baseline to 48 weeks. 
• 
Change in FD lesion histology and cell proliferation as assessed by 
minimally invasive bone biopsies from baseline to 48 weeks (adults 
with capacity to consent only) from baseline to 48 weeks 
• 
Skeletal changes assessed on skeletal survey at baseline and 48 weeks 
• 
Change from baseline to 48 weeks in: 
o Muscle strength 

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o Range-of-motion 
o Walking speed (9-minute walk) 
Change from baseline to 48 weeks in patient reported outcomes measures: 
• 
SF36: adults 
• 
SF10: children 
• 
PROMIS Pain Intensity: Pediatric and Parent Proxy version 1.0, Adult 
version 2.0 
• 
PROMIS Pain Interference: Pediatric and Parent Proxy v 2.0, Adult v 
1.1 
• 
PROMIS Mobility: Pediatric and Parent Proxy version 2.0, Adult 
Mobility Lower Extremity v 1.0 
• 
PROMIS Fatigue: Pediatric and Parent Proxy v 2.0, Adult FACIT 13a 
v1.0 
• 
Activities of Daily Living Questions: adults and children 
Study Population: 
Up to 15 subjects with FD and FGF23-mediated hypophosphatemia 
Phase: 
2 
Description of 
Sites/Facilities 
Enrolling Participants: 
Description of Study 
Intervention: 
National Institutes of Health (NIH) Clinical Center (CC) 
Burosumab is an injectable solution in single use vials at concentrations of 
30 mg/mL 
Study Duration: 
Estimated time from when the study opens to enrollment until completion 
of data analyses is approximately 20 months. 
Participant Duration: 
Up to 50 weeks (2 week washout period + 48 week treatment period + final 
adverse event review) 

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1.2 
Schema 
 
NIH 
NIH 
NIH 
evaluation 
evaluation 
evaluation 
-2 
0 
2 
4 
6 
8 
10 
12 
14 
16 
18 
20 
22 
24 
26 
28 
30 
32 
34 
36 
38 
40 
42 
44 
46 
48 
Washout period 
Burosumab Treatment 
Subjects will be treated with burosumab for 48 weeks following a 2-week washout period. Evaluations will be performed at the NIH Clinical Center at 
baseline, 24, and 48 weeks. Between visits burosumab will be administered locally, and subjects will be monitored remotely with outpatient labs. 

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1.3 
Schedule of Activities (SoA) 
 
 
 
 
Procedures 
Weeks -12 to -1 1 
Weeks -2 to 0: Washout period for subjects on therapy 2 
Baseline Visit 
(NIH CC) 3 
Week 1 
Week 2 
Week 3 
Week 4 
Week 6 
Week 8 
Week 10 
Week 12 
Week 14 
Week 16 
Week 18 
Week 20 
Week 22 
Week 24 Visit 
(NIH CC) 3 
Informed consent 
X 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
Demographics 
X 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
Medical history 
X 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
X 
Physical exam (including height, arm span, and 
weight) 
- 
X 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
X 
Vital signs 
- 
X 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
X 
Injection teaching 
- 
X 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
X 
Functional parameters 4 
- 
X 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
X 
NIH lab tests 5 
- 
X 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
X 
Outpatient lab tests 6 
- 
- 
X 
X 
X 
X 
X 
X 
X 
X 
- 
X 
- 
X 
- 
- 
Pregnancy test 7 
- 
X 
- 
- 
- 
X 
- 
X 
- 
X 
- 
X 
- 
X 
- 
X 
Bone biopsy 8 
- 
X 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
Imaging assessment 9 
- 
X 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
Patient reported outcomes 10 
- 
X 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
X 
Burosumab administration (pediatric subjects) 11 
- 
X 
- 
X 
- 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Burosumab administration (adult subjects) 11 
- 
X 
- 
- 
- 
X 
- 
X 
- 
X 
- 
X 
- 
X 
- 
X 
Adverse event collection, review and evaluation 
- 
 

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Procedures 
Week 26 
Week 28 
Week 30 
Week 32 
Week 34 
Week 36 
Week 38 
Week 40 
Week 42 
Week 44 
Week 46 
Week 48 Visit 
(NIH CC) 3 
Week 50 
Informed consent 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
Demographics 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
Medical history 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
X 
- 
Physical exam (including height, arm span, and weight) 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
X 
- 
Vital signs 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
X 
- 
Injection teaching 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
Functional parameters 4 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
X 
- 
NIH lab tests 5 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
X 
- 
Outpatient lab tests 6 
- 
X 
- 
X 
- 
X 
- 
X 
- 
X 
- 
- 
- 
Pregnancy test 7 
- 
X 
- 
X 
- 
X 
- 
X 
- 
X 
- 
X 
Bone biopsy 8 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
X 
- 
Imaging assessment 9 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
X 
- 
Patient reported outcomes 10 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
X 
- 
Burosumab administration (pediatric subjects) 11 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
- 
- 
Burosumab administration (adult subjects) 11 
- 
X 
- 
X 
- 
X 
- 
X 
- 
X 
- 
- 
- 
Study close-out teleconference (pediatric subjects) 12 
X 
Adverse event review and evaluation 12 
 
1 Informed consent will be obtained by telephone or in person prior to the baseline visit. 
2 Subjects receiving supplemental phosphate, active vitamin D metabolites, or current burosumab treatment will discontinue these medications for 
2 weeks prior to screening. 
3 Visits will be conducted in the NIH Clinical Center in the inpatient, day hospital, or clinic settings as appropriate. All visits will occur within a 
window of +/- 5 days from the planned timepoint. 
4 Muscle strength, range-of-motion, 9-minute walk test. 

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5 Serum sodium, potassium, chloride, bicarbonate, glucose, blood urea nitrogen, creatinine, albumin, total protein, calcium, magnesium, 
phosphate, parathyroid hormone, 25-hydroxyvitamin D, 1,25-dihydroxyvitamin D, aspartate aminotransferase, alanine aminotransferase, total 
bilirubin, alkaline phosphatase, osteocalcin, procollagen type 1 N-terminal propeptide, Beta-CrossLaps C-telopeptides, intact FGF23 (baseline 
visit only), C-terminal FGF23 (baseline visit only), research blood, anti-drug antibodies, neutralizing antibodies (in samples testing positive for 
neutralizing antibodies only), and burosumab concentration. 24-hour urinary calcium, creatinine, phosphate (toilet trained subjects), random 
urinary calcium, creatinine, phosphate (non-toilet trained subjects), and TmP/GFR. 
6 Serum calcium, phosphate, creatinine, and alkaline phosphatase. Random urine calcium, creatinine, and phosphate. Urine pregnancy test (girls 
and women of childbearing potential only). Outpatient labs will be obtained 3 +/-2 days and reviewed prior to burosumab administration. 
Subsequent elements on the Schedule of Events will be dictated by the timing of the previous injection. 
7 To be performed in girls and women of childbearing potential only. Female subjects of child-bearing potential must be non-pregnant and non- 
nursing. Additional pregnancy tests will be performed at any visit in which pregnancy status is in question. A serum pregnancy test will be 
performed in the event of a positive or equivocal urine pregnancy test result or can be performed if pregnancy test by urine is not feasible. 
8 To be performed only in adult subjects with capacity to consent. 
9 18Sodium fluoride-PET/CT scan, skeletal survey, renal ultrasound. Will accept outside or internal imaging for 18Sodium fluoride-PET/CT scan, and/or 
skeletal survey as baseline study imaging if obtained within 6 months prior to Week 0/Baseline visit, as a means of reducing unnecessary repeated exposure to 
radiation 
10 SF36 (adults), SF10 (children), PROMIS Pain Intensity (Pediatric and Parent Proxy version 1.0, Adult version 2.0), PROMIS Pain Interference 
(Pediatric and Parent Proxy v 2.0, Adult v 1.1), PROMIS Mobility (Pediatric and Parent Proxy version 2.0, Adult Mobility Lower Extremity v 
1.0), PROMIS Fatigue (Pediatric and Parent Proxy v 2.0, Adult FACIT 13a v1.0), Activities of Daily Living Questionnaire (adults and children). 
11 Burosumab is administered every 2 weeks in children age <18 years, and every 4 weeks in adults age ≥18 years. The initial dose will be 
administered at the NIH CC, and subsequent doses will be self/caregiver administered under the observation of the study team. If the target range 
is not reached for patients >18 year and older, dosing may be administered at every 2-week dosing intervals at the discretion of the PI. 
12 Final adverse event review will be performed 4 weeks +/- 5 days after the final dose: at the 48 week NIH CC visit for adult subjects, and at a 
teleconference at 50 weeks for pediatric subjects, or adult subjects who have been on every 2-week dosing interval. 

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2 
INTRODUCTION 
2.1 
Study Rationale 
Fibrous dysplasia (FD) is a rare, mosaic disorder of Gαs activation in which normal bone and 
marrow are replaced with fibro-osseous tissue. Disease may involve one bone or many, and may 
occur in association with extraskeletal features, termed McCune-Albright syndrome (MAS) [1]. 
Gαs mutation-bearing skeletal stem cells produce excess amounts of the phosphaturic hormone 
fibroblast growth factor-23 (FGF23). This leads to hyperphosphaturia in most patients, and those 
with a high FD tissue burden may develop frank hypophosphatemia. Because FD tissue is 
inherently poorly mineralized and structurally unsound, it is likely at increased vulnerability to 
the deleterious effects of hypophosphatemia compared to typical bone. Therefore, in addition to 
sequelae of rickets/osteomalacia, patients with FGF23-mediated hypophosphatemia present with 
increased FD-related morbidity, including progressive skeletal deformities, fractures, bone pain, 
and functional impairment [2-4]. 
Like other disorders of FGF23 excess, management of hypophosphatemia in FD has traditionally 
focused on repletion with oral phosphate and active vitamin D analogs. However, this regimen is 
complicated by dose-limiting side effects, including gastrointestinal intolerance and renal 
toxicity. Normalization of serum phosphate is therefore not a practical goal with conventional 
treatment, placing patients with FD at continued risk of skeletal complications from persistent 
hypophosphatemia. Burosumab, a human recombinant monoclonal antibody to FGF23, 
represents a new, targeted treatment approach. Multiple clinical trials have demonstrated safe, 
efficacious use of burosumab in FGF23-mediated disorders such as X-linked hypophosphatemia 
(XLH) and tumor-induced osteomalacia (TIO), leading to improved serum phosphate levels and 
skeletal outcomes without adverse gastrointestinal or renal side effects. While the underlying 
pathophysiology of FGF23 excess is shared between these conditions, there is no literature 
regarding the use of burosumab in FD. 
Given the known limitations of conventional therapy, burosumab is an intuitive choice for 
management of hypophosphatemia in FD. However, additional research into the safety and 
efficacy of burosumab is needed before it can be used routinely in this population. The potential 
for FD tissue effects is an important consideration; it is unknown whether burosumab may 
impact skeletal stem cell proliferation or other drivers of FD lesion growth and activity. Given 
the increased vulnerability of FD to deleterious effects of hypophosphatemia, investigation is 
needed to determine if targeting a mid-normal serum phosphate level (typically unachievable 
with conventional therapy) is a safe and effective therapeutic goal in patients with FD. 
Burosumab is labeled as a subcutaneous injection administered by healthcare professionals; 
however, the option of self-administration would offer many benefits in the FD population, 
including improved accessibility, cost, and convenience. Studies are needed to determine the 
feasibility of this approach. 
2.2 
Background 
Burosumab has been studied extensively in clinical trials of pediatric and adult patients with X- 
linked hypophosphatemia (XLH), an X-linked dominant disorder of FGF23 overproduction. An 
open label phase 2 study of 52 children age 5-12 years, burosumab treatment at 2-week intervals 
led to sustained improvements in serum phosphate levels and radiographic measures of rickets 
severity [5]. A subsequent phase 3 study in 61 children age 1-12 years compared burosumab to 

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conventional treatment, showing significantly greater improvements in rickets severity, growth, 
and biochemistries [6]. A randomized placebo-controlled study of adults with XLH treated with 
burosumab at 4-week intervals reported improvements in serum phosphate, patient-reported 
physical outcomes, and healing of osteomalacia-related insufficiency fractures [7 8]. A 
subsequent open-label adult phase 3 study evaluated transiliac bone biopsies after 48 weeks of 
burosumab, demonstrating improvement in histomorphometric indices related to osteomalacia 
[9]. Based on these studies, burosumab has received approval from the Food and Drug 
Administration (FDA) for treatment of XLH in adults and children age 6 months and older. 
Burosumab has been studied in adults with tumor-induced osteomalacia (TIO), a rare 
paraneoplastic process in which acquired phosphaturic mesenchymal tumors produce high levels 
of FGF23. In an open-label phase 2 study of 14 adults, burosumab treatment at 4-weeks intervals 
was associated with improved serum phosphate levels, fracture healing, and histomorphometric 
indices of osteomalacia [10]. Similar findings were reported in a second open-label study in 
adults (n=13) [11]. Based on these studies, burosumab was approved by the FDA for treatment 
of TIO in patients age 2 years and older. 
Burosumab is currently approved for administration by healthcare professionals via 
subcutaneous injection every 2 weeks for children and every 4 weeks for adults. In the clinical 
development program of burosumab, self-administration by either patient or caregiver was 
permitted and monitored in two open-label studies of XLH in Japan and South Korea, KRN23- 
003 (NCT03233126) and KRN23-004 (NCT04308096). Based on this data, the Pharmaceuticals 
and Medical Devices Agency in Japan approved self- and/or caregiver administration of 
burosumab in December 2020. Self- and/or caregiver administration was temporarily allowed by 
the FDA due to the COVID-19 pandemic. Self- and/or caregiver-administration was also 
approved by the European Medicines Agency in 2021, if suitable and if performed by an 
individual who has been trained in injection techniques. 
2.3 
Risk/Benefit Assessment 
2.3.1 Known Potential Risks 
There are no known risks of burosumab in the target population of patients with FD. The 
potential risks and adverse reactions for burosumab are based on the approved indications XLH 
and TIO [12]. 
Adverse Reactions in Clinical Trials of Burosumab-Treated Pediatric Patients with XLH 
The following data reflect safety data from burosumab treatment in 3 pediatric clinical trials of 
XLH: Study 1 is a randomized, open-label phase 3 study in children ages 1 to 12 years, who 
were randomized to treatment with burosumab or conventional treatment (burosumab n=29, 
control n=32). Study 2 is an open-label phase 2 study in children ages 5 to 12 years (n=52). 
Study 3 is an open-label phase 2 study in children ages 1 to less than 5 years (n=13). Overall, the 
patient population was 1-12 years (mean age 7.0 years), 49% male, and 88% white. 
In Study 1, burosumab-treated patients received a mean dose of approximately 0.90 mg/kg 
(range 0.8-1.2 mg/kg) every 2 weeks. All patients in this group and the active control group 
completed 64 weeks of treatment. Adverse reactions occurring in ≥10% of subjects in the 
burosumab group, with higher frequency than in the subjects in the control group, through the 
64-week treatment period in Study 1 are shown in the below Table 1: 

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Table 1. Adverse Reactions in ≥10% of Burosumab-Treated Pediatric Patients and with 
Higher Frequency Than the Active Control Group in Study 1 
 
Adverse Reaction 
Burosumab Treatment 
(n=29), n (%) 
Active Controls (n=32), n 
(%) 
Pyrexia 
16 (55%) 
6 (19%) 
Injection site reaction 
15 (52%) 
0 (0%) 
Cough 
15 (52%) 
6 (19%) 
Vomiting 
12 (41%) 
8 (25%) 
Pain in extremity 
11 (38%) 
10 (31%) 
Headache 
10 (34%) 
6 (19%) 
Tooth abscess, infection, 
and/or toothache 
10 (34%) 
4 (13%) 
Dental caries 
9 (31%) 
2 (6%) 
Diarrhea 
7 (24%) 
2 (6%) 
Decreased vitamin D levels 
7 (24%) 
1 (3%) 
Constipation 
5 (17%) 
0 (0%) 
Rash 
4 (14%) 
2 (6%) 
In Study 2, 26 patients received burosumab at a mean dose of 1.05 mg/kg (range 0.4 – 2.0 
mg/kg) every 2 weeks at Week 64; the other 26 patients received burosumab every 4 weeks. The 
mean duration of exposure in Study 2 was 124 weeks. In Study 3, patients received burosumab at 
a mean dose of 0.90 mg/kg (range 0.8 – 1.2 mg/kg) every 2 weeks at Week 40. The mean 
duration of exposure in Study 3 was 45 weeks. Adverse reactions occurring in ≥10% of 
burosumab -treated patients from Studies 2 and 3 are shown in the below Table 2: 
Table 2.Adverse Reactions in ≥10% of Burosumab-Treated Pediatric Patients in Studies 2 
and 3. 
 
