An Open-Label, Single-Arm, Phase 3 Study to Evaluate the Effects of KRN23 on Osteomalacia in Adults With X-linked Hypophosphatemia (XLH)
Phase: PHASE3
Conditions: X-linked Hypophosphatemia
Sponsor: Kyowa Kirin, Inc.

 
 
An Open-Label, Single-Arm, Phase 3 Study to Evaluate the Effects of KRN23 on 
Osteomalacia in Adults with X-linked Hypophosphatemia (XLH) 
  
 
 
Protocol Number: 
    UX023-CL304 
                        Original Protocol: 
    19 June 2015  
                        Amendment 1:              29 March 2016 
 
 
Amendment 2: 
   07 October 2016 
Amendment 3: 
   29 August 2017 
 
Investigational Product: 
KRN23 (Recombinant human IgG1 monoclonal antibody to 
fibroblast growth factor 23 [FGF23]) 
Indication: 
X-linked Hypophosphatemia (XLH) 
IND Number: 
 
76,488 
EudraCT Number: 
2015-001775-41 
Sponsor: 
Ultragenyx Pharmaceutical Inc. 
60 Leveroni Court 
Novato, CA, USA  94949 
Sponsor’s Responsible 
Medical Officer: 
 MD 
Vice President, Clinical Sciences 
Ultragenyx Pharmaceutical Inc. 
60 Leveroni Court 
Novato, CA  USA 94949 
+1 (415) 483-8800 
 
This study is to be performed in compliance with the protocol, Good Clinical Practices (GCP), 
and applicable regulatory requirements. 
 
Confidentiality Statement:  This document and the information it contains is confidential and proprietary 
and is the property of Ultragenyx Pharmaceutical Inc. (Ultragenyx). Unauthorized disclosure, reproduction, 
transmission, or use of this document or information is strictly prohibited. By accepting this document, the 
recipient agrees that the information it contains will not be disclosed without written authorization from 
Ultragenyx, except to the extent required to satisfy Institutional Review Board /Ethics Committee procedures, to 
obtain written informed consent from potential subjects, or as required by law. 

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CLINICAL STUDY PROTOCOL AMENDMENT 
SUMMARY OF CHANGES AND RATIONALE 
UX023-CL304 Amendment 1 
29 March 2016  
Original Protocol UX023-CL304 (dated 19 June 2015) has been modified by Amendment 1 
to modify certain eligibility criteria, clarify certain procedures and correct inconsistencies. 
Minor edits and typographical corrections have also been made. The major protocol changes 
that impact study design and conduct are summarized below:  
1. Sample Size: The sample size has been increased from approximately 10 subjects to 
approximately 14 subjects. A provision has also been added that at least 3 subjects 
from each sex will be enrolled. 
Rationale: The increased sample size and provision for a level of gender balance will 
help to promote a fairly diverse patient population within this small study.  
2. Study Population:  Several changes have been made to the inclusion and exclusion 
criteria (Section 7.3.1) as indicated below. 
a. Inclusion criterion #1 has been modified to change the age of eligibility to 
18 to 65, inclusive.  Previously the age was 25 to 65.  
b. Inclusion criterion #5 was modified to correct a duplicative value of 
60 mL/min. The estimated glomerular filtration rate (eGFR) should be 
≥ 60 mL/min (using the Chronic Kidney Disease Epidemiology Collaboration 
[CKD-EPI] equation); OR eGFR of 45 to < 60 mL/min at Screening with 
confirmation that the renal insufficiency is not due to nephrocalcinosis.  
c. Inclusion criterion #6 has been updated to add informed consent language for 
minors enrolled in the study. 
d. Inclusion criterion #9 has been updated with bolded text as follows 
“Participants of child‐bearing potential or with partners of child-bearing 
potential who have not undergone a total hysterectomy or bilateral 
salpingo-oophorectomy and are sexually active must consent to use of two 
effective methods of contraception as determined by the site investigator 
(i.e. oral hormonal contraceptives, patch hormonal contraceptives, vaginal 
ring, intrauterine device, physical double-barrier methods, surgical 
hysterectomy, vasectomy, tubal ligation, or true abstinence) from the period 
following the signing of the informed consent through 12 weeks after last dose 
of study drug. 
e. Exclusion criterion #4 has been modified to remove “oral” and restrict use of 
any bisphosphonates in the 2 years prior to Screening.  

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f. Additional criteria have been inserted to exclude individuals who have used 
denosumab in the 6 months prior to Screening and teriparatide in the 2 months 
prior to Screening. These medications have also been added to the list of 
prohibited medications for consistency (Section 7.5.3.10.1).  
g. Exclusion criterion #9 (previously #7) has been modified to state that patients 
with serum iPTH ≥2.5 times the upper limit of normal (ULN) will be 
excluded. Previously this value was serum iPTH ≥1.5 times ULN. 
h. An addition was made to exclusion criterion #19 to state that patients with a 
history or allergic reaction or adverse reaction tetracycline or demeclocycline 
will be excluded.  
i. A provision has been added to Exclusion criterion #21 to allow individuals to 
participate who may have a history of recurrent dental abscesses, which are 
known to be associated with XLH. 
Rationale: The modifications to inclusion/exclusion criteria provide clarification and 
additional guidance for site personnel. The age of eligibility was reduced to allow a 
more broad patient population and consent language for minors was added because 
18-year-olds are considered minors in some countries. The requirement for two forms 
of contraception aligns with the ICFs and other studies in the KRN23 program. The 
additional exclusion criteria prohibit the use of bone-modifying agents with the 
potential to confound study results. The provision to allow individuals with recurrent 
dental abscesses provides a study population representative of the XLH disease state. 
3. Schedule of Events: The schedule of events has been updated to add that serum 
1,25(OH)2D will be assayed at Week 24. In addition, post-baseline serum FGF23 
assessments will now be at Weeks 24 and 48. Previously, post-baseline serum FGF23 
assessments were scheduled for Weeks 4, 22, 24, 36, and 48.  
Rationale:  The additional serum 1,25(OH)2D measurement at Week 24 will provide 
additional data and aligns with other pharmacodynamic indicators at the time of 
primary analysis; no additional blood draws or blood volume are required for this 
assessment. Serum FGF23 levels have been measured extensively following KRN23 
administration in a subset of studies across the adult and pediatric development 
program. In this study, because KRN23 will be administered at a stable level from the 
beginning of the trial, it is anticipated that post-treatment FGF23 levels will remain 
fairly stable, therefore only two post-treatment assessments samples will be collected. 
4. Investigational Product:  Section 7.4.1 had been modified to provide additional 
flexibility in SC dosing sites; subjects may receive study drug via SC injection to the 
abdomen, upper arms or thighs.  
Rationale: This modification in dosing will allow some flexibility in SC drug 
administration for subjects. 

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5. Study Procedures and Assessments: Section 7.5 and Section 7.5.1.1 have been 
clarified to indicate that tetracycline or demeclocycline may be used for labeling for 
bone biopsy. In addition, the timing of the tetracycline labeling has been clarified: 
The bone biopsy should be performed 5 days after the last dosing day for tetracycline 
or demeclocycline. The first dose should be given on days -20, -19, and -18, and the 
second dose given on days -8, -7, and -6.  
Rationale: Demeclocycline is a standard label for use in evaluation of iliac crest bone 
biopsies and it is more readily available than tetracycline in certain countries of the 
world. The clarification of timing is to be consistent with the procedures of the central 
laboratory being used for biopsy assessments. 
6. General Assessments:  Section 7.5.3 has been modified to add that additional genetic 
testing for mutations in genes consistent with syndromes with clinical and 
biochemical phenotypic overlap with XLH will be performed if the initial PHEX 
mutation analysis result is negative or inconclusive and informed consent is provided 
by the subject. This testing will include, but not necessarily be limited to, genes for 
Autosomal Dominant Hypophosphatemic Rickets (FGF23), Autosomal Recessive 
Hypophosphatemic Rickets (DMP1, ENPP1), X-Linked Recessive 
Hypophosphatemic Rickets (CLCN5), and Hereditary Hypophosphatemic Rickets 
with Hypercalciuria (SLC34A3). 
Rationale: In subjects with a diagnosis of XLH based on clinical and biochemical 
phenotypic presentation, PHEX mutation analysis results may be inconclusive. For 
any subject with a PHEX mutation analysis result of No Mutation, Likely Benign, 
Variant of Uncertain Significance, or Possibly Pathogenic, and who provides 
informed consent, reflexive genetic testing will be performed to assess additional 
genes associated with phenotypes overlapping with XLH. In addition, Sanger 
sequencing for the functional 3’UTR variant in PHEX described in the literature 
(Mumm et al. 2015) will be performed. The additional testing may help characterize 
the genetic disorder associated with the clinical syndrome. 
7. Safety Assessments:  Several changes have been made to the safety assessments. 
a. Blood pressure (Section 7.5.3.2) will be obtained twice (2 measurements 
separated by 15 minutes) at indicted clinic visits. 
b. Section 7.5.3.6 has been updated to indicate echocardiograms (ECHO) will no 
longer be read locally at the study site. All ECHO assessments will be 
centrally read. 
c. Section 7.5.3.8 (Table 7.5.3.8.1) has been updated to add assessment of lipase 
in all subjects. 
Rationale: The second blood pressure measurement improves accuracy and an 
additional measure of safety.  
 