Adverse Reaction 
Study 2 (n=52), n 
(%) 
Study 3 (n=13), n 
(%) 
Overall (n=65), n 
(%) 
Headache 
38 (73%) 
1 (8%) 
39 (60%) 
Injection site reaction 
35 (67%) 
3 (23%) 
38 (59%) 

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Adverse Reaction 
Study 2 (n=52), n 
(%) 
Study 3 (n=13), n 
(%) 
Overall (n=65), n 
(%) 
Vomiting 
25 (48%) 
6 (46%) 
31 (48%) 
Pyrexia 
23 (44%) 
8 (62%) 
31 (48%) 
Pain in extremity 
24 (46%) 
3 (23%) 
27 (42%) 
Decreased vitamin D 
levels 
19 (37%) 
2 (15%) 
21 (32%) 
Rash 
14 (27%) 
1 (8%) 
15 (23%) 
Tooth abscess, 
toothache 
20 (38%) 
5 (38%) 
25 (40%) 
Myalgia 
9 (17%) 
1 (8%) 
10 (15%) 
Dizziness 
8 (15%) 
0 (0%) 
8 (12%) 
Hypersensitivity reactions: In Study 1 (n=29), the most frequent hypersensitivity reactions were 
rash (10%), injection site rash (10%) and injection site urticaria (7%). In Studies 2 and 3 (n=65), 
the most frequent hypersensitivity reactions were rash (22%), injection site rash (6%), and 
urticaria (5%). 
Hyperphosphatemia: No events of hyperphosphatemia were reported in pediatric studies. 
Injection Site Reactions: In Study 1, 52% of patients had a local injection site reaction (injection 
site urticaria, erythema, rash, swelling, bruising, pain, pruritus, and hematoma). In Studies 2 and 
3, approximately 58% of the patients had a local injection site reaction. Injection site reactions 
were generally mild, occurred within 1 day of injection, lasted approximately 1 to 3 days, 
required no treatment, and resolved in almost all instances. 
Adverse Reactions in Clinical Trials of Burosumab-Treated Adult Patients with XLH 
The following data reflect safety data from burosumab treatment in adult patients with XLH in a 
24-week randomized, double-blind, placebo-controlled study (Study 4) of 134 patients, age 20- 
63 years (mean age 41 years). Most were white (81%) and female (65%). A total of 68 and 66 
patients received at least one dose of burosumab or placebo, respectively. The mean dose of 
burosumab was 0.95 mg/kg (range 0.3 – 1.2 mg/kg) subcutaneously every 4 weeks. Adverse 
reactions reported in ≥5% of burosumab-treated patients, and ≥2 patients greater than the placebo 
group are shown in the following Table 3: 
Table 3. Adverse Reactions Occurring in ≥5% of Burosumab-Treated Adult Patients, and 
in at ≥2 Patients More Than with Placebo in the 24-Week Placebo-Controlled Period of 
Study 4 

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Adverse Reaction 
Burosumab Treatment 
(n=68), n (%) 
Placebo Group (n=66), n 
(%) 
Back pain 
10 (15%) 
6 (9%) 
Headache 
9 (13%) 
6 (9%) 
Tooth infection 
9 (13%) 
6 (9%) 
Restless leg syndrome 
8 (12%) 
5 (8%) 
Decreased vitamin D levels 
8 (12%) 
3 (5%) 
Dizziness 
7 (10%) 
4 (6%) 
Muscle spasms 
5 (7%) 
2 (3%) 
Constipation 
6 (9%) 
0 (0%) 
Hyperphosphatemia 
4 (6%) 
0 (0%) 
Hypersensitivity Reactions: Approximately 6% of patients in both the burosumab and placebo 
groups experienced a hypersensitivity event, which were mild-moderate and did not require 
study discontinuation. 
Hyperphosphatemia: Six percent of patients in the burosumab group experienced 
hyperphosphatemia meeting the protocol-specified criteria for dose reduction (either a single 
serum phosphate greater than 5.0 mg/dL or serum phosphate greater than 4.5 mg/dL [upper limit 
of normal] on two occasions). A single patient required a second dose reduction for continued 
hyperphosphatemia. 
Injection Site Reactions: Approximately 12% of patients in both the burosumab and placebo 
groups had a local reaction (injection site reaction, erythema, rash, bruising, pain, pruritus, and 
hematoma) at the site of the injection. Injection site reactions were generally mild in severity, 
occurred within 1 day of injection, lasted approximately 1 to 3 days, required no treatment, and 
resolved in almost all instances. 
Restless Legs Syndrome: Approximately 12% of the burosumab group had worsening of baseline 
or new onset of restless legs syndrome of mild to moderate severity; these events did not lead to 
dose discontinuation. 
Adverse Reactions in Clinical Trials of Burosumab-Treated Adult Patients with TIO 
The following data reflect pooled safety data from burosumab treatment in adult patients with 
TIO in two open-label trials (Studies 5 and 6) that enrolled a total 27 patients. Patients ranged 
from 33-73 years of age and 14 (52%) were male. The mean dose of burosumab was 0.77 mg/kg 
every 4 weeks and the mean duration of exposure was 121 weeks. Adverse reactions from both 
studies are shown below in Table 4: 

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Table 4. Adverse Reactions Reported in Adult Patients with TIO in Study 5 and Study 6 
 
Adverse Reaction 
Overall (n=27), n (%) 
Tooth abscess 
5 (19%) 
Muscle spasm 
5 (19%) 
Dizziness 
4 (15%) 
Constipation 
4 (15%) 
Injection site reaction 
4 (15%) 
Rash 
4 (15%) 
Headache 
3 (11%) 
Vitamin D deficiency 
2 (7%) 
Hyperphosphatemia 
2 (7%) 
Restless leg syndrome 
2 (7%) 
Hypersensitivity reactions: 22% of patients experienced a hypersensitivity reaction. The most 
frequent hypersensitivity reactions were eczema (11%) and rash (15 %), and reactions were 
mild-moderate in severity. 
Hyperphosphatemia: 2 patients (7%) experienced hyperphosphatemia which was managed with 
dose reduction. 
Injection Site Reactions: The frequency of injection site reactions was 15% (injection site 
reaction, injection site pain, and injection site swelling). Reactions were generally mild in 
severity, required no treatment and resolved in all cases. 
Restless Leg Syndrome: 2 patients (7%) experienced symptoms of restless legs syndrome, which 
were mild and did not require treatment interruption. 
Immunogenicity 
There is potential for immunogenicity with all therapeutic proteins. In XLH clinical studies, none 
(0/13) of the 1 to 4-year-old patients, 19% (10/52) of the 5- to 12-year-old patients, and 15% 
(20/131) of the adult patients tested positive for anti-drug antibodies after receiving burosumab. 
Three 5- to 12-year-old patients tested positive for neutralizing antibodies. Anti-drug antibodies 
were not associated with clinically-relevant changes in pharmacokinetics, pharmacodynamics, 
efficacy, or safety. In one TIO clinical study, 14% (2/14) of the adult patients tested positive for 
anti-drug antibodies after receiving burosumab, and one of these patients tested positive for 
neutralizing antibodies. In another TIO clinical study, none of the 13 adult patients tested 
positive for anti-drug antibodies. 

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Additional Important Potential Risks 
Pregnancy and Lactation 
There are no available data on burosumab use in pregnant women to inform a drug-associated 
risk of adverse developmental outcomes. In utero, burosumab-twza exposure in cynomolgus 
monkeys did not result in teratogenic effects. Adverse effects such as late fetal loss and preterm 
birth were observed in pregnant cynomolgus monkeys, however, these effects are unlikely to 
indicate clinical risk because they occurred at a drug exposure that was 15-fold higher, by AUC, 
than the human exposure at the maximum recommended human dose of 2 mg/kg every 2 weeks 
and were accompanied by maternal hyperphosphatemia and placental mineralization. Currently, 
Women of child-Bearing Potential (WOCBP) will be consented to receive pregnancy testing 
prior to burosumab initiation and at intervals throughout the trial and required to utilize 
contraception and agree to avoid pregnancy during the experimental treatment. There is no 
information regarding the presence of burosumab in human milk, or the effects on milk 
production or the breastfed infant. Women who are breastfeeding will therefore be excluded 
from participating in this study. 
Ectopic Mineralization 
In rabbits and cynomolgus monkeys, ectopic mineralization in multiple tissues and organs was 
observed at doses of burosumab-twza that resulted in supra-physiologic serum phosphate levels. 
In a study in wild type and hypophosphatemic Hyp mice, a murine model of XLH, ectopic 
mineralization was markedly less in Hyp mice. In clinical trials of XLH and TIO no clinically 
meaningful changes related to potential ectopic mineralization were observed. Although ectopic 
mineralization is a known risk related to XLH disease, and is exacerbated by the current standard 
of care consisting of oral phosphate and/or active vitamin D supplementation, burosumab does 
not appear to be associated with progression of cardiac or renal ectopic mineralization beyond 
the natural course of pre-existing disease. 
Hyperphosphatemia 
Increases in serum phosphate to above the upper limit of normal may be associated with an 
increased risk of nephrocalcinosis. For this reason, dose interruption and/or dose reduction may 
be required based on a patient’s serum phosphate. In clinical trials of TIO, 7% of patients 
experienced events of hyperphosphatemia, which were managed with dose reduction. In the double- 
blind period of Study 4 in patients with XLH, 6% of patients in the treatment group experienced 
hyperphosphatemia, which was managed with dose reduction. A single patient required a second 
dose reduction for continued hyperphosphatemia. To date, no dose-limiting toxicity of 
hyperphosphatemia (ie, a serum phosphate value of ≥ 6.5 mg/dL) has been seen in the pediatric 
studies of burosumab in XLH. 
Burosumab Effects on FD Lesion Activity 
There are no known risks of burosumab on FD lesion growth or metabolic activity. However, 
because FD is a benign neoplastic process, it is important to consider potential metabolic effects 
of any novel therapy. Burosumab does not have tumoricidal activity, and the natural history of 
FD lesions is to progress slowly. Reports of lesion progression may be seen, and therefore lesion 
metabolic activity will be monitored. 
Alternative Therapies to Burosumab for Patients with FD and FGF23 excess 

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Should patients elect not to participate in the study, they may be treated with oral active vitamin 
D analogs (calcitriol or alfacalcidiol) in combination with supplemental phosphate, termed 
conventional therapy. This approach is the current mainstay of treatment in patients with FD. 
Because FGF23 impairs 1α-hydroxylase activity, administration of active vitamin D analogs is 
necessary to maintain mineral metabolism and prevent secondary hyperparathyroidism. 
However, because these analogs increase calcium absorption, they carry a dose-related risk of 
hypercalciuria, nephrocalcinosis, and nephrolithiasis [13 14]. Oral phosphate supplements are 
short-acting and typically require administration 3-5 times daily, making adherence to therapy 
challenging. They are also associated with often dose-limiting gastrointestinal irritation [13 14]. 
Conventional therapy may partially ameliorate the metabolic effects of excess FGF23, however 
dose-related toxicities make normalization of serum phosphate an impractical goal, placing 
patients at risk for complications of persistent hypophosphatemia. 
Potential Risks Associated with Study Procedures 
Multiple blood and urine collections will occur introducing known common risks (discomfort, 
bruising) for blood draws and/or intravenous catheter placement introducing smaller risks of 
complications including fainting (usually a vasovagal response to sight or insertion of needles) or 
inflammation of the insertion site (including potentially pain and swelling) and the potential for 
infection or venous thrombosis. 
Bone biopsies in adult subjects may cause discomfort and pain for several days and can be 
treated safely with acetaminophen or more potent analgesics as needed. Bleeding and infection at 
the site of biopsy are possible but rare. Subjects may experience some transient anesthesia- 
related symptoms such as nausea, vomiting, decreased appetite, fatigue, and decreased blood 
pressure. Subjects may undergo a routine pre-anesthesia consult and be asked to sign a separate 
surgical consent form prior to the procedure. Only biopsies judged to be minimally invasive 
according to the judgement of the PI and surgeon will be performed. A bone biopsy will not be 
done if there is no site containing FD that allows a minimally invasive procedure with minimal 
risk of fracture. 
At baseline and 48 weeks the following radiologic procedures will be performed: 1) 18Sodium 
fluoride-PET/CT scan to evaluate metabolic activity of FD lesions, 2) skeletal survey to include 
x-rays of the arms, legs, pelvis, skull, and lateral spine to evaluate for skeletal deformities and 
metaphyseal irregularities, and 3) CT-guided bone biopsy (adults with capacity to consent only). 
This radiation exposure is not necessary for medical care and is for research purposes only. The 
effective dose that participants will receive from participation in this research study is 2.1 rem 
for adults with capacity to consent; 1.7 rem for adults without capacity to consent, 1.8 rem for 
children ages 4-17; and 0.6 rem for children ages 1-4. 
2.3.2 Known Potential Benefits 
There are no known definitive benefits of burosumab in the target population of patients with FD 
and FGF23-mediated hypophosphatemia. However, potential benefits may be inferred from 
studies of XLH and TIO, which share excess FGF23 production as a common etiology. In 
clinical trials of XLH, burosumab achieved normalization of serum phosphate without increasing 
urinary calcium levels, drastically reducing the risk of renal complications. Benefits of phosphate 
normalization included improved skeletal mineralization, as evidenced by radiographic 
improvement in rachitic features, and improved histomorphometric markers on transiliac bone 