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Central reading of ECHOs provides standardization of data obtained from multiple 
clinical sites and reduces potential bias due to inter-reader variability and other 
factors in interpreting ECHO as a safety variable.  
 
Mild asymptomatic elevations in serum amylase have been observed in some subjects 
at baseline and during the study. Amylase is produced by several organs including the 
pancreas and salivary gland and so elevated amylase levels are not diagnostic in the 
absence of other information. In ongoing and completed KRN23 studies at baseline 
mild elevations of amylase (<2x ULRR) have been noted. Post treatment mild shifts 
in amylase elevation (< 2xULRR) has been noted without association with GI 
symptoms. No adverse events of pancreatitis have been observed. The testing for 
serum lipase when serum amylase levels are elevated will allow a determination of 
whether the amylase elevations are from pancreatic or salivary gland sources. 
 
8. Ethics:  Section 8.1.2 has been updated to state that both the sponsor and 
investigator will make every effort to assure the study described in this protocol is 
conducted in full conformance with those principles, current FDA regulations, ICH 
Good Clinical Practices (GCP) guidelines, and local ethical and regulatory 
requirements. 
Rationale: The modification follows guidance received from the Ethics Committee in 
Denmark. 
9. Record Retention: Section 8.4.3 has been updated to state that all study records must 
be retained for at least 25 years after the end of the clinical trial or in accordance with 
national law. 
Rationale: This administrative change has been made to reflect upcoming changes to 
EU clinical trial regulations and current regulations by other health authorities. 
10. Safety Contact Information: The medical monitor information for this study has 
been updated in Section 8.5.4.7. 
Rationale: Administrative change. 

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 CLINICAL STUDY PROTOCOL AMENDMENT 
SUMMARY OF CHANGES AND RATIONALE 
UX023-CL304 Amendment 2 
07 October 2016  
Protocol UX023-CL304 Amendment 1 (dated 30 March 2016) has been modified by 
Amendment 2 with the addition of a 48-week long Treatment Extension Period. Minor edits 
and typographical corrections have also been made. The major protocol changes that impact 
study design and conduct are summarized below:  
1. Overall Study Design: A 48-week Treatment Extension Period was added to the 
study design.  The corresponding Schedule of Events for this period is provided in 
Table 2.3. 
Rationale: Extending the study by 48 weeks provides an option for subjects to 
continue to receive open-label treatment with KRN23, while enabling additional 
long-term safety assessments. During this extension period, the number and 
frequency of assessments have been reduced to minimize burden on participants; 
most variables specified as exploratory will not be followed during this additional 
treatment period. Targeted radiographs will only be performed at clinic visit(s) 
following newly diagnosed fractures during the Extension Period to minimize 
radiation exposure. 
2. Primary Analysis: Section 7.6.4.1 was narrowed to focus on osteoid volume 
(osteoid volume/bone volume, OV/BV) as the primary efficacy endpoint. The other 
histomorphometric parameters were specified as secondary endpoints under 
Section 7.6.4.2. 
 
Rationale: To specify a principal comparison, the primary efficacy endpoint was 
defined to focus on osteoid volume (measured as a percentage of total bone volume) 
as it is the most consistent histomorphometric parameter to quantify the amount of 
osteoid tissue accumulation, which is the hallmark of osteomalacia. Osteoid volume 
combines both direct measurements of osteoid surface/total surface plus osteoid 
thickness. The remaining histomorphometric indices – including osteoid thickness, 
osteoid surface, and mineralization lag time – were assigned as secondary efficacy 
endpoints to further assess osteomalacia burden.     
 
3. Contraception Methods: The list of examples of highly effective contraception 
methods was updated in Section 7.5.3.9. 
 
Rationale: This change was made to better clarify the acceptable methods of 
contraception in compliance with the Clinical Trial Facilitation Group (CTFG) 
advice. 

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4. Schedule of Events: The frequency of pregnancy testing in females with child-
bearing potential was increased to every 4 weeks. 
 
Rationale: Pregnancy testing in appropriate subjects will be performed every 4 weeks 
in compliance with the Clinical Trial Facilitation Group (CTFG) advice. 
5. End of Study: Section 7.4.3.1 was updated to clarify that the End of Study is the last 
subject’s Safety Follow-up Phone Call (12 weeks (± 5 days) after the Final Dose). 
Rationale: This change was made to define the End of Study. 
 
6. Exploratory Endpoints: In Section 7.6.4.4, language describing the exploratory 
endpoint of pseudofracture healing has been modified to read: Healing of pre-existing 
pseudofractures and/or Looser zones, as defined by skeletal survey at baseline and 
subsequent targeted radiography. Previously this endpoint had indicated “time to 
healing” of pre-existing pseudofractures and/or Looser zones.   
 
An additional change was made in Section 7.6.4.4 to clarify that the endpoints for 
Brief Fatigue Inventory (BFI) will be based on BFI question 3-Worst Fatigue, and a 
BFI Global Fatigue score calculated by averaging all 9 items on the BFI, rather than 
separate BFI Severity and BFI Interference scores.   
 
Rationale: Language has been updated to more accurately reflect the planned 
analysis.  
 
7. Study Objectives: In Section 6, the Pharmacokinetics Objective has been clarified 
as: Assess the PK of KRN23 throughout the dosing cycle following the first doses and 
at steady state. It had previously stated, “…following single and multiple doses.” 
 
Rationale: Wording was clarified to avoid misinterpretation as there is no single dose 
treatment in this study. 
 
8. Genetic Testing: In Section 7.5.3, one gene, for Raine Syndrome (FAM20C), has 
been added to the list of genes that may be assessed for mutation in subjects whose 
initial PHEX mutation analysis is negative or inconclusive and who provide informed 
consent. The wording “not necessarily limited to” regarding the list of genes has been 
removed. 
Rationale: This change was made to more precisely identify the genes that may be 
assessed for mutations if a subject has a negative or inconclusive PHEX mutation 
result. 