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biopsies. In a child with FD who was unable to be managed with conventional therapy, 
clinically-indicated burosumab treatment was associated with marked improvements in serum 
phosphate and other metabolic indices [15]. As a once to twice monthly injection, burosumab has 
the benefit of markedly superior convenience compared to conventional therapy, which requires 
oral medications 3-5 times daily. Burosumab is also better-tolerated than conventional therapy, 
without the frequent dose-limiting gastrointestinal side effects. 
2.3.3 Assessment of Potential Risks and Benefits 
Taken together, available data support investigation of burosumab as a potential therapy targeted 
to excess FGF23 production in patients with FD. Current standard of care, which includes oral 
phosphate and active vitamin D supplementation, is complicated by an undesirable safety and 
tolerability profile, resulting in suboptimal therapeutic effects. Because FD tissue is inherently 
poorly mineralized and structurally unsound, patients are at extremely high risk for fractures and 
progressive deformities; these complications occur with increasing frequency and severity in the 
setting of hypophosphatemia [2-4]. Burosumab is the first therapy that offers the possibility of 
normalizing serum phosphate in patients with FD. 
The study is designed to minimize known potential risks (as described above) while maximizing 
therapeutic treatment to increase the probability of establishing a definitive proof-of-concept of 
the potential utility of burosumab as a treatment for FGF23-mediated hypophosphatemia in 
patients with FD. 
3 
OBJECTIVES AND ENDPOINTS 
 
OBJECTIVES 
ENDPOINTS 
JUSTIFICATION FOR 
ENDPOINTS 
Primary 
Evaluate the efficacy of 
burosumab to normalize 
serum phosphate levels 
in subjects with FD and 
FGF23-mediated 
hypophosphatemia at 48 
weeks 
The proportion of subjects achieving serum 
phosphate levels within the target range (Z-score 
-1 to +2) at Week 48 
Serum phosphate is the 
primary driver of skeletal 
complications in patients 
with FGF23-mediated 
hypophosphatemia and has 
been correlated with poor 
clinical outcomes in patients 
with FD 
Secondary 
Evaluate the efficacy of 
burosumab to normalize 
serum phosphate levels 
in subjects with FD and 
FGF23-mediated 
hypophosphatemia at 24 
weeks 
Proportion of subjects achieving serum 
phosphate levels within the target range (Z-score 
-1 to +2) at Week 24 
Serum phosphate is the 
primary driver of skeletal 
complications in patients 
with FGF23-mediated 
hypophosphatemia and has 
been correlated with poor 
clinical outcomes in patients 
with FD 

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OBJECTIVES 
ENDPOINTS 
JUSTIFICATION FOR 
ENDPOINTS 
Evaluate the safety and 
tolerability of burosumab 
in patients with FD 
Adverse events and clinical safety laboratory 
tests for up to 48 weeks 
Safety endpoints for 
expected and unexpected 
adverse events 
Evaluate the effect of 
burosumab on increasing 
serum phosphate and 
additional mineral 
markers 
Change and percent change from baseline to 
post-baseline visits in serum phosphate, serum 
1,25(OH)2D, ratio of renal tubular maximum 
reabsorption rate of phosphate to glomerular 
filtration rate (TmP/GFR) 
Safety endpoint for 
monitoring metabolic impact 
of burosumab in patients 
with FD 
Evaluate the impact of 
burosumab on FD lesion 
activity 
• Change in FD lesion activity using 18F-NaF 
PET/CT total lesion activity from baseline to 
48 weeks 
• Change and percent change in serum bone 
turnover markers, including procollagen 1 N- 
terminal propeptide (P1NP), beta crosslaps C- 
telopeptides (CTX), osteocalcin, and bone- 
specific alkaline phosphatase from baseline to 
48 weeks. 
• Change in FD lesion histology and cell 
proliferation as assessed by minimally invasive 
bone biopsies from baseline to 48 weeks 
(adults with capacity to consent only) from 
baseline to 48 weeks 
• Skeletal changes assessed on skeletal survey at 
baseline and 48 weeks. 
Safety endpoints to 
determine if burosumab 
impacts metabolic activity of 
FD lesions, which are a 
benign neoplastic process 
Evaluate the effect of 
burosumab on functional 
parameters 
Change from baseline to 48 weeks in: 
• Muscle strength 
• Range-of-motion 
• Walking speed (9-minute walk) 
Outcome measures that 
reflect activities of daily 
living 
Evaluate the effect of 
burosumab on pain and 
health-related quality of 
life 
Change from baseline to 48 weeks in patient 
reported outcomes measures: 
• SF36: adults 
• SF10: children 
• PROMIS Pain Intensity: Pediatric and Parent 
Proxy version 1.0, Adult version 2.0 
• PROMIS Pain Interference: Pediatric and 
Parent Proxy v 2.0, Adult v 1.1 
• PROMIS Mobility: Pediatric and Parent Proxy 
version 2.0, Adult Mobility Lower Extremity v 
1.0 
• PROMIS Fatigue: Pediatric and Parent Proxy v 
2.0, Adult FACIT 13a v1.0 
• Activities of Daily Living Questions: adults 
and children 
Outcome measures to 
determine pain and health- 
related quality of life 
4 
STUDY DESIGN 

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4.1 
Overall Design 
This is a single center, single-arm, open-label study to evaluate the efficacy and safety of 
burosumab treatment for FGF23-mediated hypophosphatemia in patients with FD/MAS. All 
subjects will be co-enrolled and screened through Screening and Natural History protocol 98-D- 
0145, a longstanding natural history study of FD/MAS protocol 98-D-0145. Up to 15 subjects 
will be enrolled, with the goal of a minimum 10 subjects receiving 48 weeks of burosumab 
treatment with week 50 for a final adverse event review. Research activity will be conducted at 
the NIH Clinical Center, with outpatient laboratory monitoring and burosumab self- and/or 
caregiver administration between NIH visits. Study subjects will be evaluated weekly on weeks 
1-4 and then every two weeks for weeks 6-50. 
4.2 
Scientific Rationale for Study Design 
An open-label study is proposed because: 1) the target population for this intervention is 
extremely small, making sufficient recruitment for a larger placebo-controlled study infeasible. 
FD/MAS is estimated to occur in approximately 1/100,000 – 1/1,000,000 individuals, and 
patients with clinically significant hypophosphatemia comprise only 15-30% of the overall 
FD/MAS population. 2) The primary endpoint of serum phosphate is an objective, quantifiable, 
and well-established surrogate marker that is relatively resistant to outcome assessment bias. 3) 
Burosumab has been well-studied in phase 2 and 3 studies in other conditions and has an overall 
well-established safety profile. The current study design is well-equipped to capture potential 
adverse effects that are specific to the FD/MAS population. 
4.3 
Justification for Dose 
Dosing for pediatric and adult subjects will be based on current FDA-approved regimens for 
XLH and TIO. Doses will be adjusted to target a serum phosphate level between -1 and +2 
standard deviations for age and sex. The justification for targeting a mid-high normal phosphate 
level is based on the following rationale: FD bone is inherently structurally unsound and poorly 
mineralized, and patients with FD have an overall high prevalence of skeletal morbidity 
compared to other FGF23 excess disorders. Even mild degrees of hypophosphatemia have been 
associated with increased fractures and deformities in patients with FD [1-4]. It is therefore 
feasible that patients with FD may experience clinical benefit from maintaining a higher 
therapeutic target for serum phosphate levels. The current study provides an important 
opportunity to investigate the safety and efficacy of this approach in patients with FD and is 
supported by the well-established and favorable safety profile of burosumab in phase 2 and 3 
studies. 
5 
STUDY POPULATION 
5.1 
Inclusion Criteria 
In order to be eligible to participate in this study, an individual must meet all of the following 
criteria: 
1. Confirmed diagnosis of fibrous dysplasia 
2. Serum phosphate <10th percentile for age and sex, AND intact serum FGF23 ≥30 
pg/mL[16] 
3. Age ≥1 year 
4. Provision of signed and dated informed consent/assent form 

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5. Stated willingness of subject or Legally Authorized Representative (LAR) to comply 
with all study procedures and availability for the duration of the study 
6. For females of reproductive potential: agreement to use highly effective contraception for 
during study participation. Highly effective contraception methods include: 
• Total abstinence (when this is in line with the preferred and usual lifestyle of the 
participant). Periodic abstinence (e.g., calendar, ovulation, symptothermal, post- 
ovulation methods) and withdrawal are not acceptable methods of contraception 
• Female sterilization (have had surgical bilateral oophorectomy with or without 
hysterectomy) or tubal ligation at least six weeks before taking study treatment. 
• Male sterilization (at least 6 months prior to screening). For female participants on the 
study the vasectomized male partner should be the sole partner for that participant. 
• Combination of the following (a+b or a+c, or b+c): 
a. Use of oral, injected or implanted hormonal methods of contraception or other 
forms of hormonal contraception that have comparable efficacy (failure rate 
<1%), for example hormone vaginal ring or transdermal hormone contraception 
b. Placement of an intrauterine device (IUD) or intrauterine system (IUS) 
c. Barrier methods of contraception: Condom or Occlusive cap (diaphragm or 
cervical/vault caps) with spermicidal foam/gel/film/cream/vaginal suppository 
7. For males of reproductive potential: use of condoms or other methods described above to 
ensure effective contraception with partner 
8. Minimum body weight of 7.5 kilograms 
5.2 
Exclusion Criteria 
An individual who meets any of the following criteria will be excluded from participation in this 
study: 
1. Pregnancy or lactation 
2. Known allergic reactions to burosumab or drug component 
3. Treatment with another investigational drug within 30 days of screening 
4. Treatment with burosumab within 30 days of screening 
5. Have any condition which in the opinion of the PI could present a concern for subject 
safety or difficulty with data interpretation 
6. Severe renal impairment or end stage renal disease, defined as: pediatric patients with 
estimated glomerular filtration rate (eGFR) 15 mL/min/1.73m2 to 29 mL/min/1.73m2 or 
end stage renal disease (eGFR < 15 mL/min/1.73m2), adult patients with creatinine 
clearance (CLcr) 15 mL/min to 29 mL/min or end stage renal disease (CLcr < 15 
mL/min) 
5.3 
Inclusion of Vulnerable Participants 
5.3.1 Children 
Children ≥1 year will be included in this study. Burosumab has been well-studied in children 
with good safety and tolerability in phase 2 and 3 studies. Children with FD have higher 
incidence of hypophosphatemia compared to adults [17], and are at increased risk for growth- 
related and skeletal complications. 
5.3.2 Adults who Lack Capacity to Consent to Research Participation 

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Adults who lack capacity to consent may be included in this study. Due to the likelihood of 
direct benefit from burosumab, and the favorable safety profile of burosumab in phase 2 and 3 
studies, exclusion of this population is not appropriate. Adults who lack capacity to consent will 
be excluded from pre- and post-treatment bone biopsies, which entail more than minimal risk 
without the possibility of direct benefit. 
For adult subjects, the study team will do a clinical assessment to determine if they have 
capacity. In situations where the clinical assessment determines that the capacity is in question, 
an assessment by ACAT (Ability to Consent Assessment Team) will be initiated. In the situation 
where the subject is known not to have capacity, this study will allow a Legally Authorized 
Representative (LAR) to sign consent providing the legal paperwork is filed with the Admissions 
Department per policy (i.e., legal guardianship, durable power of attorney, next of kin, etc). 
Oversight for the provisions of protection for adults unable to consent will be informed by the PI. 
The PI will be responsible for proper implementation of the HRPP Policy 403 - Research with 
Subjects Lacking Capacity to Consent. 
5.4 
Inclusion of Pregnant Women, fetuses or neonates 
Not applicable 
5.5 
Lifestyle Considerations 
Subject will need to commit weekly and bi-weekly research procedures as well as contraception 
requirements. 
5.6 
Screen Failures 
Screen failures are defined as subjects who consent to participate in the clinical trial but are not 
subsequently assigned to the study intervention or entered in the study. A minimal set of screen 
failure information is required to ensure transparent reporting of screen failure participants, to 
meet the Consolidated Standards of Reporting Trials (CONSORT) publishing requirements and 
to respond to queries from regulatory authorities. Minimal information includes demography, 
screen failure details, eligibility criteria, and any Serious Adverse Event (SAE). 
Individuals who do not meet the criteria for participation in this trial (screen failure) because of 
an insufficiently low serum phosphate or low FGF23 level may be rescreened up to 3 times. 
Rescreened individuals should be assigned the same subject number as for the initial screening. 
5.7 
Strategies for Recruitment and Retention 
Subjects will be recruited from the existing cohort of subjects enrolled in the protocol, Screening 
and Natural History of Patients with Polyostotic Fibrous Dysplasia and the McCune-Albright 
Syndrome (98-D-0145), and new referrals. All potentially eligible subjects enrolled onto 
protocol 98-D-0145 will be invited to participate in the burosumab study. The study will also be 
posted on ClinicalTrials.gov. Additional recruitment may proceed through referrals from 
worldwide clinical and research experts involved in this specialized area of mineral metabolism. 
Outreach through patient advocacy organizations worldwide will also be pursued. Written flyers 
may be distributed at patient advocacy events. Subjects may be self‐referred and/or referred by 
the Patient Recruitment and Public Liaison Office however, prior to enrollment onto the 
burosumab study all subjects will need to be enrolled and screened through protocol 98-D-0145. 
5.7.1 Costs 

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Subjects will not be billed for any research or related clinical care that participants will receive at 
the NIH Clinical Center for this study. The NIH Clinical Center will provide short-term medical 
care for any injury resulting from participation in this clinical trial. 
5.7.2 Compensation 
There will be no financial compensation given for participation in this study. Air/train/bus travel 
will be arranged by the NIH travel agency unless there are extenuating circumstances requiring 
the participant to book his/her own travel. For minor subjects and adults who lack capacity for 
consent, travel and Children’s Inn/hotel accommodation will also be provided for 1 parent or 
LAR. Miscellaneous out-of-pocket travel expenses (e.g., baggage receipts, airport parking, taxis) 
will be reimbursed if a receipt is provided. Subjects traveling by car from > 50 miles will be 
reimbursed mileage per NIH policies. Subject copays or co-insurance for local laboratories will 
be paid or reimbursed if an invoice or receipt is provided. 
6 
STUDY INTERVENTION 
6.1 
Study Interventions Administration 
This is an open-label study of burosumab. All subjects will receive burosumab for 48 weeks 
according to regimens described in the Section 6.1.2, Dosing and Administration. 
6.1.1 Study Intervention Description 
Burosumab is supplied in sterile, preservative-free, clear to slightly opalescent and colorless to 
pale brown-yellow solution in single-dose vials containing 30 mg/mL concentrations. 
Burosumab should be securely stored at 2 to 8°C and protected from light. It should not be 
frozen. Burosumab will be administered subcutaneously without dilution in the abdomen, upper 
arm, or thigh. The site of injection will be rotated. No more than 1.5 mL will be administered in 
a single injection. If a subject needs more than 1.5 mL per administration, multiple injections 
must be administered, and a different site must be used for each injection. 
6.1.2 Dosing and Administration 
Burosumab initiation for pediatric and adult subjects will be based on currently approved 
regimens for XLH and TIO. 
For pediatric subjects (age < 18 years) who weigh less than 10 kg, the starting dose is 1 mg/kg of 
body weight, rounded to the nearest 1 mg, administered every 2 weeks. For pediatric subjects 
who weigh 10 kg and greater, the starting dose regimen is 0.8 mg/kg of body weight, rounded to 
the nearest 10 mg, administered every 2 weeks. The minimum starting dose is 10 mg up to a 
maximum dose of 90 mg. For adults (age 18 years and older) the starting dose regimen is 0.5 
mg/kg body weight, rounded to the nearest 10 mg up to a maximum dose of 90 mg, administered 
every 4 weeks. 
After burosumab administration, doses will be titrated in an effort to achieve a target fasting peak 
serum phosphate level between –1 and +2 standard deviations for age and sex (Table 5). If the 
subject’s peak serum phosphate level at week 2 remains below the target range, the subject’s 
dose may be increased at week 4 by 0.2 to 0.5 mg/kg at the discretion of the Investigator. Doses 
will then continue to be titrated in increments of 0.2 to 0.5 mg/kg at 4-week intervals in 
individual subjects to achieve the target peak serum phosphate range. If the target range is not 
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intervals at the discretion of the PI and adjusted in increments of 0.2 to 0.5 mg/kg to a maximum 
dose of 90 mg every 2 weeks. 
Table 5. Burosumab Target Phosphate Ranges for Pediatric and Adult Subjects 
 
Age (years) 
Normal Phosphate 
Range (mg/dL) 
Target Peak Serum Phosphate Range 
(Z-score –1 to +2; mg/dL) 
1 to <5 
4.3 - 6.8 
4.9 - 6.8 
5 to <13 
4.1 - 5.9 
4.6 - 5.9 
13 to <16 (girls) 
3.2 - 5.5 
3.8 - 5.5 
13 to <16 (boys) 
3.5 - 6.2 
4.2 - 6.2 
16-18 
2.9 – 5 
3.4 - 5 
>18 
2.5 - 4.5 
3 - 4.5 
From: summary of age and sex-partitioned reference intervals from the CALIPER study, 
including thousands of healthy children and adolescents from a multiethnic population and 
measured using the Abbot Architect analyzer [18]. 
Following this initial dose titration phase, doses may be titrated at later weeks at the discretion of 
the PI, if there are concerns about safety, suboptimal efficacy, or if a subject has not yet achieved 
the target range of serum phosphate. To optimize serum phosphate levels throughout the dose 
cycle, Investigators may increase the dose of burosumab in 0.5 mg/kg increments in those 
subjects whose trough serum phosphate level (just prior to the next dose) is below the lower limit 
of the target range on 2 consecutive measurements performed at 4-week intervals (Table 6). 
Table 6. Burosumab Dose Titration Scheme 
 
Study Week 
Serum 
Phosphate 
Level Z-score 
1
Dose Adjustment 
Week 2 
Less than –1 
Increase the dose by 0.2 to 0.5 mg/kg at next dose 
Week 2 6, 10 (adults) 
Week 1, 2, 3 
(pediatrics) 
> +2 3 
Decrease the dose by 0.2 to 0.5 mg/kg 
Weeks 4, 8, 12, 16, 20, 
24, 28, 32, 36, 40, 44 
Less than –1 2 
Increase the dose by 0.2 to 0.5 mg/kg 
–1 to +2 
Continue the current dose 
> +2 3 
Skip dose 

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1 See Table 5 for target phosphate levels according to age and sex-adjusted Z-scores 
2 If phosphate levels are below –1 standard deviation on 2 consecutive measurements, the 
burosumab dose may be increased by 0.5 mg/kg 
3 If phosphate is Z-score > +2, withhold the next dose and reassess the serum phosphate level in 
2 weeks. Once serum phosphate is in target range or less than Z-score –1, treatment may be 
restarted at 0.2 mg/kg less than prior administered dose. If more than 2 sequential phosphate 
measurements are > +2 Z-score range, the patient may be considered for study discontinuation. 
6.1.2.1 Dose Limiting Toxicity 
A dose limiting toxicity is defined as the occurrence of any of the following: 
• A Grade ≥ 3 toxicity that is probably or possibly related to the investigational product, 
defined according to the Common Terminology Criteria for Adverse Events (CTCAE) 
Version 5.0. 
• A confirmed serum phosphate level of ≥ 8 mg/dL for pediatric subjects, or ≥ 6.5 mg/dL 
for adult subjects (defined as hyperphosphatemia) at any time after dosing. 
If a subject experiences a dose limiting toxicity, the planned dosing for that subject will 
be evaluated by the Investigators. The outcome of this investigation will determine the 
subject’s continuation or withdrawal from the study, as described in the Section 
Discontinuation of Study Intervention. 
The following laboratory abnormalities will necessitate discontinuation of study drug: 
• Documented decline in estimated glomerular filtration rate (eGFR) to <30 
mL/min/1.73m2 for pediatric patients, or <30 mL/min for adults 
6.1.2.2 Dose Modifications 
See the Section 6.1.2, Dosing and Administration for dose modification criteria in response to 
serum phosphate. 
6.1.2.3 Drug Administration 
For the initial NIH visit, the NIH pharmacy will dispense the burosumab vial(s) directly to the 
NIH Patient Care Unit responsible for administering the drug. Subjects and/or caregivers will 
receive injection teaching from a study team member at the initial NIH visit, which will include 
verbal and written instructions (see Appendix 2). The subject and/or caregiver’s proficiency will 
be assessed by observation of injection of normal saline into a teaching model device. All home 
injections will be supervised by the study team via telehealth appointment. A study team member 
will travel to home sites for the second dose to observe patient home administration and verify 
proficiency and injection teaching and inspection of burosumab storage and handling at home. 
Subjects will receive an additional proficiency check and injection teaching at Week 24. If in the 
opinion of the PI, caregivers are not suitably proficient to administer injections, a study team 
member who is a licensed medical professional will travel to subject’s home location and 
administer the medication to prevent interruption of therapy. Subjects may also return to NIH for 
injections. Federal, state and local policies, procedures and regulations dictate practice related to 
the safe transportation of the medication and handling of waste in/from the subjects’ homes. For 

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subjects receiving home injections, the NIH Pharmacy will ship the study drug and supplies to 
the subject’s home. The drug will be shipped on ice, and subjects will be instructed to store the 
drug in a refrigerator until time of use. Subjects will also be instructed on safe disposal of 
needles after use. 
6.2 
Preparation/Handling/Storage/Accountability 
6.2.1 Acquisition and Accountability 
The site research pharmacist or delegated personnel will maintain an accurate record of the 
receipt of the burosumab (shipped by Kyowa Kirin), including the date and quantity received. In 
addition, an accurate drug disposition record will be kept that specifies the amount to be 
administered to each participant, the date of dispensation, and any amount returned. Subjects will 
be instructed to return any unused drug during the final study visit. This inventory record must 
be available for inspection at any time. The NIH pharmacy in collaboration with the PI is 
responsible for keeping accurate records of the amount of drug dispensed, returned and 
remaining at the conclusion of the study. 
6.2.2 Formulation, Appearance, Packaging, and Labeling 
Burosumab will be provided as a sterile, preservative-free, clear to slightly opalescent and 
colorless to pale brown-yellow solution. Single-dose vials will be dispensed in 10 mg/mL, 20 
mg/mL, and/or 30 mg/mL concentrations. Burosumab is manufactured by Kyowa Kirin, Inc, 
Bedminster, NJ, U.S. License No. 2077 
6.2.3 Product Storage and Stability 
Kyowa Kirin, Inc will provide drug supplies to the study center. Burosumab vials will be stored 
under refrigerated conditions at 36°F to 46°F (2°C to 8°C). Reuse of vials is not permitted after 
the seal is broken. The expiration date is labeled and use of burosumab after the expiration date 
is not permitted. 
6.2.4 Preparation 
Not applicable 
6.3 
Measures to Minimize Bias: Randomization and Blinding 
Not applicable 
6.4 
Study Intervention Compliance 
Outpatient burosumab administration will be directly observed and documented by a member of 
the study team via telehealth assessment. Participants will return any unused burosumab vials at 
their next designated NIH visit, which will be reviewed for accountability and an estimate of 
compliance. 
6.5 
Concomitant Therapy 
At screening and enrollment, the study staff at NIH will question each subject specifically on the 
use of all concomitant medications and record the medication, dosage, and duration of use in the 
appropriate CRF. In general, upon admission and throughout the study, site staff will monitor, 
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prescribe any concomitant medications or treatments deemed necessary to provide adequate 
supportive care. 
All subjects who are receiving conventional therapy at screening will be instructed to stop taking 
pharmacologic vitamin D metabolites or analogs (e.g., calcitriol, alfacalcidiol, doxercalciferol, 
and paricalcitol) and oral phosphate supplements on Week -2. These medications will remain 
prohibited throughout the conduct of the study. Any subject who resumes or requires the use of 
any of these medications will be discontinued from the study. Patient safety during this washout 
time period will be monitored and adverse events will be reported as described in Section 10.5. 
7 
STUDY INTERVENTION DISCONTINUATION AND PARTICIPANT 
DISCONTINUATION/WITHDRAWAL 
7.1 
Study Intervention Discontinuation 
Discontinuation from burosumab does not mean discontinuation from the study, and remaining 
study procedures should be completed as indicated by the study protocol. If a clinically 
significant finding is identified after enrollment (including, but not limited to changes from 
baseline), the investigator or qualified designee will determine if any change in participant 
management is needed. Any new clinically relevant finding will be reported as an adverse event 
(AE). 
The data to be collected at the time of study intervention discontinuation for subjects who 
prematurely discontinue burosumab will include the following, as described in detail in Section 
10.8: 
• NIH lab tests 
• Physical Medicine and Rehabilitation evaluation 
• Administration of questionnaires for patient-reported outcomes 
• Activities of Daily Living questionnaires 
Subjects are free to withdraw from participation in the study at any time upon request. 
An investigator may discontinue or withdraw a subject from the study for the following reasons: 
• Completion of study intervention 
• If any clinical adverse event (AE), laboratory abnormality, or other medical condition or 
situation occurs such that continued participation in the study would not be in the best 
interest of the participant 
• Investigator discretion 
• Positive pregnancy test 
• Subject unable to receive burosumab for 12 weeks 
7.2 
Participant Discontinuation/Withdrawal from the Study 
If subjects discontinue participation or are terminated early from the study, they should be 
converted back to their outpatient conventional therapy regimen of oral phosphate and active 
vitamin D analogs. Subjects will be instructed to undergo outpatient laboratory testing of their 
blood phosphate within 1-7 days of discontinuing study medication and to have those results sent 
to NIH investigators for review. A telephone contact should be arranged for the investigative 
staff to review the lab results and advise on optimizing their outpatient clinical management. 

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All subjects who received burosumab and terminated early from the study, regardless of cause, 
should undergo a 30-day (± 7 days) follow-up telephone call after the last dose of burosumab. 
The reason for early termination from the study will be reflected in the CRF. If a subject 
terminates early from the study because of an AE, the PI/study staff must record the AE as the 
reason for discontinuation. 
7.3 
Lost to Follow-up 
A subject will be considered lost to follow-up if he or she missed at least 3 documented phone 
calls, followed by no response after a registered letter to the participant’s last known mailing 
address is received. 
The following actions must be taken if a subject fails to return to the clinic for a required study 
visit: 
• The site will attempt to contact the subject and reschedule the missed visit and counsel the 
subject on the importance of maintaining the assigned visit schedule and ascertain if the 
subject wishes to and/or should continue in the study. 
• Before a subject is deemed lost to follow-up, the investigator or designee will make every 
effort to regain contact with the subject (where possible, 3 telephone calls and, if necessary, a 
certified letter to the subject’s last known mailing address or local equivalent methods). 
These contact attempts should be documented in the subject’s medical record or study file. 
• Should the subject continue to be unreachable, they will be considered to have withdrawn 
from the study with a primary reason of lost to follow-up. 
8 
STUDY ASSESSMENTS AND PROCEDURES 
8.1 
Screening Procedures 
Screening for this protocol will be done under protocol 98-D-0145 (NCT00001727). 
Screening process: 
New subjects participating in protocol 98-D-0145 will have an evaluation as part of that study to 
confirm the diagnosis of FD/MAS, obtain routine and bone-specific blood work (per that 
protocol) and to characterize the extent of disease. Subjects diagnosed with FD/MAS will be 
offered enrollment into the burosumab protocol. 
Subjects already enrolled into protocol 98-D-0145 with confirmed FD/MAS and 
hypophosphatemia will be offered enrollment into the burosumab protocol. If the subject is 
interested in enrollment and hasn’t had a recent visit for the 98-D-0145 protocol, the subject will 
be asked to come back to NIH for an evaluation to obtain an updated history, physical exam and 
blood work as part of protocol 98-D-0145. 
Identifiable subject data will be shared between protocol 98-D-0145 and this study. The data 
captured on 98-D-0145 that will be shared and used to demonstrate eligibility for this study 
includes the diagnosis of FD/MAS, results of laboratory, imaging and other measures that define 
and characterize the scope of the disease. The outcome results of the following procedures/tests 
from the protocol 98-D-0145 will be evaluated as screening tests to determine eligibility into the 
burosumab protocol: imaging studies, serum phosphate, and serum FGF23 levels. 