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 CLINICAL STUDY PROTOCOL AMENDMENT 
SUMMARY OF CHANGES AND RATIONALE 
UX023-CL304 Amendment 3 
29 August 2017  
Protocol UX023-CL304 Amendment 2 (dated 07 October 2016) has been modified by 
Amendment 3 to extend treatment duration for study subjects in the United States (US) and 
to describe the data monitoring through the Treatment Extension Periods. Minor edits, 
clarifications, and typographical corrections have also been made. The major protocol 
changes that impact study design and conduct are summarized below:  
1. Study Design and Duration:  In Sections 7.1 and 7.4.3.1 and other relevant sections, 
a second Treatment Extension Period II that includes an additional up to 
approximately 45 weeks of KRN23 treatment, until end of September 2018, has been 
added for subjects enrolled at sites in the US only.  (The duration of this period will 
vary for individual subjects and will be determined by the time from start of Week 97 
through final visit schedule 30 September 2018.)  In addition, in these sections and 
Section 8.5.4.1 and other relevant sections, Safety Follow-up telephone calls (TCs) 
over an interval of up to 8 weeks following the End of Study or Early Termination 
Visit have been added for subjects not immediately continuing KRN23 treatment 
under commercial use or another mechanism upon completion of study drug 
treatment or early withdrawal from this study.  The maximum study duration has 
consequently been changed to up to approximately 149 weeks.  For subjects outside 
of the US, the duration of study treatment will remain 96 weeks, followed by Safety 
Follow-up TCs over an interval of up to 8 weeks following the End of Study or Early 
Termination Visit if not continuing KRN23 treatment under commercial use or 
another mechanism upon completion of study drug or early withdrawal from this 
study.  The end of study is defined as the last day that protocol-specified assessments 
(including telephone contact) are conducted for the last subjects in the study. 
Rationale: Treatment Extension Period II has been added for subjects at US sites to 
provide KRN23 treatment to these subjects until a time when KRN23 is expected to 
be commercially available in the US.  Safety and Efficacy parameters will continue to 
be assessed while the subjects remain on study drug.  Subjects enrolled outside the 
US may have access to continued KRN23 treatment after completion of Extension 
Period I through various regional mechanisms, in accordance with local laws and 
regulations.  Safety Follow-up TCs have been added after the extension periods to 
collect information as appropriate on ongoing or new adverse events, serious adverse 
events, and concomitant medications after subjects discontinue study drug but before 
KRN23 treatment under commercial use or another mechanism begins. 
   

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2. Anti-KRN23 Antibodies: In Section 7.5.3.8.2 and the Schedule of Events, the term 
HAHA (human anti-human antibody) in reference to anti-KRN23 antibody testing, 
has been replaced with the term ADA (anti-drug antibody). 
Rationale: This change is a clarification. The immunogenicity of KRN23 is evaluated 
by quantifying total anti-drug antibodies (ADA), independent of isotype, in human 
serum. While the study protocol previously used the term “HAHA” for this 
assessment, it has been replaced with the more correct and specific term, ADA. 
3. Safety Monitoring: Section 7.6.7 and Section 8.5.4.6 have been updated to describe 
safety monitoring during the Treatment Extension Periods I and II of the study. 
Rationale:  In this open-label study, the DMC will continue to monitor safety through 
Week 48 as planned.  During the Treatment Extension Periods I and II, safety will be 
monitored on an ongoing basis by the Study Safety Review Team (SSRT), an internal 
safety review team defined and in place since the original protocol. 
4. Exploratory Efficacy Endpoints: In Section 7.6.4.4, the exploratory endpoint of 
healing of pre-existing pseudofractures and/or Looser zones, as defined by skeletal 
survey at baseline and subsequent targeted radiography has been updated to clarify 
that it comprises the following components: the number of active pseudofractures 
and/or fractures as defined by skeletal survey at baseline and the numbers and 
percentages of the baseline active pseudofractures/fractures that were healed, partially 
healed, unchanged, and worsened at post-baseline visits, and the number of subjects 
with baseline active pseudofractures and/or fractures at baseline and the numbers of 
those subjects who had changes from baseline to healed, partially healed, unchanged, 
and worsened at post-baseline visits. Also, the descriptions of other exploratory 
endpoints were updated for clarity.  
Rationale: The section was updated to reflect the exploratory efficacy endpoints 
planned for analysis in this study.  
5. Physical Examination: Section 7.5.3.4 was modified to specify that the 
genitourinary component of the physical exam will be performed as age-appropriate 
at the Investigator’s discretion. 
Rationale: this modification was added to clarify that the genitourinary scope should 
be non-invasive and as per age-appropriate standard of care, at the Investigator's 
discretion based on the clinical judgement and/or safety need. 
 
 

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2 SYNOPSIS 
TITLE OF STUDY: 
An Open-Label, Single-Arm, Phase 3 Study to Evaluate the Effects of KRN23 on Osteomalacia in 
Adults with X-linked Hypophosphatemia (XLH) 
PROTOCOL NUMBER: 
UX023-CL304 
STUDY SITES: 
Approximately 14 sites globally 
PHASE OF DEVELOPMENT: 
Phase 3 
RATIONALE:  
XLH is a disorder of hypophosphatemia, renal phosphate wasting, and defective bone 
mineralization caused by inactivating mutations in the PHEX gene (phosphate-regulating gene 
with homologies to endopeptidases on the X chromosome). In the absence of functional PHEX, 
release of fibroblast growth factor 23 (FGF23) by osteocytes is greatly increased. Excess 
circulating FGF23 signals the kidney tubules to decrease phosphate reabsorption by 
down-regulating NaPi-IIa and NaPi-IIc in the tubular cells and suppressing 1,25-dihydroxyvitamin 
D (1,25(OH)2D) production, resulting in decreased intestinal absorption of calcium and phosphate 
producing hypophosphatemia. In adults with XLH, a hallmark of the disease is osteomalacia, a 
defect in bone mineralization due to chronically low serum phosphorus. Osteomalacia is 
characterized by a lack of proper mineralization, a prolonged mineralization process, and an 
accumulation of osteoid tissue. It is also associated with a reduction in bone remodeling and 
reduced bone quality and is a key contributor to the symptoms of bone and joint pain and the 
non-traumatic pseudofractures and reduced quality of life experienced by adults with XLH.  
KRN23 is a recombinant fully human IgG1 monoclonal antibody being developed to treat XLH by 
binding to FGF23 and inhibiting its activity, thereby increasing serum phosphorus levels and 
improving osteomalacia and related symptoms. Histologic and histomorphometric analyses of iliac 
crest bone biopsies are the gold standard for evaluating changes in osteomalacia, thus it is 
important to characterize changes in bone biopsy parameters in response to KRN23 treatment. 
Bone biopsy studies in adults with XLH receiving oral phosphate and vitamin D therapy have 
shown incomplete healing of osteomalacia. In addition, there are no systematic studies in adults to 
show this regimen improves symptoms or outcomes, and there are concerns about the risk of 
long-term complications, particularly nephrocalcinosis, which increases with dose and duration of 
therapy. More efficacious, safer, and convenient therapies clearly are needed for adults who 
continue to experience XLH-related symptoms and complications. 
A Phase 1 study established the pharmacokinetic (PK) profile of KRN23. A Phase 1/2 study and 
associated extension study evaluated the pharmacodynamics (PD) of KRN23 on phosphate 
metabolism and related measures of the phosphate-calcium mineral control system. The safety data 
from these studies have shown that KRN23 in single and repeated monthly doses up to 1.0 mg/kg 

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was well tolerated by adult XLH subjects. KRN23 sufficiently increased serum phosphorus levels 
such that improvements in bone physiology, structure, and function would be expected.  
A randomized, double-blind, placebo-controlled Phase 3 study is being conducted to confirm the 
efficacy and safety of KRN23 treatment, and establish the beneficial impact on patient-reported 
and functional outcomes in adults with XLH. The current open-label study will examine the 
efficacy of KRN23 on bone quality, including the effects on osteomalacia at the tissue level, and 
provide an additional assessment of safety.  Long term safety and efficacy data will be collected 
during the Treatment Extension Periods I and II. 
PRIMARY EFFICACY HYPOTHESIS: 
Treatment with 1.0 mg/kg KRN23 monthly will improve XLH-associated osteomalacia as 
determined by osteoid volume (osteoid volume/bone volume, OV/BV). 
OBJECTIVES: 
Primary Efficacy Objective:   
Establish the effect of KRN23 treatment on improvement in XLH-associated osteomalacia as 
determined by osteoid volume (osteoid volume/bone volume, OV/BV).  
Secondary Efficacy Objectives: 
The key secondary efficacy objective is to establish the effect of KRN23 treatment on increasing 
serum phosphorus levels in adults with XLH   
Other secondary efficacy objectives are to establish the effect of KRN23 treatment in adults with 
XLH on: 
• 
Changes from baseline in additional histomorphometric parameters – including osteoid 
thickness (O.Th), osteoid surface/bone surface (OS/BS), and mineralization lag time (MLt) 
• 
Changes from baseline in parameters of bone mineralization including mineral apposition 
rate (MAR), mineralizing surface (MS/BS), bone formation rate (BFR), and others  
• 
Additional PD markers reflecting the status of phosphorus homeostasis and renal function 
• 
Bone remodeling as assessed by bone turnover markers 
Exploratory Efficacy Objectives: 
• 
Examine the effect of KRN23 treatment in adults with XLH on pseudofracture/fracture 
healing 
• 
Patient reported outcomes (PROs) assessing skeletal pain and fatigue 
Pharmacokinetic Objective: 
Assess the PK of KRN23 throughout the dosing cycle following the first doses and steady state  