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Subjects who have lab work returned that fulfill all eligibility and no exclusion criteria will be 
scheduled for an NIH visit. Visits will be conducted in the NIH Clinical Center in the inpatient, 
day hospital, or clinic settings as appropriate. If the subject is eligible for the burosumab protocol 
based on the screening tests performed within protocol 98-D-0145 and is interested, the protocol 
will be explained to them and the consent process implemented. If willing to participate in the 
study, the subject or LAR will be asked to sign informed consent. Consent for participation in the 
burosumab protocol will be obtained before any study specific procedures are performed. If a 
subject declines to participate in the burosumab protocol, they have the option to remain in 
protocol 98-D-0145. 
8.2 
Study Evaluations & Procedures 
All subjects who are currently receiving active vitamin D analogs and oral phosphate 
supplements will be asked to discontinue these medications at week -2 prior to baseline visit. 
The following procedures and imaging assessments will occur according to Section 1.3, 
Schedule of Activities (SoA) in order to support determination of efficacy, as per the primary 
and secondary objectives: 
Serum phosphate concentrations: Samples will be collected and tests performed at the NIH 
Clinical Center. Between NIH visits, samples will be collected and evaluated at outpatient 
laboratories near subjects’ homes. 
Physical Medicine and Rehabilitation evaluation: 9-minute walk/run test (ambulatory 
patients), range-of-motion testing, activity of daily living assessment, and manual muscle testing. 
Standardized and validated measures of functional status used routinely by the Clinical Center 
Rehabilitation Department will be obtained. 
Administration of questionnaires for patient-reported outcomes 
Patients will be asked to complete questionnaires to assess change from baseline to 48 weeks in 
patient reported outcomes measures. Adults will be asked to complete the patient‑reported 36- 
item Short Form Health Survey (SF-36). Pediatric patients age 5-18 will be asked to complete 
the SF-10™ Child Health Survey. The following PROMIS questionnaires will be administered: 
• PROMIS Pain Intensity: Pediatric and Parent Proxy version 1.0 (children), Adult version 
2.0 (adults) 
• PROMIS Pain Interference: Pediatric and Parent Proxy v 2.0 (children), Adult v 1.1 
(adults) 
• PROMIS Mobility: Pediatric and Parent Proxy version 2.0 (children), Adult Mobility 
Lower Extremity v 1.0 (adults) 
• PROMIS Fatigue: Pediatric and Parent Proxy v 2.0 (children), Adult FACIT 13a v1.0 
(adults) 
Pediatric questionnaires will be administered to subjects age 8-17 years, and Parent Proxy 
questionnaires will be administered to caregivers of subjects age 7 years and younger. Parent 
Proxy questionnaires may be administered to caregivers of subjects age 8 years and older at the 
discretion of the PI if considered developmentally appropriate. 
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Patients and/or caregivers will be asked during the Baseline clinical visit to provide a list of 3 
activities of daily living that are affected by FD skeletal features at home or school/work (e.g., 
mobility, climbing stairs, dressing, playing with peers, catching a bus, etc) and to estimate the 
extent of impact upon their activity level (see Appendices). These activities will then be 
reassessed at Week 24 and Week 48 for the level of change since Baseline on the extent of the 
impact upon these 3 activities. 
8.2.2 Biospecimen Evaluations 
NIH lab tests: The following laboratory evaluations will be obtained and performed at the NIH 
Clinical Center according to Section 1.3, Schedule of Activities (SoA). For some tests, the NIH 
Clinical Center may contract and send samples to specialized outside laboratory facilities. 
• Serum sodium, potassium, chloride, bicarbonate, glucose, blood urea nitrogen, creatinine, 
albumin, total protein, calcium, magnesium, phosphate, parathyroid hormone, 25- 
hydroxyvitamin D, 1,25-dihydroxyvitamin D, aspartate aminotransferase, alanine 
aminotransferase, total bilirubin, alkaline phosphatase, bone-specific alkaline 
phosphatase, osteocalcin, procollagen type 1 N-terminal propeptide, Beta-CrossLaps C- 
telopeptides, intact FGF23, C-terminal FGF23, and TmP/GFR. 
• 24-hour urinary calcium, creatinine, phosphate. 
Outpatient lab tests: The following laboratory evaluations will be obtained at outside laboratory 
facilities close to subjects’ homes: 
• Serum calcium, phosphate, creatinine, alkaline phosphatase. 
• Random urine calcium, creatinine, phosphate. 
The following laboratory evaluations will be performed at BioAgilytix Labs, LLC and Toray 
Research Center, Inc, specialty lab services that have been previously contracted by Ultragenyx: 
• Anti-burosumab antibodies, and burosumab concentration. If anti-burosumab antibodies 
are detected, these samples will subsequently be evaluated for the presence of 
neutralizing antibodies. 
Clinical Safety lab tests: 
• Serum sodium, potassium, chloride, bicarbonate, glucose, blood urea nitrogen, creatinine, 
calcium, phosphate, aspartate aminotransferase, alanine aminotransferase, total bilirubin, 
alkaline phosphatase 
• Random urine calcium, creatinine, phosphate 
• Anti-burosumab antibodies, neutralizing antibodies (in samples with detectable anti- 
burosumab antibodies), and burosumab concentration 
The total amount of blood to be drawn over this study is 203 mL. The maximum amount drawn 
over an 8-week period is 67.5 mL. This is below the maximum safety threshold for adults of 550 
mL over an 8-week period determined by the NIH Clinical Center. Based on the minimum 
weight requirement for this study (7.5 kg), this corresponds to a maximum potential blood draw 
volume of 9 mL/kg over an 8-week period for pediatric patients. This is below the maximum 
safety threshold of 9.5 mL/kg over an 8-week period determined by the NIH Clinical Center. 

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The maximum amount of blood drawn in a single day will not exceed 5 mL/kg for pediatric 
subjects. Bone tissue from a minimally invasive biopsy pre- and post-treatment will be obtained 
in adult subjects at the NIH. Tissue will be limited to 1-4 cores from standard bone biopsy 
needles. 
8.2.3 Correlative Studies for Research/Pharmacokinetic Studies 
Not applicable 
8.2.4 Samples for Genetic/Genomic Analysis 
8.2.4.1 Description of the scope of genetic/genomic analysis 
Not applicable, genetic/genomic analysis will not be performed in this study. 
8.2.4.2 Description of how privacy and confidentiality of medical information/biological 
specimens will be maximized 
All subject data in this clinical trial will be anonymized using the same system, each subject’s 
identity will remain anonymous in the clinical trial database. 
The clinical trial database, which may be shared with appropriate regulatory agencies, in addition 
to access from the pharmaceutical collaborators and investigators, will contain 
clinical/demographic data on subject’s age, ethnicity, sex, diagnosis, treatment, response to 
treatment, adverse events as per the standards of human clinical research, however, all the data 
will be anonymized without any link to individual identifying information. 
8.2.4.3 Management of Results 
The results of all clinical documentation and laboratory data performed at the NIH Clinical 
Center will be available to subjects through the NIH online patient portal and through NIH 
medical records on request. Clinical documentation and laboratory data will be shared with 
subjects’ home clinicians on request. Subjects will be encouraged to inform their home clinicians 
about participation in the study, and the Investigators will maintain close communication with 
home clinicians regarding any clinically relevant issues. 
8.2.4.4 Genetic counseling 
Not applicable, genetic counseling will not be performed in this study. 
8.3 
Safety and Other Assessments 
8.3.1 Physical Examination 
At the times detailed in the Section 1.3, Schedule of Activities (SoA), subjects will undergo a 
complete physical examination (PE), which is to be completed by a physician or an appropriately 
trained health professional. Any abnormal physical examination finding that is deemed clinically 
important (i.e., is associated with symptoms and/or requires medical intervention) and is changed 
from baseline will be recorded as an AE as described in Section 8.4. 
8.3.2 Vital Signs 
Vital signs will be assessed in accordance with times and details indicated in the Section 1.3, 
Schedule of Activities (SoA). Any abnormal vital sign that is deemed clinically significant (i.e., 

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is associated with symptoms and/or requires medical intervention) will be recorded as an AE as 
described in Section 8.4. 
8.3.3 Clinical Laboratory Determinations 
Blood and urine samples for clinical laboratory tests will be collected at the times detailed in the 
Section 1.3, Schedule of Activities (SoA). Samples will be collected for evaluation of anti- 
burosumab antibodies at NIH visits according to the Section 1.3, Schedule of Activities (SoA). 
Samples will be sent to BioAgilytix Labs, LLC and Toray Research Center, Inc, specialty lab 
services that have been previously contracted by Kyowa Kirin to evaluate for the development of 
anti-burosumab antibodies, burosumab concentration, and neutralizing antibodies, respectively. 
At any time during the study, abnormal laboratory parameters which are clinically relevant (e.g., 
require dose interruption of study treatment, lead to clinical symptoms or signs, or require 
therapeutic intervention), whether specifically requested in the protocol or not, will be recorded 
on the Adverse Events eCRF page and defined according to the Common Terminology Criteria 
for Adverse Events (CTCAE) Version 5.0. 
Samples will be collected, processed, and stored according to the instructions provided in the 
Laboratory Manual. 
The investigator or qualified sub-investigator will review all laboratory results for clinical 
significance. Any laboratory result deemed clinically significant (i.e., is associated with signs 
and symptoms and/or requires medical intervention) will be recorded as an AE as described in 
Section 8.4. 
8.3.4 
18F-sodium fluoride PET/CT bone scan 
Because FD is a benign neoplastic process, 18F-NaF PET/CT scans will be performed at NIH 
visits on Weeks 0 and 48 to evaluate for any potential deleterious effects of burosumab on FD 
lesion activity. Subjects will receive intravenous 18F-Sodium Fluoride via a placed catheter. 
Images will be obtained 1 hour after injection and will last approximately 1 ½ hours. Only 
subjects who can hold still without requiring sedation will undergo scanning. 
8.3.5 Renal Ultrasound 
Renal ultrasounds to assess for nephrocalcinosis will be performed at NIH visits on Weeks 0 and 
48. 
8.3.6 Skeletal Survey 
Plain film x-rays of the arms, legs, pelvis, ribs, and lateral spine will be obtained at Weeks 0 and 
48 to evaluate for the development or progression of skeletal deformities, and to assess for 
rachitic metaphyseal changes in growing children. 
8.3.7 Bone Biopsy 
Percutaneous core needle bone biopsies will be performed in adult subjects with capacity to 
consent at Weeks 0 and 48. Because FD is a benign neoplastic process, biopsies will be 
performed to evaluate for any potential deleterious effects of burosumab on FD tissue. This will 
include evaluation of tissue histology for changes in cell proliferation and neoplastic bone 
content. The first biopsy will be performed prior to burosumab therapy (baseline) and the second 
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by a licensed, credentialed practitioner in Interventional Radiology or the operating room of the 
NIH Clinical Center under local anesthesia with sedation. The biopsies will be performed from 
areas containing FD. The PI and the surgeon will jointly determine which sites are to be 
biopsied. All subjects will be evaluated by an anesthesiologist, who will determine the level of 
anesthesia needed based on clinical evaluation of the patient and planned procedure. Only 
biopsies judged to be minimally invasive (i.e. percutaneous procedures that allow bone to be 
removed via a core needle) will be performed. A bone biopsy will not be done if there is no site 
containing FD that allows a minimally invasive procedure with minimal risk of fracture. 
8.4 
Adverse Events and Serious Adverse Events 
8.4.1 Definition of Adverse Event 
An adverse event (AE) is defined as any untoward medical occurrence associated with the use of 
a drug in humans, whether or not considered drug related (21 CFR 312.32 (a)). An AE can 
therefore be any unfavorable and unintended sign (including an abnormal laboratory finding, for 
example), symptom, or disease temporally associated with the use of a medicinal 
(investigational) product, whether or not related to the medicinal (investigational) products. 
Pre-existing diseases or conditions will not be considered AEs unless there is an increase in the 
frequency or severity, or a change in the quality, of the disease or condition. Worsening of a pre- 
existing condition is considered an AE. 
Any abnormal laboratory test results (hematology, clinical chemistry, or urine) or other safety 
assessments (e.g., vital sign measurements), including those that worsen from Screening/baseline 
that are felt to be clinically significant in the medical and scientific judgment of the Investigator 
are to be recorded as AEs. Elective surgeries to correct or prevent skeletal deformities are 
considered standard treatment for FD [19], and will not be reported as AE’s. These events will be 
recorded as part of the medical history at each NIH visit, according to the Schedule of Activities. 
8.4.2 Definition of Serious Adverse Events (SAE) 
A serious adverse event (SAE) is an AE that meets any of the following criteria in the view of 
either the Investigator, Ultragenyx, or Kyowa Kirin: 
• Death 
• Life-threatening 
− A life-threatening AE is an event that places the patient or subject at immediate 
risk of death. It does not include events that if it had occurred in a more serious or 
severe form might have caused death. For example, drug induced hepatitis that 
resolved without evidence of hepatic failure would not be considered life threatening 
even though drug induced hepatitis can be fatal. 
• Inpatient hospitalization or prolongation of existing hospitalization 
− Hospitalization is defined as a full admission to hospital for a period of 24 hours 
or longer for diagnosis and treatment. This includes prolongation of an existing 
inpatient hospitalization. Examples of visits to a hospital facility that do not meet 
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• Emergency room visits (that do not result in a full hospital admission) 
• Preplanned or elective procedures prior to study enrollment (e.g., outpatient 
surgery) 
• Protocol procedures 
− Hospitalization signifies that the subject has been detained (usually involving at 
least an overnight stay) at the hospital or emergency ward for observation and/or 
treatment that would not have been appropriate in the physician's office or 
outpatient setting. When in doubt as to whether 'hospitalization' occurred or was 
necessary, the AE should be considered serious. 
− AEs requiring hospitalization should be considered SAEs. Hospitalization 
planned prior to study enrollment (eg, for elective surgery or routine clinical 
procedures) that are not the result of AE (e.g., elective surgery for a pre-existing 
condition that has not worsened) need not be considered AEs or SAEs. If anything 
untoward is reported during the procedure, that occurrence must be reported as an 
AE, either 'serious' or 'nonserious' according to seriousness criteria described 
above. 
• Disability/Incapacity 
− An AE is disabling or incapacitating if it results in substantial and/or permanent 
disruption of the subject’s ability to carry out normal life functions. 
• Congenital anomaly/birth defect not present at screening 
• Important Medical Events that may not result in death, be immediately life- 
threatening, or require hospitalization may be considered serious when, based upon 
appropriate medical judgment, they may jeopardize the patient or subject and may 
require medical or surgical intervention to prevent one of the criteria listed in the 
definition. Examples of such events are: 
− Intensive treatment in an emergency room or at home for allergic bronchospasm 
− Blood dyscrasias that do not result in inpatient hospitalization 
− Development of drug dependency or drug abuse 
8.4.3 Classification of an Adverse Event 
8.4.3.1 Severity of Event 
The Investigators will provide an assessment of the severity of each AE by recording a severity 
rating on the appropriate AE reporting page of the participant’s CRF. The severity of all AEs 
will be graded using the Common Terminology Criteria for Adverse Events (CTCAE) version 
5.0. 
8.4.3.2 Relationship to Study Intervention 
All adverse events (AEs) must have their relationship to study intervention assessed by the 
investigator who examines and evaluates the subject based on temporal relationship and their 
clinical judgment and the information provided in the Reference Safety Information. Treatment- 

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related conditions must be distinguished from disease-related conditions. The degree of certainty 
about causality will be graded using the categories below. In a clinical trial, the study product 
must always be suspect. 
• Related: The available evidence suggests there is a reasonable possibility that the study 
drug caused the adverse. For example, a temporal relationship exists between the AE 
onset and administration of the study drug that cannot be readily explained by the 
subject’s clinical state, concurrent disease or concomitant therapies. ‘Reasonable 
possibility’ means there is evidence to suggest a causal relationship between the drug and 
the AE. 
• Not related: The available evidence suggests an unrelated AE is one for which there is 
not a reasonable possibility that the drug caused the AE. The adverse event is most likely 
related to factors other than the administration of the study drug. Such other factors may 
include the underlying disease state, comorbidities, an intercurrent illness, concomitant 
medication(s) or procedures. 
A causality assessment should include, for example, assessment of temporal relationship, 
physiologic plausibility, dechallenge/rechallenge information, association with (or lack of 
association with) underlying disease, and presence (or absence) of a more likely cause. The PI 
may change the causality assessment at any time based on new accumulated information. 
Note: The Investigator’s assessment of causality for individual AEs is part of the study 
documentation process and will be recorded in the CRF and SAE form, if applicable. AEs 
recorded without the Investigator’s assessment of the relationship to study drug will be followed 
up until causality is assigned. 
8.4.3.3 Expectedness 
An adverse event or suspected adverse reaction is considered “unexpected” if it is not listed in 
the investigator brochure or is not listed at the specificity or severity that has been observed or is 
not consistent with the risk information described in the general investigational plan. The 
sponsor will evaluate the available information and decide whether there is a reasonable 
possibility that the drug caused the adverse event and, therefore, that the event meets the 
definition of a suspected adverse reaction. The suspected adverse reaction will then be reported 
expeditiously in an IND safety report if it also meets the definitions of serious and unexpected 
(21 CFR 312.32(c)(1)(i)). 
8.4.4 Time Period and Frequency for Event Assessment and Follow-Up 
The occurrence of an adverse event (AE) or serious adverse event (SAE) may come to the 
attention of study personnel during study visits and interviews of a subject presenting for medical 
care, or upon review by a study monitor. 
All AEs including local and systemic reactions not meeting the criteria for SAEs will be captured 
on the appropriate case report form (CRF). Information to be collected includes event 
description, time of onset, clinician’s assessment of severity, relationship to study product 
(assessed only by those with the training and authority to make a diagnosis), and time of 
resolution/stabilization of the event. All AEs occurring while on study must be documented 
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Any medical condition that is present at the time that the subject is screened will be considered 
as baseline, recorded as patient medical history, and not recorded as an AE. However, if the 
subject’s condition deteriorates at any time during the study, it will be recorded as an AE. 
Changes in the severity of an AE will be documented to allow an assessment of the duration of 
the event at each level of severity to be performed. AEs characterized as intermittent require 
documentation of onset and duration of each episode. At each study visit, the investigator will 
inquire about the occurrence of AE/SAEs since the last visit. The study team will record all 
reportable events with start dates occurring any time after informed consent is obtained until 4 
weeks after the last burosumab dose. Events will be followed for outcome information until 
resolution or stabilization. 
8.4.5 Adverse Event Reporting 
Any untoward medical occurrences or unfavorable and unintended signs, symptoms, or diseases 
that occur in the pretreatment, treatment, or posttreatment period are to be considered AEs (and 
SAEs if appropriate), and consequently recorded and reported as such. 
Subjects are to be queried regarding any AEs or SAEs at the time of each vital sign assessment, 
as well as at each visit, according to the Schedule of Activities (Section 1.3). Subjects will be 
asked to volunteer information with a nonleading question such as, “How do you feel?” Study 
center personnel will then record all pertinent information in the subject’s CRF. 
All AEs and SAEs reported by the subject (or subject’s legal representative) or observed or 
otherwise identified by the investigator (or other study center personnel) at a defined study visit 
or during any communication with the subject (or subject’s legal representative) occurring 
outside a defined study visit (from the time the subject signs the ICF to 30 ± 7 days after the last 
dose of burosumab) must be documented. 
All AEs must be recorded on the appropriate AE reporting page of the subject’s CRF whether or 
not they are considered causally related to the burosumab. 
For every AE, the investigator must: 
• Provide an assessment of the severity, causal relationship to burosumab, and seriousness 
of the event (i.e., whether it is a SAE) 
• Document all actions taken with regard to burosumab 
• Detail any other treatment measures taken for the AE 
• Document resolution of the AE (with or without sequelae); ongoing; or lost to follow-up. 
8.4.6 Serious Adverse Event Reporting 
In consultation with the PI, a trained member of the study team will be responsible for conducting 
an evaluation of all adverse events and shall report the results of such evaluation to the NIH 
Institutional Review Board (IRB) as per Policy 801. 
All SAEs will be reported to the NIDCR Office of the Clinical Director within 7 days of 
investigator awareness. The study sponsor will be responsible for notifying the Food and Drug 
Administration (FDA) of any unexpected fatal or life-threatening suspected adverse reaction as 
soon as possible, but in no case later than 7 calendar days after the sponsor's initial receipt of the 
information. In addition, the sponsor must notify FDA and all participating investigators in an 
Investigational New Drug (IND) safety report of potential serious risks, from clinical trials or any 

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other source, as soon as possible, but in no case later than 15 calendar days after the sponsor 
determines that the information qualifies for reporting. 
8.4.7 Reporting of Serious Adverse Events to Kyowa Kirin Pharmacovigilance 
In addition to any IND reporting requirements to the FDA, all serious adverse events (regardless 
of causality) must be reported to Kyowa Kirin via a MedWatch 3500A Form or equivalent form 
within 24 hours of knowledge of the event to: drugsafety@kyowakirin.com. 
8.4.8 NIH Intramural IRB Reporting of IND Safety Reports 
Only IND Safety Reports that meet the definition of an unanticipated problem or is new 
information that might affect the willingness of subjects on the NIH study to enroll or remain in 
the study will need to be reported to the NIH Intramural IRB. 
8.4.9 Events of Special Interest 
Not applicable 
8.4.10 Reporting of Pregnancy and other Special Situations 
Pregnancies in subjects or partners must be reported within 24 hours of knowledge of 
investigator awareness to Kyowa Kirin at drugsafety@kyowakirin.com. The reporting period for 
pregnancies is the period from the signing of the ICF until 30 ± 7 days after the last dose of 
burosumab. Reported pregnancy of a subject or a subject’s partner, while participating in the 
study, will be monitored for the full duration and/or followed until the outcome of the pregnancy 
is known. In the event of a pregnancy in the partner of a subject, the Investigator should make 
every effort to obtain the female partner’s consent for release of protected health information. 
Pregnancies in subjects or partners will be reported to the NIDCR Office of the Clinical Director 
within 7 days of investigator awareness. 
In addition, the following other special situations arising with the use of burosumab whether or 
not associated with an adverse event must be reported to Kyowa Kirin 
drugsafety@kyowakirin.com within 24 hours of knowledge of the event: 
• Overdose, defined as a known deliberate or accidental administration of investigational 
drug, to or by a study subject, at a dose above that which is assigned to that individual 
subject according to the study protocol 
• Suspected or confirmed transmission of infectious agents via product (must always itself 
be considered an SAE) 
8.4.11 Safety Updates from Kyowa Kirin to NIH 
During the course of the study, Kyowa Kirin will report to the investigator any safety related 
major issues (issues potentially leading to major impact on the risk-benefit balance of a 
product/compound and/or on patients’ or public health including health hazard or lawsuits, 
which may require regulatory actions such as product recall, product withdrawals, removal of 
approved indications, failure to obtain product registration renewal due to safety reason, 
termination of studies, label changes, or prompt communication to patients and healthcare 
professionals) or any new information about the study product, that does not fall within the 
definition of an IND safety report, that poses a significant health or safety risk to study 

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participants or affects the willingness of study participants to continue their participation in the 
study. 
8.5 
Unanticipated Problems 
8.5.1 Definition of Unanticipated Problems (UP) 
Any incident, experience, or outcome that meets all of the following criteria: 
• Unexpected in terms of nature, severity, or frequency given (a) the research procedures 
that are described in the protocol-related documents, such as the Institutional Review 
Board (IRB)-approved research protocol and informed consent document; and (b) the 
characteristics of the participant population being studied; and 
• Related or possibly related to participation in the research (“possibly related” means there 
is a reasonable possibility that the incident, experience, or outcome may have been 
caused by the procedures involved in the research); and 
• Suggests that the research places participants or others (which many include research 
staff, family members or other individuals not directly participating in the research) at a 
greater risk of harm (including physical, psychological, economic, or social harm) than 
was previously known or expected. 
8.5.2 
Unanticipated Problem Reporting 
The investigator will report unanticipated problems (UPs) to the NIH Institutional Review Board 
(IRB) as per Policy 801. 
9 
STATISTICAL CONSIDERATIONS 
9.1 
Statistical Hypothesis 
This single-arm open-label trial is to gather preliminary information on the effectiveness and 
safety of burosumab in FD patients. Estimates for the primary and secondary endpoints will be 
provided. 
• Primary Endpoint: The proportion of subjects achieving serum phosphate levels within 
the target range (Z-score -1 to +2) at Week 48. 
• Secondary Endpoints: 
o Proportion of subjects achieving serum phosphate levels within the target range 
(Z-score -1 to +2) at Week 24 
o Adverse events and clinical safety laboratory tests for up to 4 weeks following the 
final burosumab dose (48 weeks for adults, 50 weeks for children). 
o Proportion of subjects achieving mean serum phosphate levels above the target 
range (Z-score >+2), as averaged across dose cycles between Baseline and Week 
48 
o Change and percent change from baseline to post-baseline visits in serum 
phosphate, serum 1,25(OH)2D, ratio of renal tubular maximum reabsorption rate 
of phosphate to glomerular filtration rate (TmP/GFR) 
o Change in FD lesion activity using 18F-NaF PET/CT total lesion activity from 
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o Change and percent change in serum bone turnover markers, including 
procollagen 1 N-terminal propeptide (P1NP), beta crosslaps C-telopeptides (CTX), 
osteocalcin, and bone-specific alkaline phosphatase from baseline to 48 weeks 
o Change in FD lesion histology and cell proliferation as assessed by minimally 
invasive bone biopsies from baseline to 48 weeks (adults with capacity to consent 
only) from baseline to 48 weeks 
o Change from baseline to 48 weeks in muscle strength, range-of-motion, and 
walking speed (9-minute walk) 
o Change from baseline to 48 weeks in patient reported outcomes measures: SF36 
(adults), SF10 (children), Brief Pain Inventory (adults and children), Brief Fatigue 
Inventory (adults and children) 
9.2 
Sample Size Determination 
For the primary endpoint, the proportion of subjects achieving serum phosphate levels within the 
target range (Z-score -1 to +2) at Week 48, we will use the Clopper-Pearson exact method to 
calculate the confidence interval of the proportion. Table 7 below shows different widths 
achieved assuming different true proportions. Calculations were done using the statistical 
software PASS (Power Analysis and Sample Size, NCSS). With a sample size of 10, we will be 
able to provide a two-sided 95% confidence interval (CI) with a width of no more than 0.44 
when the true proportion is 0.9 (which we expect to be most likely). A total of 15 subjects will be 
recruited to ensure that 10 of them will have at least 48 weeks of follow-up time. 
Table 7. Confidence interval widths achieved assuming different true proportions (N=10) 
 