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Safety Objective:   
Establish the safety and tolerability profile of KRN23 in the treatment of adults with XLH 
including adverse events (AEs), ectopic mineralization risk, cardiovascular effects, and 
immunogenicity profile 
STUDY DESIGN AND METHODOLOGY: 
UX023-CL304 is a Phase 3 open-label, single-arm, multicenter study to establish the effects of 
KRN23 on bone quality and osteomalacia associated with XLH. Approximately 14 adult subjects 
with a diagnosis of XLH supported by typical clinical and biochemical features and who have not 
received oral phosphate and vitamin D therapy in the past two years will be enrolled. At least 
3 subjects of each sex will be enrolled. Iliac crest bone biopsies will be performed at baseline and 
48 weeks. Baseline histologic and histomorphometric assessments of the bone biopsy specimens 
will be performed as each biopsy is completed to assess sample quality and confirm the presence 
of osteomalacia in at least 8 subjects. If a subject is determined not to have osteomalacia at the 
time of the initial biopsy, that subject will continue on study but will not undergo the second bone 
biopsy procedure at Week 48. All other assessments will be completed as scheduled. The goal of 
the study is to assess changes in bone quality; histologic and histomorphometric evaluation of iliac 
crest bone biopsies will be supported by changes in serum phosphorus and biochemical markers of 
bone turnover and additional PD markers associated with FGF23-mediated processes. 
Pseudofractures and PROs will provide additional information on KRN23 efficacy. Safety, 
immunogenicity, and PK of KRN23 will also be evaluated. 
KRN23 will be administered via subcutaneous (SC) injections monthly (Q4W, 28 days) for 
48 weeks.  Subjects who complete the 48 weeks of the Open-Label Treatment Period will then 
continue into an additional 48-week Treatment Extension Period I (until Week 96).  For subjects at 
study sites outside of the United States (US), the Week 96 Visit will be their End of Study (EOS) 
efficacy visit (referred to as EOS I).  For subjects at sites in the US, treatment will continue for up 
to an additional 45 weeks  in an open-label Treatment Extension Period II, until the end of 
September 2018, at which time they will have their EOS efficacy visit (referred to as EOS II).  
(The duration of this period will vary for individual subjects and will be determined by the time 
from the start of Week 97 through their EOS II Visit).  For subjects not immediately continuing 
KRN23 treatment under commercial use or another mechanism upon completion of study drug 
treatment or early withdrawal from this study, a Safety Follow-up telephone call (TC) will occur 
4 weeks (+5 days) after the subject’s final study site visit (ie EOS I [non-US subjects], EOS II [US 
subjects], or Early Termination [ET] visit) to collect information on any ongoing or new AEs, 
serious adverse events (SAEs), and concomitant medications.  If the subject is not continuing 
KRN23 therapy under commercial use or another mechanism at that time, an additional Safety 
Follow-up TC will occur at 8 weeks (+ 5 days) after the subject’s final study site visit. The end of 
this study is defined as the last day that the protocol specified assessments (including telephone 
contact) are conducted for the last subject.   
NUMBER OF SUBJECTS PLANNED: 
Approximately 14 adult subjects are expected to be enrolled in the study including at least 
8  subjects with a confirmed diagnosis of osteomalacia  

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DIAGNOSIS AND CRITERIA FOR INCLUSION AND EXCLUSION: 
Individuals eligible to participate in this study must meet all of the following criteria: 
1) Male or female, aged 18 - 65 years, inclusive 
2) Diagnosis of XLH supported by classic clinical features of adult XLH (such as short 
stature or bowed legs), and at least ONE of the following at Screening: 
• 
Documented PHEX mutation in either the patient or in a directly related 
family member with appropriate X-linked inheritance  
• 
Serum iFGF23 level > 30 pg/mL by Kainos assay 
3) Biochemical findings consistent with XLH based on overnight fasting (min. 8 hours):   
• 
Serum phosphorus < 2.5 mg/dL at Screening 
• 
TmP/GFR < 2.5 mg/dL at Screening  
4) Presence of skeletal pain attributed to XLH/osteomalacia, as defined by a score of ≥ 4 on 
the Brief Pain Inventory question 3 (BPI-Q3, Worst Pain) at Screening. (Skeletal pain that, 
in the opinion of the investigator, is attributed solely to causes other than 
XLH/osteomalacia—for example, back pain or joint pain in the presence of severe 
osteoarthritis by radiograph in that anatomical location—in the absence of any skeletal 
pain likely attributed to XLH/osteomalacia should not be considered for eligibility) 
5) Estimated glomerular filtration rate (eGFR) ≥ 60 mL/min (using the Chronic Kidney 
Disease Epidemiology Collaboration [CKD-EPI] equation) or eGFR of 45 to <60 mL/min 
at Screening with confirmation that the renal insufficiency is not due to nephrocalcinosis 
6) Provide written informed consent after the nature of the study has been explained, and 
prior to any research-related procedures. If the subject is a minor, provide written assent 
and have a legally authorized representative willing and able to provide written informed 
consent  
7) Willing to provide access to prior medical records for the collection of biochemical and 
radiographic data and disease history  
8) Females of child-bearing potential must have a negative urine pregnancy test at Screening 
and Baseline and be willing to have additional pregnancy tests during the study. Females 
considered not to be of childbearing potential include those who have not experienced 
menarche, are post-menopausal (defined as having no menses for at least 12 months 
without an alternative medical cause) or are permanently sterile due to total hysterectomy, 
bilateral salpingectomy, or bilateral oophorectomy.   
9) Participants of child‐bearing potential or fertile males with partners of child-bearing 
potential who are sexually active must consent to use a highly effective method of 
contraception as determined by the site Investigator from the period following the signing 
of the informed consent through the final Safety Follow-up TC (as defined in 
Section 7.4.3.1) 
10) Must, in the opinion of the investigator, be willing and able to complete all aspects of the 
study, adhere to the study visit schedule and comply with the assessments 

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Individuals who meet any of the following exclusion criteria will not be eligible to participate in 
the study: 
1) Use of any pharmacologic vitamin D metabolite or analog (e.g. calcitriol, doxercalciferol, 
and paricalcitol) within the 2 years before Screening 
2) Use of oral phosphate within 2 years before Screening  
3) Use of aluminum hydroxide antacids, acetazolamides, and thiazides within 7 days prior to 
Screening  
4) Use of bisphosphonates in the 2 years prior to Screening 
5) Use of denosumab in the 6 months prior to Screening 
6) Use of teriparatide in the 2 months prior to Screening 
7) Chronic use of systemic corticosteroids defined as more than 10 days in the 2 months prior 
to Screening 
8) Corrected serum calcium level ≥ 10.8 mg/dL (2.7 mmol/L) at Screening 
9) Serum iPTH ≥ 2.5 times the upper limit of normal (ULN) at Screening 
10) Use of medication to suppress PTH (cinacalcet for example) within 60 days prior to 
Screening 
11) Prothrombin time/Partial thromboplastin time (PT/PTT) outside the normal range at 
Screening 
12) Evidence of any disease or use of anticoagulant medication (such as warfarin, heparin, 
direct thrombin inhibitors, or xabans that, in the opinion of the investigator, cannot be 
discontinued) that may increase the risk of bleeding during the biopsy procedure 
13) Pregnant or breastfeeding at Screening or planning to become pregnant (self or partner) at 
any time during the study 
14) Unable or unwilling to withhold prohibited medications throughout the study 
15) Documented dependence on narcotics 
16) Use of KRN23, or any other therapeutic monoclonal antibody within 90 days prior to 
Screening  
17) Use of investigational product or investigational medical device within 30 days prior to 
Screening, or requirement for any investigational agent prior to completion of all 
scheduled study assessments. 
OR, in Japan, use of any investigational product or investigational medical device within 
4 months prior to Screening, or requirement for any investigational agent prior to 
completion of all scheduled study assessments. 
18) Presence or history of any hypersensitivity, allergic or anaphylactic reactions to any 
monoclonal antibody or KRN23 excipients that, in the judgment of the investigator, places 
the subject at increased risk for adverse effects 
19) History of allergic reaction or adverse reactions to tetracycline or demeclocycline 