True 
proportion 
0.5 
0.6 
0.7 
0.8 
0.9 
0.95 
CI width 
0.63 
0.62 
0.59 
0.53 
0.44 
0.38 
95% CI 
(0.19, 0.81) 
(0.26, 0.88) (0.35, 0.93) (0.44, 0.97) (0.55, 1) 
(0.62, 1) 
9.3 
Populations for Analyses 
• Safety Analysis Dataset: This will include participants who took at least one dose of 
burosumab. 
• Efficacy Analysis Dataset: This will include all participants who received at least one 
dose of burosumab and have sufficient post-baseline assessment data to enable analyses 
of study endpoints. For the proportions evaluated at week 48 (the primary endpoint and 
some secondary endpoints), subjects who have completed 48 weeks of therapy and 
returned for the week 48 assessment will be included in the analysis. 
9.3.1 Evaluable for toxicity 
All participants will be evaluable for toxicity from the time of their first treatment with 
burosumab. 
9.3.2 Evaluable for objective response 
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9.3.3 Evaluable Non-Target Disease Response 
Not applicable. 
9.4 
Statistical Analyses 
9.4.1 General Approach 
We will report summary statistics such as means, standard deviation, median and interquartile 
range for continuous variables, and frequencies and proportions for categorical variables. The 
strength of statistical evidence throughout the study will be assessed using point estimates, 
confidence intervals, together with p values in drawing conclusions. For this small disease 
population trial, we will make all efforts to minimize the occurrence of missing data. For 
longitudinal continuous data, linear mixed effects models will handle the missing data under the 
assumption that values are missing at random. All analyses will be conducted in SAS (version 
9.4, SAS Institute, Cary NC). 
9.4.2 Analysis of the Primary Endpoints 
The 95% Clopper-Pearson exact confidence interval will be calculated for the proportion of 
subjects achieving serum phosphate levels within the target range (Z-score -1 to +2) at Week 48. 
The primary endpoint will be evaluated in the Efficacy Analysis Dataset. 
9.4.3 Analysis of the Secondary Endpoint(s) 
The 95% Clopper-Pearson exact confidence interval will be provided for the proportions listed in 
the secondary endpoints. P-values will be calculated. This will be done in the Efficacy Analysis 
Dataset. If data is missing for categorical outcomes, it will be imputed by either carrying the last 
observation forward or assuming non-response. 
For change from baseline type of secondary endpoints, baseline scores and change over time 
scores will be summarized by mean, standard deviation, median, and interquartile range. Linear 
mixed models will be used to analyze the longitudinal change scores collected at multiple post 
baseline visits if normality assumption is met. The confidence interval will be calculated for 
change scores at Week 48 based on these models. P-values will be provided as well. All subjects 
with any data at post baseline visits will be included in these models. For outcomes variables that 
are collected only at Week 48 post baseline, a 95% confidence interval and the p value from the 
one‐sample t test will be reported for the change score (from baseline to Week 48) 
If the normality assumption is violated when fitting the linear mixed effects models to the raw 
data, other common transformation methods (such as log or square-root transformation will be 
explored. If no suitable transformation method is found, p-values will be reported by using the 
exact Wilcoxon signed rank test. 
9.4.4 Safety Analyses 
Adverse events will be coded as per the Common Terminology Criteria for Adverse Events 
(CTCAE) Version 5.0 and each AE will be counted once only for a given participant. The 
severity, frequency, and relationship of AEs to study intervention will be presented by System 
Organ Class (SOC) and preferred term groupings. Each AE will be report will include start date, 
stop date, severity, relationship, expectedness, outcome, and duration. Summaries of AEs, AEs 
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serious treatment-emergent AEs will be presented in a separate table. Safety analyses will be 
conducted in the Safety Analysis Dataset. 
9.4.5 Baseline Descriptive Statistics 
All baseline descriptive characteristics, including demographics, clinical, and laboratory 
variables will be summarized descriptively for the burosumab treated subjects. Descriptive 
statistics will include means, standard deviation, median and interquartile range for continuous 
variables, and frequencies and proportions for categorical variables. 
9.4.6 Planned Interim Analyses 
There is no planned interim analysis. 
9.4.7 Sub-Group Analyses 
Not applicable 
9.4.8 Tabulation of Individual Participant Data 
Not applicable 
9.4.9 Exploratory Analyses 
Not applicable 
10 REGULATORY AND OPERATIONAL CONSIDERATIONS 
10.1 Informed Consent Process 
10.1.1 Consent/Assent Procedures and Documentation 
Standard Consent Procedures: The informed consent document will be provided as a physical 
or electronic document to the subject or consent designee(s) as applicable for review prior to 
consenting. A designated study investigator will carefully explain, either in-person or remotely 
(e.g., via telephone or other NIH approved remote platforms used in compliance with policy, 
including HRPP Policy 303) the procedures and tests involved in this study, and the associated 
risks, discomforts, and benefits. In order to minimize potential coercion, as much time as is 
needed to review the document will be given, including an opportunity to discuss it with friends, 
family members and/or other advisors, and to ask questions of any designated study investigator. 
A signed informed consent document will be obtained prior to entry onto the study. 
The initial consent process as well as re-consent, when required, may take place in person or 
remotely (e.g., via telephone or other NIH approved remote platforms used in compliance with 
policy, including HRPP Policy 303) per discretion of the designated study investigator and with 
the agreement of the subject/consent designee(s). Whether in person or remote, the privacy of the 
subject will be maintained. When in person, consenting investigators and subject/consent 
designee, will be located in a private area (e.g., clinic consult room or private inpatient room). 
When consent is conducted remotely, the subject/consent designee will be informed of the 
private nature of the discussion and will be encouraged to relocate to a more private setting if 
needed. If consent is obtained remotely, subjects and investigators will view individual copies of 
the approved consent document at their respective locations. 
For electronic consent: The study team will confirm with the subject that they are comfortable 
using the electronic consenting before proceeding with obtaining consent. If not, other methods 

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will be utilized. When an electronic document with a digital signature is used for the 
documentation of consent, this study will use the iMedConsent™ platform which is 21 CFR, Part 
11 compliant to obtain the required signatures. During the consent process, subjects/LARs and 
investigators will view the same approved consent document simultaneously in their respective 
locations. The identity of the subject will be determined by verifying a government issued 
identification card via the telehealth platform, prior to obtaining the signature. Electronic 
signature with a timestamp will be provided by required parties through system prompts. Once 
the completed consent has been saved, it will post to CRIS within a few minutes. All consents 
completed in iMedConsent™ will post to both the Documents tab and the Consents tab in CRIS. 
If the research participant has a FollowMyHealth™ account a copy of the completed consent will 
be posted to their account within two business days. The study team will provide the research 
participant with a printed copy of the signed document. 
Assent Procedures for Minors: Where deemed appropriate by the clinician and the child’s 
parent(s) or guardian, the child will also be included in all discussions about the trial and age- 
appropriate language will be used to describe the procedures and tests involved in this study, 
along with the risks, discomforts and benefits of participation. Assent procedures for minors may 
take place in person or remotely (e.g., via telephone or other NIH approved remote platforms 
used in compliance with policy, including HRPP Policy 303). Children under the age 7 will not 
be required to provide assent as they typically do not have the ability to fully understand the 
nature of research. Verbal assent will be obtained from minor participants age 7-12 who are old 
enough to understand the nature of the study and its implications but are too young to provide a 
signature. Written assent will be obtained from minors age 13 years and older whenever possible 
using a similar procedure as outlined in the above Standard Consent Procedures section. Dissent 
will be respected in children of all ages. The consent/assent process will be documented in the 
child’s medical record, including the assessment of the child’s ability to provide assent (verbal 
versus written) as applicable. If any enrolled subjects reach the age of 18 while enrolled in the 
trial, they will be contacted to determine whether they wish to continue on the trial and informed 
consent will be obtained from them at that time. 
Privacy measures as described in the section titled Confidentiality and Privacy will be 
implemented for all minor in-person and remote consent process. During the remote consent 
process, minors with their parents/legal guardians and designated study investigators will view 
individual copies of the approved consent document at their respective locations. The assent 
process will be documented in the medical record. 
Consent Procedures from Parents/Legal Guardians for Minors: Parental permission will be 
obtained in line with NIH policies regarding child custody. 
10.1.2 Consent for minors when they reach the age of majority 
When a pediatric subject reaches age 18, continued participation (including ongoing interactions 
with the subject or continued analysis of identifiable data) will require that consent be obtained 
from the now adult with the standard protocol consent document to ensure legally effective 
informed consent has been obtained. 
If reconsent is not feasible, we request waiver of informed consent to continue to use data and/or 
specimens for those individuals who become lost to follow up or who have been taken off study 
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Requirements for Waiver of Consent consistent with 45 CFR 46.116(f)(3): 
(1) The research involves no more than minimal risk to the subjects. 
a. Analysis of samples and data from this study involves no additional risks to 
subjects. 
(2) The research could not practicably be carried out without the waiver or alteration. 
a. Considering the length of time between the minor’s last contact with the 
research team and their age of majority, it will likely be very difficult to locate 
them again. A significant reduction in the number of samples analyzed is 
likely to impact the quality of the research. 
(3) As the research involves using identifiable private information or identifiable 
biospecimens, the research could not practicably be carried out without using such 
information or biospecimens in an identifiable format. 
a. Though the purpose of future studies cannot yet be known, they often involve 
the correlation of clinical outcomes and clinical interventions with laboratory 
studies. Such information would be unavailable if access to medical record 
numbers was unavailable. 
(4) The waiver or alteration will not adversely affect the rights and welfare of the 
subjects. 
a. Retention of these samples or data does not affect the welfare of subjects. 
(5) Whenever appropriate, the subjects will be provided with additional pertinent 
information after participation. 
a. We only request a waiver of consent for those subjects who have been lost to 
follow-up or who have been taken off study prior to reaching the age of 
majority. 
10.1.3 Consent of Subjects who are, or become, decisionally impaired 
For adult subjects, the study team will do a clinical assessment to determine if they have 
capacity. In situations where the clinical assessment determines that the capacity is in question, 
an assessment by ACAT (Ability to Consent Assessment Team) will be initiated. In the situation 
where the subject is known not to have capacity, this study will allow a Legally Authorized 
Representative (LAR) to sign consent providing the legal paperwork is filed with the Admissions 
Department per policy (i.e., legal guardianship, durable power of attorney, next of kin, etc.) 
Oversight for the provisions of protection for adults unable to consent will be informed by the PI. 
The PI will be responsible for proper implementation of the NIH guidance SOP 403, Research 
Involving Adults Who Are or May Be Unable to Consent. The legally authorized representative 
and adult subject will be included in all discussions about the trial and cognitively appropriate 
language will be used to describe the procedures and tests involved in this study, along with the 
risks, discomforts and benefits of participation. Verbal assent will be obtained from subjects who 
understand the nature of the study and its implications but are unable to provide a signature. 
Dissent will be respected in all subjects. The consent process will be documented in the subject’s 
medical record, including the assessment of the subject’s ability to provide verbal assent as 
applicable. 
It is possible but unlikely that subjects enrolled in the protocol may permanently lose the 
capacity to consent for themselves during the course of this study. In the event this occurs, the 

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subjects will remain in the study at the discretion of the PI because of the likelihood of direct 
benefit associated with study participation. If subjects will remain in the study, a legally 
authorized representative will be identified consistent with Policy 403 and informed consent 
obtained as described above. 
10.2 Study Discontinuation and Closure 
This study may be temporarily suspended or prematurely terminated if there is sufficient 
reasonable cause. Written notification, documenting the reason for study suspension or 
termination, will be provided by the suspending or terminating party to subjects, investigator, 
funding agency, the Investigational New Drug (IND) sponsor and regulatory authorities, as 
appropriate. If the study is prematurely terminated or suspended, the PI will promptly inform 
subjects, the Institutional Review Board (IRB), FDA, and Ultragenyx and Kyowa Kirin and will 
provide the reason(s) for the termination or suspension. Subjects will be contacted, as applicable, 
and be informed of changes to study visit schedule. 
Circumstances that may warrant termination or suspension include, but are not limited to: 
• Determination of unexpected, significant, or unacceptable risk to subjects 
• Demonstration of efficacy that would warrant stopping 
• Insufficient compliance to protocol requirements 
• Data that are not sufficiently complete and/or evaluable 
• Determination that the primary endpoint has been met 
• Determination of futility 
Study may resume once concerns about safety, protocol compliance, and data quality are 
addressed, and satisfy the investigators, IRB, and the FDA. 
10.3 Confidentiality and Privacy 
Subject confidentiality and privacy are strictly held in trust by the participating investigators. 
This confidentiality is extended to cover testing of biological samples and clinical information 
relating to subjects. Therefore, the study protocol, documentation, data, and all other information 
generated will be held in strict confidence. No information concerning the study or the data will 
be released to any unauthorized third party without prior written approval of the investigators. 
All research activities will be conducted in as private a setting as possible. 
The study monitor, other authorized representatives of the sponsor, representatives of the 
Institutional Review Board (IRB), and/or regulatory agencies may inspect all documents and 
records required to be maintained by the investigator, including but not limited to, medical 
records (office, clinic, or hospital) and pharmacy records for the participants in this study. The 
clinical study site will permit access to such records. 
All subjects’ records will only be identified by subject number. Subjects’ names are not to be 
transmitted to Ultragenyx and Kyowa Kirin. The investigator will keep a master subject list on 
which the subject number and the full name, address, and telephone number of each subject are 
listed. The subject’s contact information will be securely stored at NIH Clinical Center for 
internal use during the study. At the end of the study, all records will continue to be kept in a 
secure location for as long a period as dictated by the reviewing IRB, Institutional policies, or the 
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Data collection will involve the use of a 21 CFR part 11 compliant EDC system, only authorized 
personnel will have access to the EDC system. 
All data collected in the context of this study will be stored in a secure location and evaluated 
according to regulatory requirements and applicable guidance for electronic records. Data will be 
stored and evaluated in such a way as to guarantee subject confidentiality in accordance with the 
legal stipulations applying to confidentiality of data. Study records (e.g., copies of CRFs, 
regulatory documents) will be retained at the NIH Clinical Center, along with adequate source 
documentation, according to local regulatory requirements and ICH requirements. 
The investigator must retain a copy of all records that support CRFs for this study (e.g., ICFs, 
clinical laboratory reports, source documents, drug dispensing records) for a period of at least 15 
years after study completion unless local regulations or NIH Clinical Center policies require a 
longer retention period. 
If the investigator retires, relocates, or for other reasons withdraws from the responsibility of 
keeping the study records, custody must be transferred to a suitable alternate custodian employee 
of the study center or to a suitably qualified and responsible third party. 
To further protect the privacy of study participants, a Certificate of Confidentiality has been 
issued by the National Institutes of Health (NIH). This certificate protects identifiable research 
information from forced disclosure. It allows the investigator and others who have access to 
research records to refuse to disclose identifying information on research participation in any 
civil, criminal, administrative, legislative, or other proceeding, whether at the federal, state, or 
local level. By protecting researchers and institutions from being compelled to disclose 
information that would identify research participants, Certificates of Confidentiality help achieve 
the research objectives and promote participation in studies by helping assure confidentiality and 
privacy to participants. 
10.4 Future use of Stored Specimens and Data 
A unique subject code, as opposed to personal identifiers, will be used on the CRFs, and in the 
study database. A subject code log that links the names to identification numbers will be securely 
maintained at the NIH. 
Data collected for this study will be analyzed and transmitted to Ultragenyx and Kyowa Kirin via 
a secure, encrypted Internet connection and stored on a secure server. 
All stored samples are coded and do not have personal identifiers. The codes for identifiers are 
contained in a subject code log that is maintained in secure research files at the NIH. Samples 
received for anti-burosumab antibody evaluation by Ultragenyx and Kyowa Kirin from subjects 
consented to this protocol will be destroyed after use. 
With the participant’s approval and as approved by the IRB, identified biological samples will be 
stored at the NIH. These samples could be used to research the causes of FGF23 excess in FD, its 
complications and other conditions for which individuals with FD are at increased risk, and to 
improve treatment. 
During the conduct of the study, an individual subject can choose to withdraw consent to have 
biological specimens stored for future research. However, withdrawal of consent with regard to 
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10.5 Safety Oversight 
The PI will be responsible for monitoring the data and accruing safety information. Serious 
adverse event (SAE) monitoring will be supported by an independent medical monitor as 
determined by the PI in collaboration with the Office of Clinical Director and the Office of 
Clinical Trials Operations and Management (OCTOM), NIDCR. 
The investigator will be responsible for monitoring the data and accruing safety information. The 
investigator is responsible for monitoring the study progress and study data. The investigator will 
also maintain responsibility for ensuring the accuracy, completeness, timeliness, and legibility of 
the data. The investigator and associate investigators are also required to keep accurate and 
timely records to ensure that the conduct of the study is fully documented. The investigator will 
review individual study participant data upon each patient encounter. Trends will be discussed 
with the NIH, Ultragenyx, and Kyowa Kirin study teams to ensure participant safety; study 
compliance and recruitment goals are met. 
This study will be monitored by an NIDCR Division of Intramural Research Data and Safety 
Monitoring Committee (DSMC). Assessment and recommendations by the DSMC in relation to 
the study will be made to the NIDCR Clinical Director. The DSMC will include members with 
expertise in a broad range of areas, including human subjects’ protection, biostatistics, clinical 
trial implementation, pediatrics, and medical bone and mineral metabolism. The PI and NIDCR 
OCD will receive assessments and recommendations from the DSMC following interval 
meetings. These assessments and recommendations will be submitted to the IRB at the time of 
Continuing Review, or as needed if safety concerns arise. 
An independent study monitor on contract with NIDCR, NIH will review data and safety 
parameters of the study. Independent study monitors are qualified by training and experience to 
monitor the progress and safety of clinical trials. Personnel monitoring this study will not be 
affiliated in any way with the trial conduct. The PI and NIDCR OCD will receive reports from 
the independent study monitor following interim monitoring visits. The results will be 
summarized for the DSMC at interval meetings and for the IRB at Continuing Review, or as 
needed if safety concerns arise. 
10.6 Clinical Monitoring 
The independent study monitor will routinely monitor the progress of the study by conducting 
on-site or virtual/remote visits thereafter. The monitor will also be able to review query statuses 
remotely, which may warrant more frequent communication with the NIH investigator and study 
staff. The investigator will make available to the study monitor the source documents, the signed 
consent forms, and all other study-related documents. The investigator will be responsible for 
reviewing eCRFs, resolving data queries generated by the study monitor via the system, 
providing missing or corrected data, approving all changes performed on the data, and endorsing 
the participants data within the EDC system. 
Following written Standard Operating Procedures (SOPs), the clinical trial monitors will verify 
that the clinical trial is conducted, and data are generated, and biological specimens are collected, 
documented (recorded), and reported in compliance with the protocol, International Council on 
Harmonisation Good Clinical Practice (ICH GCP), and applicable regulatory requirements (e.g., 
Good Laboratory Practices (GLP), Good Manufacturing Practices (GMP)). Additional details of 