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20) Prior history of positive test for human immunodeficiency virus antibody, hepatitis B 
surface antigen, and/or hepatitis C antibody 
21) History of recurrent infection (other than dental abscesses, which are known to be 
associated with XLH) or predisposition to infection, or of known immunodeficiency 
22) Presence of malignant neoplasm (except basal cell carcinoma) 
23) Presence of a concurrent disease or condition that would interfere with study participation 
or affect safety  
24) Presence or history of any condition that, in the view of the investigator, places the subject 
at high risk of poor treatment compliance or of not completing the study   
INVESTIGATIONAL PRODUCT, DOSE, AND MODE OF ADMINISTRATION 
KRN23 is a sterile, clear, colorless, and preservative-free solution supplied in single-use 5-mL 
vials containing 1 mL of KRN23 at a concentration of 30 mg/mL. KRN23 will be administered 
without dilution. All subjects will receive 1.0 mg/kg KRN23 monthly (Q4W, 28 days) rounded to 
the nearest 10 mg. The amount of drug administered will be calculated based on baseline weight 
and a 1.0 mg/kg KRN23 dose level (rounded to the nearest 10 mg) up to a maximum dose of 
90 mg. The dose will remain fixed for the duration of the study, provided serum phosphorous 
levels do not exceed 5.0 mg/dL (1.61 mmol/L) at any time or 4.5 mg/dL (1.45 mmol/L) on two 
occasions. The dose will be recalculated if body weight changes by more than 20% from the 
baseline measurement. 
Subjects will receive study drug via SC injection to the abdomen, upper arms, or thighs; the 
injection site will be rotated with each injection. No more than 1.5 mL may be administered to a 
single injection site. If the dose requires more than 1.5 mL, multiple injections must be 
administered, each at a different injection site.   
If serum phosphorus increases above 5.0 mg/dL (1.61 mmol/L) at any time the actual dose will be 
decreased by half. If serum phosphorous increases above the ULN (4.5 mg/dL; 1.45 mmol/L) but 
does not exceed 5.0 mg/dL (1.61 mmol/L), the dose will be adjusted only if a second serum 
phosphorus result exceeds the ULN. Following a downward dose adjustment, the investigator 
together with the medical monitor should determine how and when to dose titrate up. Unscheduled 
serum phosphorus assessments may be necessary. Based on the totality of the data from studies 
INT-001 and INT-002 over a period of 16 months in which most subjects were treated with 
1.0 mg/kg KRN23 and no subject experienced an elevation of serum phosphorus that approached 
the 4.5 mg/dL (1.45 mmol/L) threshold, it is considered unlikely that dose adjustment will be 
necessary. 
 
REFERENCE THERAPY, DOSE, AND MODE OF ADMINISTRATION: 
The study is a single-arm, open-label study. All subjects will be on active treatment; no reference 
therapy or placebo will be administered.  

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DURATION OF TREATMENT: 
The planned duration of treatment in this study is up to 96 weeks for subjects at sites outside of the 
US. For subjects at sites in the US, the planned duration of treatment is up to approximately 
141 weeks, until end of September 2018.  All Subjects will receive treatment with KRN23 for 
48 weeks as part of the Open-Label Treatment Period. Subjects will then continue into an 
additional 48-week Treatment Extension Period I and, if at a US site, up to approximately 
45 weeks, until end of September 2018, in Treatment Extension Period II. The duration of 
Treatment Extension Period II will vary for individual subjects and will be determined by the time 
from the start of Week 97 through their end of study visit.   
CRITERIA FOR EVALUATION: 
Primary Efficacy Endpoint:  
The primary endpoint is the percent change from baseline in osteoid volume/bone volume 
(OV/BV) at Week 48 based on analysis of iliac crest bone biopsies  
Key Secondary Efficacy Endpoint: 
The key secondary efficacy endpoint is the proportion of subjects achieving mean serum 
phosphorus levels above the lower limit of normal (LLN; 2.5 mg/dL [0.81 mmol/L]) at the 
mid-point of the dose interval (i.e., Weeks 2, 6, 14, and 22), as averaged across dose cycles 
between baseline and Week 24. 
Secondary Efficacy Endpoints: 
• 
Percent changes from baseline in additional histomorphometric parameters – including 
osteoid thickness (O.Th), osteoid surface/bone surface (OS/BS), and mineralization lag 
time (MLt) 
• 
Changes from baseline in MAR, MS/BS, BFR and additional measures of bone formation 
and remodeling 
• 
Additional measures to assess serum phosphorus levels between baseline and Week 24 
include: 
o Proportion of subjects achieving mean serum phosphorus levels above the LLN 
(2.5 mg/dL [0.81 mmol/L]) at the end of the dosing cycle (4 weeks after dosing), 
as averaged across dose cycles  
o Mid-point of dosing cycle:  mean change from baseline and percent change from 
baseline averaged across dose cycles 
o End of dosing cycle: mean change from baseline, and percent change from 
baseline averaged across dose cycles 
o Cumulative exposure: area under the curve (AUC) 

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• 
Change from baseline over time in serum 1,25(OH)2D, urinary phosphorus, ratio of renal 
tubular maximum reabsorption rate of phosphate to glomerular filtration rate (TmP/GFR), 
and tubular reabsorption of phosphate (TRP) 
• 
Change and percent change from baseline over time in serum biochemical markers of 
bone turnover, including procollagen type 1 N-propeptide (P1NP), carboxy-terminal 
cross-linked telopeptide of type I collagen (CTx), and bone-specific alkaline phosphatase 
(BALP) 
Exploratory Efficacy Endpoints:  
• 
Healing of active pseudofractures and/or fractures, as defined by skeletal survey at 
baseline and subsequent targeted radiography  
• 
Change from baseline in BPI Pain Severity and in Pain Interference scores over time 
• 
Change from baseline over time in Brief Fatigue Inventory (BFI) Q3-Worst Fatigue 
Scores  
• 
Change from baseline over time in BFI Global Fatigue Score, calculated by averaging all 
9 items on the BFI  
Drug Concentration Measurements: 
PK samples will be obtained from all subjects throughout the study at time points representing the 
peak and trough exposure levels. .  
Safety Assessments: 
Safety will be evaluated by the incidence, frequency and severity of AEs and SAEs, including 
clinically significant changes from baseline to scheduled time points in the following safety 
variables:  
General Safety Variables: 
• 
Vital signs and weight 
• 
Physical examinations 
• 
eGFR 
• 
Chemistry, hematology, and urinalysis, including additional KRN23/XLH biochemical 
parameters of interest (creatinine, calcium, and intact parathyroid hormone (iPTH) 
• 
Immunogenicity (anti-drug antibody [ADA] against KRN23) 
• 
Concomitant medications 
Ectopic Mineralization Safety Assessments: 
• 
Renal ultrasound 

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• 
Echocardiogram (ECHO) and electrocardiogram (ECG)  
STATISTICAL METHODS: 
A full description of the statistical evaluations will be provided in the Statistical Analysis Plan 
(SAP). 
Sample Size: 
The study will enroll approximately 14 adult subjects with XLH including at least 8 subjects with a 
confirmed diagnosis of osteomalacia. To ensure a level of gender balance, at least 3 subjects of 
each sex will be enrolled. At least 6 paired biopsy specimens are expected at the end of the study. 
A reduction in excess osteoid is expected to be shown in all subjects with paired biopsies with an 
estimated ≥ 50% reduction from baseline in osteoid thickness. The sample size and study duration 
are believed to be sufficient to enable characterization of KRN23 effects on bone tissue and 
skeletal health.  
Analysis Populations: 
Primary Analysis Set:  The primary analysis set will include enrolled subjects with baseline and 
follow-up (Week 48 or ET) bone biopsy data.    
Full Analysis Set:  The full analysis set for efficacy is defined as all enrolled subjects who receive 
at least one dose of study drug.  
Safety Analysis Set:  The safety analysis set consists of all enrolled subjects who receive at least 
one dose of study drug. This analysis set will be used for the analyses of all safety endpoints. 
Treatment Extension Analysis Set:  The treatment extension analysis set consists of all enrolled 
subjects who continued after open-label treatment period and received at least one dose during the 
Treatment Extension Period I.  This analysis set will be used for the analyses of efficacy and safety 
endpoints.  
Primary Efficacy Analysis: 
The primary analysis will be performed using the primary analysis set. Osteoid volume (osteoid 
volume/bone volume, OV/BV) at baseline, 48 weeks, and the percent change from baseline at 
48 weeks will be summarized.  

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Secondary Efficacy Analyses: 
The key secondary endpoint will be summarized as the proportion of subjects who achieve a serum 
phosphorus level above the LLN (2.5 mg/dL [0.81 mmol/L]), at 2 weeks post-dose (between 
baseline and Week 24, on average). Additional analyses of serum phosphorus including observed 
values, change from baseline, percent change from baseline over time and area under the curve will 
be summarized. Similar analyses will be performed for 1,25(OH)2D, urinary phosphorus, 
TmP/GFR, and TRP. Additional histomorphometric indices (O.Th, OS/BS, and MLt) and the 
percent change from baseline at 48 weeks will be summarized.   
In general, observed values at baseline and end of study, and percent changes from baseline to end 
of the study for bone quality parameters and markers of bone turnover will be summarized. 
Safety Analysis: 
All AEs will be coded using the Medical Dictionary for Regulatory Activities (MedDRA). 
The incidence and frequency of AEs will be summarized by System Organ Class, Preferred Term, 
severity, and relationship to treatment. The incidence and frequency of AEs and SAEs will be 
summarized. A by-subject listing will be provided for those subjects who experience a SAE, 
including death, or experience an AE associated with early withdrawal from the study or study 
drug treatment. 
Clinical laboratory data will be summarized by the type of laboratory test. The frequency and 
percentage of subjects who experience abnormal clinical laboratory results (i.e., outside of 
reference ranges) and/or clinically significant abnormalities will be presented for each clinical 
laboratory measurement. 
A review of safety data will be conducted by the Data Monitoring Committee (DMC) periodically 
through the end of the Treatment Period (Week 48).  During Treatment Extension Periods I and II, 
safety data will be reviewed by the Ultragenyx Study Safety Review Team (SSRT) on an ongoing 
basis. 

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Table 2.1: 
Schedule of Events—Screening and Baseline Visits 
 
Screening1 
 
Baseline1 
VISIT TYPE/NUMBER 
 
TC 1 
TC 2 
V1 
STUDY WEEK or DAY 
Week −4 
Week −3 
Week −1 
Day -2 
Day -1 
Day/Wk 0 
Informed Consent, Inclusion/Exclusion Criteria 
X 
 
 
 
 
 
Medical History, Demographics, Height 2 
X 
 
 
 
 
 
PHEX Mutation Analysis 3,4 
 
 
 
X 
 
 
Tetracycline HCl or Demeclocycline Label 5 
 
X 
X 
 
 
 
Bone Biopsy 1 
 
 
 
 
X 
 
Bone Turnover Markers 6 
 
 
 
X 
 
 
Serum Phosphorus, Calcium, iPTH, Creatinine/eGFR 6 
X 
 
 
X 
 
 
Serum 1,25(OH)2D 6 
 
 
 
X 
 
 
Serum iFGF23  
X4 
 
 
X 
 
 
2-hr Urine 6,7 
X 
 
 
X 
 
 
24-hr Urine 6,7 
 
 
 
X 
 
 
BPI, BFI 8,9 
X 
 
 
X 
 
 
Skeletal survey 10 
 
 
 
X 
 
 
Anti-KRN23 (ADA) 
 
 
 
 
 
X 
Vital Signs 11 
X 
 
 
X 
X 
X 
Physical Examination 
X 
 
 
X 
 
 
Weight12 
 
 
 
X 
 
 
Renal Ultrasound 1 
X 
 
 
 
 
 
ECHO, ECG 1 
 
 
 
X 
 
 
Chemistry, Hematology (with PT/PTT), Urinalysis/pregnancy test6, 13, 14 
X 
 
 
X 
 
 
Concomitant Medications 
X 
 
 
X 
X 
X 
Adverse Events 
X 
 
 
X 
X 
X 
KRN23 ADMINISTRATION 
 
 
 
 
 
X 
 

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Table 2.2: 
Schedule of Events—Open Label Treatment Period (Weeks 1 – 48) 
VISIT TYPE/NUMBER15 
HH 
V2 
V3 
V4 
HH
V5 
HH
V6 
V7 
HH
V8 
HH
V9 
HH  
V10 
HH
V11 
V12 
V13 
HH   
V14 
HH
V15 
V16 
HH
V17 
HH 
V18 
TC
3 
TC
4 
V191 
WEEK 
1 
2 
4 
6 
8 
12 
14 
16 
20 
21 
22 
24 
28 
32 
36 
40 
44 
45 
47 
481 
Day 
1 
Day 
2 
Tetracycline HCl or 
Demeclocycline Label5 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
X 
 
 
Bone Biopsy 1 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X16 
Bone Turnover Markers 6 
 
 
 
 
 
X 
 
 
 
 
 
X 
 
 
 
 
 
 
 
X 
 
Serum Phosphorus, Calcium 6  
X 
X 
X 
X 
 
X 
X 
 
X 
X 
X 
X 
X 
 
X 
 
 
 
 
X 
 
Serum 1,25(OH)2D 6 
X 
X 
X 
 
 
 
 
 
X 
X 
X 
X 
 
 
 
 
 
 
 
X 
 
iPTH6 
X 
X 
X 
 
 
 
 
 
X 
X 
X 
 
 
 
 
 
 
 
 
X 
 
Serum iFGF236 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
X 
 
Serum Creatinine/eGFR6 
 
X 
X 
 
 
X 
 
 
 
 
X 
X 
 
 
 
 
 
 
 
X 
 
2-hr Urine 6,7 
 
X 
X 
 
 
X 
 
 
 
 
X 
X 
 
 
 
 
 
 
 
X 
 
24-hr Urine 6,7  
 
 
 
 
 
X 
 
 
 
 
 
X 
 
 
X 
 
 
 
 
X 
 
BPI, BFI 8,9 
 
 
 
 
 
X 
 
 
 
 
 
X 
 
 
X 
 
 
 
 
X 
 
Targeted Radiography 10 
 
 
 
 
 
X 
 
 
 
 
 
X 
 
 
X 
 
 
 
 
X 
 
KRN23 PK 
X 
X 
X 
 
 
 
 
 
 
X 
X 
X 
 
 
 
 
 
 
 
X 
 
Anti-KRN23 (ADA) 
 
 
X 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
X 
 
Vital Signs 11 
 
 
X 
 
 
X 
 
 
 
 
 
X 
 
 
X 
 
 
 
 
X 
 
Weight 12  
 
 
 
 
 
X 
 
 
 
 
 
X 
 
 
X 
 
 
 
 
X 
 
Physical Examination 
 
 
 
 
 
X 
 
 
 
 
 
X 
 
 
X 
 
 
 
 
X 
 
Renal Ultrasound  
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
X 
 
ECHO, ECG  
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
X 
 
Chemistry, Hematology (with 
PT/PTT), Urinalysis 6, 13 
 
 
X 
 
 
X 
 
 
 
 
 
X 
 
 
X 
 
 
 