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monitoring (including Clinical, Safety, Data, Quality, and overall Trial monitoring) will be 
available in designated monitoring plan documents. 
Additional details of the processes and procedures for clinical study research site monitoring will 
be documented in the clinical monitoring plan prepared by the NIDCR Clinical Research 
Operations and Management Support (CROMS) contractors, in collaboration with the OCD and 
OCTOM 
10.7 Quality Assurance and Quality Control 
Internal quality assurance activities will include study team meetings, where the protocol team 
will review any new consents, unanticipated problems, and adverse events, and quarterly 
reporting of quality assurance/quality improvement activities to the NIDCR Office of the 
Clinical Director Clinical Operations Manager and NIDCR-OCTOM. 
Quality control (QC) procedures will be implemented beginning with the data entry system and 
data QC checks that will be run on the database will be generated. Any missing data or data 
anomalies will be communicated to the site(s) for clarification/resolution. 
10.8 Data Handling and Record Keeping 
10.8.1 Data Collection and Management Responsibilities 
Data collection is the responsibility of the clinical trial staff at the site under the supervision of 
the site investigator. The investigator is responsible for ensuring the accuracy, completeness, 
legibility, and timeliness of the data reported. 
All source documents should be completed in a neat, legible manner to ensure accurate 
interpretation of data. 
Hardcopies or electronic copies of the study visit and outpatient lab results will be provided for 
use as source document worksheets for recording data for each subject enrolled in the study. 
Data recorded in the electronic case report form (eCRF) derived from source documents should 
be consistent with the data recorded on the source documents. 
Clinical data (including adverse events (AEs), concomitant medications, and expected adverse 
reactions data) and clinical laboratory data will be entered into electronic data capture system 
that is 21 CFR Part 11-compliant. The data system includes password protection and internal 
quality checks, such as automatic range checks, to identify data that appear inconsistent, 
incomplete, or inaccurate. Clinical data will be entered into the electronic data capture system 
directly from the source documents. 
10.8.2 Study Records Retention 
Study documents should be retained for a minimum of 2 years after the last approval of a 
marketing application in an International Conference on Harmonisation (ICH) region and until 
there are no pending or contemplated marketing applications in an ICH region or until at least 2 
years have elapsed since the formal discontinuation of clinical development of the study 
intervention, and as per the NIH Intramural Records Retention Schedule. 
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It is the responsibility of the investigator to use continuous vigilance to identify and report 
deviations to the NIH Institutional Review Board as per Policy 801. 
10.9.1 NIH Definition of Protocol Deviation 
A protocol deviation is any change, divergence, or departure from the IRB-approved research 
protocol. 
• Major deviations: Deviations from the IRB approved protocol that have, or may have the 
potential to, negatively impact the rights, welfare or safety of the subject, or to 
substantially negatively impact the scientific integrity or validity of the study. 
• Minor deviations: Deviations that do not have the potential to negatively impact the 
rights, safety or welfare of subjects or others, or the scientific integrity or validity of the 
study. 
10.10 Publication and Data Sharing Policy 
10.10.1 
Human Data Sharing Plan 
This study will be conducted in accordance with the following publication and data sharing 
policies and regulations: 
This study is conducted in collaboration with Ultragenyx, Inc and Kyowa Kirin and publications 
of data from this study will be in alignment with the NIH, Kyowa Kirin, and Ultragenyx Inc 
Clinical Trials Agreement. 
National Institutes of Health (NIH) Public Access Policy ensures that the public has access to the 
published results. NIH funded research requires that NIH scientists submit final peer-reviewed 
journal manuscripts that arise from NIH funds to the digital archive PubMed Central upon 
acceptance for publication. 
This study will comply with the NIH Data Sharing Policy and the Clinical Trials Registration 
and Results Information Submission rule. As such, this trial will be registered at 
ClinicalTrials.gov, and results information from this trial will be submitted to ClinicalTrials.gov. 
In addition, every attempt will be made to publish results in peer-reviewed journals. Results from 
this trial will be made available 12 months after the primary study completion date. Results from 
this study may also be shared at scientific conferences. Investigators from NIH and Ultragenyx 
and Kyowa Kirin will consider requests from qualified researchers for access to clinical data. 
10.10.2 
Genomic Data Sharing Compliance 
Not applicable 
10.11 Collaborative Agreements 
10.11.1 
Agreement Type 
The NIDCR investigator(s), Kyowa Kirin, and Ultragenyx will sign the protocol and Clinical 
Trials Agreement to confirm agreement. The investigator(s) will not implement any amendment 
(deviation or changes of the protocol) without agreement by the Ultragenyx and Kyowa Kirin 
and IRB approval, except where necessary to eliminate immediate hazard(s) to subjects, or when 
change(s) involve only logistical or administrative aspects of the study. Any logistical or 

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administrative changes will be done in agreement with Ultragenyx and Kyowa Kirin and 
documented within 30 days on implementation. 
10.12 Conflict of Interest Policy 
The independence of this study from any actual or perceived influence, such as by the 
pharmaceutical industry, is critical. Therefore, any actual conflict of interest of persons who have 
a role in the design, conduct, analysis, publication, or any aspect of this trial will be disclosed 
and managed. Furthermore, persons who have a perceived conflict of interest will be required to 
have such conflicts managed in a way that is appropriate to their participation in the design and 
conduct of this trial. The study leadership in conjunction with the NIH, NIDCR has established 
policies and procedures for all study group members to disclose all conflicts of interest and will 
establish a mechanism for the management of all reported dualities of interest. 
11 Abbreviations 
 
 
AE 
Adverse Event 
CC 
Clinical Center 
CFR 
Code of Federal Regulations 
CMP 
Clinical Monitoring Plan 
CONSORT Consolidated Standards of Reporting Trials 
CRF 
Case Report Form 
DSMC 
Data Safety Monitoring Committee 
eCRF 
Electronic Case Report Forms 
FD 
Fibrous dysplasia 
FDA 
Food and Drug Administration 
FGF23 
Fibroblast growth factor 23 
GCP 
Good Clinical Practice 
GLP 
Good Laboratory Practices 
GMP 
Good Manufacturing Practices 
ICH 
International Conference on Harmonisation 
ICMJE 
International Committee of Medical Journal Editors 
IND 
Investigational New Drug Application 
IRB 
Institutional Review Board 
LAR 
Legally Authorized Representative 
MAS 
McCune-Albright syndrome 
NCT 
National Clinical Trial 
NIH 
National Institutes of Health 
NIH IC 
NIH Institute or Center 
PI 
Principal Investigator 
QC 
Quality Control 
SAE 
Serious Adverse Event 
SOA 
Schedule of Activities 
SOC 
System Organ Class 
SOP 
Standard Operating Procedure 

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TIO 
Tumor-Induced Osteomalacia 
UP 
Unanticipated Problem 
US 
United States 
XLH 
X-linked hypophosphatemia 

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12 REFERENCES 
1. Boyce AM, Collins MT. Fibrous Dysplasia/McCune-Albright Syndrome: A Rare, Mosaic 
Disease of Gαs Activation. Endocr Rev 2020;41(2):345-70 doi: 
10.1210/endrev/bnz011[published Online First: Epub Date]|. 
2. Berglund JA, Tella SH, Tuthill KF, et al. Scoliosis in Fibrous Dysplasia/McCune-Albright 
Syndrome: Factors Associated With Curve Progression and Effects of Bisphosphonates. J 
Bone Miner Res 2018;33(9):1641-48 doi: 10.1002/jbmr.3446[published Online First: 
Epub Date]|. 
3. Leet AI, Chebli C, Kushner H, et al. Fracture incidence in polyostotic fibrous dysplasia and 
the McCune-Albright syndrome. J Bone Miner Res 2004;19(4):571-7 doi: 
10.1359/jbmr.0301262[published Online First: Epub Date]|. 
4. Pan KS, Heiss JD, Brown SM, Collins MT, Boyce AM. Chiari I Malformation and Basilar 
Invagination in Fibrous Dysplasia: Prevalence, Mechanisms, and Clinical Implications. J 
Bone Miner Res 2018;33(11):1990-98 doi: 10.1002/jbmr.3531[published Online First: 
Epub Date]|. 
5. Carpenter TO, Whyte MP, Imel EA, et al. Burosumab Therapy in Children with X-Linked 
Hypophosphatemia. N Engl J Med 2018;378(21):1987-98 doi: 
10.1056/NEJMoa1714641[published Online First: Epub Date]|. 
6. Imel EA, Glorieux FH, Whyte MP, et al. Burosumab versus conventional therapy in children 
with X-linked hypophosphataemia: a randomised, active-controlled, open-label, phase 3 
trial. Lancet 2019;393(10189):2416-27 doi: 10.1016/s0140-6736(19)30654-3[published 
Online First: Epub Date]|. 
7. Insogna KL, Briot K, Imel EA, et al. A Randomized, Double-Blind, Placebo-Controlled, 
Phase 3 Trial Evaluating the Efficacy of Burosumab, an Anti-FGF23 Antibody, in Adults 
With X-Linked Hypophosphatemia: Week 24 Primary Analysis. J Bone Miner Res 
2018;33(8):1383-93 doi: 10.1002/jbmr.3475[published Online First: Epub Date]|. 
8. Portale AA, Carpenter TO, Brandi ML, et al. Continued Beneficial Effects of Burosumab in 
Adults with X-Linked Hypophosphatemia: Results from a 24-Week Treatment 
Continuation Period After a 24-Week Double-Blind Placebo-Controlled Period. Calcif 
Tissue Int 2019;105(3):271-84 doi: 10.1007/s00223-019-00568-3[published Online First: 
Epub Date]|. 
9. Insogna KL, Rauch F, Kamenický P, et al. Burosumab Improved Histomorphometric 
Measures of Osteomalacia in Adults with X-Linked Hypophosphatemia: A Phase 3, 
Single-Arm, International Trial. J Bone Miner Res 2019;34(12):2183-91 doi: 
10.1002/jbmr.3843[published Online First: Epub Date]|. 
10. Jan de Beur SM, Miller PD, Weber TJ, et al. Burosumab for the Treatment of Tumor- 
Induced Osteomalacia. J Bone Miner Res 2021;36(4):627-35 doi: 
10.1002/jbmr.4233[published Online First: Epub Date]|. 
11. Imanishi Y, Ito N, Rhee Y, et al. Interim Analysis of a Phase 2 Open-Label Trial Assessing 
Burosumab Efficacy and Safety in Patients With Tumor-Induced Osteomalacia. J Bone 

53 
Abbreviated Title: Burosumab for FD 
Version Date: 02/20/2024 
Template version date 05.06.2021 
 
 
Miner Res 2021;36(2):262-70 doi: 10.1002/jbmr.4184[published Online First: Epub 
Date]|. 
12. Crysvita (burosumab) [package insert]. Bedminster, NJ: Kyowa Kirin Inc; 2020. 
13. Linglart A, Biosse-Duplan M, Briot K, et al. Therapeutic management of hypophosphatemic 
rickets from infancy to adulthood. Endocr Connect 2014;3(1):R13-30 doi: 10.1530/ec-13- 
0103[published Online First: Epub Date]|. 
14. Nielsen LH, Rahbek ET, Beck-Nielsen SS, Christesen HT. Treatment of hypophosphataemic 
rickets in children remains a challenge. Dan Med J 2014;61(7):A4874 
15. Gladding A, Szymczuk V, Auble BA, Boyce AM. Burosumab treatment for fibrous 
dysplasia. Bone 2021;150:116004 doi: 10.1016/j.bone.2021.116004[published Online 
First: Epub Date]|. 
16. Kato H, Hidaka N, Koga M, et al. Performance evaluation of the new chemiluminescent 
intact FGF23 assay relative to the existing assay system. J Bone Miner Metab 2021 doi: 
10.1007/s00774-021-01258-7[published Online First: Epub Date]|. 
17. Florenzano P, Pan KS, Brown SM, et al. Age-Related Changes and Effects of 
Bisphosphonates on Bone Turnover and Disease Progression in Fibrous Dysplasia of 
Bone. J Bone Miner Res 2019;34(4):653-60 doi: 10.1002/jbmr.3649[published Online 
First: Epub Date]|. 
18. Adeli K, Higgins V, Trajcevski K, White-Al Habeeb N. The Canadian laboratory initiative 
on pediatric reference intervals: A CALIPER white paper. Crit Rev Clin Lab Sci 
2017;54(6):358-413 doi: 10.1080/10408363.2017.1379945[published Online First: Epub 
Date]|. 
19. Stanton RP, Ippolito E, Springfield D, Lindaman L, Wientroub S, Leet A. The surgical 
management of fibrous dysplasia of bone. Orphanet J Rare Dis 2012;7 Suppl 1(Suppl 
1):S1 doi: 10.1186/1750-1172-7-s1-s1[published Online First: Epub Date]|.