 
X 
 
Urine Pregnancy Test 14 
 
 
X 
 
X 
X 
 
X 
X 
 
 
X 
X 
X 
X 
X 
X 
 
 
X 
 

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VISIT TYPE/NUMBER15 
HH 
V2 
V3 
V4 
HH
V5 
HH
V6 
V7 
HH
V8 
HH
V9 
HH  
V10 
HH
V11 
V12 
V13 
HH   
V14 
HH
V15 
V16 
HH
V17 
HH 
V18 
TC
3 
TC
4 
V191 
WEEK 
1 
2 
4 
6 
8 
12 
14 
16 
20 
21 
22 
24 
28 
32 
36 
40 
44 
45 
47 
481 
Day 
1 
Day 
2 
Concomitant Medications 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
X 
X 
Adverse Events 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
X 
X 
KRN23 ADMINISTRATION 
 
 
X 
 
X 
X 
 
X 
X 
 
 
X 
X 
X 
X 
X 
X 
 
 
X 
 
 
 
 

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Table 2.3:  
Schedule of Events – Treatment Extension Period I (Weeks 49-96), Early Termination, and Safety Follow-up 
 
 
Treatment Extension Period I 
 
Early Termination 
Safety 
Follow-up 
VISIT TYPE/NUMBER15 
HH 
V20 
HH 
V21 
 
V22 
HH 
V23 
HH 
V24 
HH 
V25 
 
V26 
HH 
V27 
HH 
V28 
 
V29 
HH 
V30 
HH 
V31 
HH 
V32 
V331 
EOS 
I19 
 
ET1, 20 
Follow-up 
Phone Call18 
 
 
WEEK 
 
 
52 
 
56 
 
60 
 
64 
 
68 
 
70 
 
72 
 
76 
 
80 
 
84 
 
88 
 
92 
 
94 
 
96 
TC 5 
TC 6 
ET 
Week 
-3 
Week 
-1 
Day 
1 
Day 
2 
Bone Biopsy1 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X16 
 
Tetracycline HCl or 
Demeclocycline Label5, 16 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
X 
 
 
 
Bone Turnover Markers 6 
 
 
 
 
 
 
X 
 
 
 
 
 
 
X 
 
 
X 
 
 
Serum Phosphorus, Calcium 6  
 
 
X 
 
 
X 
X 
 
 
X 
 
 
X 
X 
 
 
X 
 
 
Serum 1,25(OH)2D 6 
 
 
X 
 
 
X 
X 
 
 
X 
 
 
X 
X 
 
 
X 
 
 
iPTH6 
 
 
X 
 
 
X 
X 
 
 
X 
 
 
X 
X 
 
 
X 
 
 
Serum iFGF236 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
X 
 
 
Serum Creatinine/eGFR6 
 
 
X 
 
 
 
X 
 
 
X 
 
 
 
X 
 
 
X 
 
 
2-hr Urine 6,7 
 
 
X 
 
 
 
X 
 
 
X 
 
 
 
X 
 
 
X 
 
 
24-hr Urine 6,7  
 
 
 
 
 
 
X 
 
 
 
 
 
 
X 
 
 
X 
 
 
BPI, BFI 8,9 
 
 
 
 
 
 
X 
 
 
 
 
 
 
X 
 
 
 
 
 
Targeted Radiography 10 
Only at clinic visits following a newly diagnosed fracture17 
 
Anti-KRN23 (ADA) 
 
 
 
 
 
 
X 
 
 
 
 
 
 
X 
 
 
X 
 
 
KRN23 PK 
 
 
 
 
 
X 
X 
 
 
 
 
 
 
X 
 
 
X 
 
 
Vital Signs 11 
 
 
X 
 
 
 
X 
 
 
X 
 
 
 
X 
 
 
X 
 
 
Weight 12  
 
 
 
 
 
 
X 
 
 
 
 
 
 
X 
 
 
X 
 
 
Physical Examination 
 
 
 
 
 
 
X 
 
 
 
 
 
 
X 
 
 
X 
 
 
Renal Ultrasound  
 
 
 
 
 
 
X 
 
 
 
 
 
 
X 
 
 
X 
 
 
ECHO, ECG  
 
 
 
 
 
 
X 
 
 
 
 
 
 
X 
 
 
X17 
 
 
Chemistry, Hematology (with 
PT/PTT), Urinalysis 6, 13 
 
 
X 
 
 
 
X 
 
 
X 
 
 
 
X 
 
 
X13 
 
 
Urine Pregnancy Test 14 
X 
X 
X 
X 
X 
 
X 
X 
X 
X 
X 
X 
 
X 
 
 
X 
 
 
Concomitant Medications 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
X 
X 
X 
Adverse Events 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
X 
X 
X 

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Treatment Extension Period I 
 
Early Termination 
Safety 
Follow-up 
VISIT TYPE/NUMBER15 
HH 
V20 
HH 
V21 
 
V22 
HH 
V23 
HH 
V24 
HH 
V25 
 
V26 
HH 
V27 
HH 
V28 
 
V29 
HH 
V30 
HH 
V31 
HH 
V32 
V331 
EOS 
I19 
 
ET1, 20 
Follow-up 
Phone Call18 
 
 
WEEK 
 
 
52 
 
56 
 
60 
 
64 
 
68 
 
70 
 
72 
 
76 
 
80 
 
84 
 
88 
 
92 
 
94 
 
96 
TC 5 
TC 6 
ET 
Week 
-3 
Week 
-1 
Day 
1 
Day 
2 
KRN23 
ADMINISTRATION21 
X 
X 
X 
X 
X 
 
X 
X 
X 
X 
X 
X 
 
X21 
 
 
 
 
 
 
 
Footnotes to Table 2.1, Table 2.2, and Table 2.3 
1 
The Baseline visit should occur no more than 31 days following the Screening visit. The bone biopsy must be completed on a day with no other procedures, 
and prior to dosing on Day 0. Renal ultrasound, ECHO, ECG, and x-rays may be performed within 3 days of indicated clinic visit to accommodate 
scheduling availability. The Baseline, Week 48, and Week 96 (or Early Termination; ET) assessments may be completed in any reasonable order (except 
where indicated) to allow for flexibility in scheduling. However, all Screening/Baseline assessments and inclusion/exclusion criteria must be satisfied prior 
to dosing.  
2 
Medical history will include any available previous PHEX mutation analysis results for the subject or relevant family members with appropriate X-linked 
inheritance pattern. Height (in meters) will be obtained using a stadiometer (without shoes).  
3 
PHEX mutation analysis will be performed for all qualified subjects. If the Baseline result for PHEX mutation analysis is negative or inconclusive (i.e., No 
Mutation, Likely Benign, Variant of Uncertain Significance, or Possibly Pathogenic), and informed consent is provided by the subject, reflexive genetic 
testing will be performed to assess additional genes associated with phenotypes overlapping with XLH. A new blood sample for genetic analysis may be 
collected if necessary. 
4 
For patients without prior PHEX mutation analysis who fail screening on the basis of the Kainos iFGF23 assay, PHEX analysis may be conducted before the 
baseline visit  
5 
Available test results related to eligibility will be communicated to the subject within 1 week of the Screening visit by telephone call (TC1). If eligible, 
tetracycline HCl (or demeclocycline) will be provided to the subject with instructions for administration. The bone biopsy should be performed 5 days after 
the last dosing day for tetracycline or demeclocycline:  The first dose should be given on days -20, -19, and -18 following TC1, and the second dose given on 
days -8, -7, and -6 following a second telephone call (TC2). The same instructions apply to TC3 and TC4 prior to the Week 48 (or TC5 and TC6 prior to ET 
if applicable) bone biopsy. 
6 
Blood and urine to be collected after a minimum overnight fasting time of 8 hours and prior to drug administration (if applicable). 
7 
Both 2-hr and 24-hr urine will be used for measurements of urinary phosphorus, creatinine and calcium; 2-hr urine will be used for the derivation of 
TmP/GFR and TRP. 
8 
Only the BPI Question 3 (Worst Pain) will be administered at Screening for eligibility. The complete short-form BPI and BFI will be administered at all 
other indicated visits. 
9 
Administer BPI first followed by BFI. The BPI and BFI should be administered prior to the performance of any invasive procedures. 
10 
X-rays will be taken at locations pre-determined by skeletal survey (chest, lateral spine, right and left hand/wrist, right and left humerus, right and left 
radius/ulna, right and left femur/pelvis, right and left tibia/fibula, and right and left foot). If active pseudofracture(s) or fracture(s) are detected at baseline, 

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targeted X-rays at that location will be obtained as indicated.  During the Treatment Extension Period I, targeted x-rays will only be performed at clinic 
visit(s) to follow healing of any newly diagnosed fractures. 
11 
Vital sign measurements consist of seated systolic/diastolic BP measured in millimeters of mercury (mm Hg; 2 measurements separated by 15 minutes), HR 
(beats per minute), respiration rate (breaths per minute), and temperature in degrees Celsius (°C). Obtain at the beginning of the visit before any additional 
assessments are completed 
12 
Weight will be recorded in kilograms. Dose of study drug must be adjusted if weight increases by more than 20% from baseline.  
13 
Serum chemistry panels may include PD parameters (i.e. serum phosphorus), and safety parameters of interest (i.e. calcium) to avoid duplication of testing. 
Screening and Week 48 Day1 hematology will include Prothrombin time/Partial thromboplastin time (PT/PTT). ET hematology will include PT/PTT if a 
bone biopsy is also scheduled (if a subject discontinues the study between 24 and 48 weeks) 
14 
Urine pregnancy test for women of childbearing potential only. A serum pregnancy test will be performed in the event of a positive or equivocal urine 
pregnancy test result. 
15 
During the Open-Label Treatment Period (Weeks 1 – 48) and Treatment Extension Period I (Weeks 49-96) subjects will return to the clinic and/or have 
home health (HH) visits as indicated (± 5 days). HH visits may also be conducted at the clinic depending on subject proximity to the investigational site and 
local availability of home health care resources. 
16 
Bone biopsies will not be performed at Week 48 (or at ET) for subjects who do not have evidence of osteomalacia on the initial biopsy. Bone biopsies will 
not be performed at the ET Visit if the subject discontinues within 6 months of the baseline biopsy or if the subject terminates the study after 48 weeks. Prior 
to ET biopsy, tetracycline HCl (or demeclocycline) will be provided to the subject with instructions for administration. The bone biopsy should be performed 
5 days after the last dosing day for tetracycline or demeclocycline The first dose should be given on days -20, -19, and -18 following TC5, and the second 
dose given on days -8, -7, and -6 following a subsequent telephone call (TC6) prior to the ET biopsy (if eligible).   
17 
Targeted X-rays and ECHO will not be performed at ET if the assessment was conducted within 3 months of termination.  Targeted X-rays will not be taken 
at ET if the subject terminates the study after 48 weeks.   
18 
To be completed for all subjects who complete the EOS I or ET Visit and are not immediately continuing KRN23 treatment under commercial use or another 
mechanism. The site personnel will initiate a Safety Follow-up telephone call (TC) 4 weeks (+ 5 days) after the EOS I/ET Visit to collect information on 
whether KRN23 treatment has been started through another mechanism and, if not, any ongoing or new AEs, SAEs, or concomitant medications. 
Appropriate follow-up of AEs/SAEs should continue until all safety concerns, in the Investigator’s opinion, are resolved. If the subject is not continuing 
KRN23 therapy under commercial use or another mechanism at that time, then site personnel will initiate a subsequent Safety Follow-up TC at 8 weeks 
(+ 5 days) after the EOS I/ET Visit to collect information on whether KRN23 treatment has been started through another mechanism and, if not, any ongoing 
or new AEs, SAEs, or concomitant medications.    
19 
For subjects at study sites outside of the US, their final scheduled site visit at Week 96 will be their End of Study (EOS) efficacy visit; this visit is referred to 
as EOS I.  No study drug will be administered to these subjects at this visit under the current protocol.  If the subject will be continuing KRN23 treatment 
under commercial use or another mechanism, the first dose of that treatment should not be administered until after completion of all of the EOS I Visit 
assessments.   
20 
If a subject will be continuing KRN23 treatment under commercial use or another mechanism, the first dose of that treatment should not be administered 
until after completion of all of the ET Visit assessments. 
21 
Study drug will be administered every 28 days (± 5 days and no fewer than 14 days apart). For subjects outside the US, no study drug will be administered at 
the Week 96 Visit. 
 
 

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Table 2.4: 
Schedule of Events – Treatment Extension Period II (Week 97 – End of Study II) Plus Safety Follow-up 
(Sites in United States Only) 
VISIT FREQUENCY or VISIT ID 1  
Q4W (HH Visit) 
Q12W  
Q24W  
EOS II12  
Safety Follow-up 
TC13 
Serum Phosphorus 2   
 
X 
 
X 
 
Serum Calcium 2 
 
X 
 
X 
 
Serum 1,25(OH)2D 2 
 
X 
 
X 
 
Serum iPTH 2  
 
X 
 
X 
 
Serum iFGF23  
 
 
 
X 
 
Serum Creatinine/eGFR 2 
 
 
 
X 
 
Bone turnover markers 2 
 
 
 
X 
 
2-hr Urine 2, 3 
 
 
 
X 
 
24-hr Urine 2, 3 
 
 
 
X 
 
Targeted X-ray 4 
Only at clinic visits following a newly diagnosed fracture  
BPI, BFI 5, 6 
 
 
X 
X  
 
KRN23 PK 7 
 
 
 
X 
 
Anti-KRN23  (ADA) 
 
 
 
X 
 
Vital Signs 8 
 
X 
 
X 
 
Physical Examination, Weight 9 
 
X 
 
X 
 
Renal Ultrasound 
 
 
 
X 
 
ECHO, ECG 
 
 
 
X  
 
Chemistry, Hematology, Urinalysis 2 
 
X 
 
X 
 
Urine Pregnancy Test 10 
X 
 
 
X 
 
AEs/Concomitant Medication 
X 
 
 
X 
X 
KRN23 Administration 11 
X 
 
 
 
 
1 
During Treatment Extension Period II (Weeks 97 – End of Study II for subjects at sites in the US only), clinic visits will occur at 12-week intervals (± 5 
days). Subjects have home health (HH) visits at 4-week intervals (± 5 days). HH visits may also be conducted at the clinic depending on subject proximity to 
the investigational site and local availability of home health care resources. 
2 
Blood and urine to be collected after a minimum overnight fasting time of 8 hours and prior to drug administration (if applicable). Peak serum phosphorus 
may be collected as an unscheduled laboratory assessment if necessary. 

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3 
Both 2-hr and 24-hr urine will be used for measurements of urinary phosphorus, creatinine and calcium; 2-hr urine will be used for the derivation of 
TmP/GFR and TRP.   
4 
Targeted x-rays will only be performed at clinic visit(s) to follow healing of any newly diagnosed fractures. 
5 
Administer BPI first followed by BFI. The BPI and BFI should be administered prior to the performance of any invasive procedures. 
6 
The complete short-form BPI and BFI will be administered 
7 
Obtain blood samples for KRN23 measurement prior to drug administration (if applicable). 
8 
Vital sign measurements consist of seated systolic/diastolic BP measured in millimeters of mercury (mm Hg; 2 measurements separated by 15 minutes), HR 
(beats per minute), respiration rate (breaths per minute), and temperature in degrees Celsius (°C). Obtain at the beginning of each indicated visit before any 
additional assessments are completed. 
9 
Weight will be recorded in kilograms. Dose of study drug must be adjusted if weight changes by more than 20% from baseline. 
10 
For women of childbearing potential only. A serum pregnancy test will be performed in the event of a positive or equivocal urine pregnancy test result 
11 
Study drug will be administered every 28 days (± 5 days and no fewer than 14 days apart)  
12 
For subjects who complete Treatment Extension Period II, their final End of Study (EOS) efficacy visit is referred to as EOS II and should occur before 
30 September 2018. If a subject will be continuing KRN23 treatment under commercial use or another mechanism, the first dose of that treatment should not 
be administered until after completion of all of the EOS II Visit assessments. 
13 
To be completed for all subjects who complete the EOS II Visit and are not immediately continuing KRN23 treatment under commercial use or another 
mechanism. The site personnel will initiate a Safety Follow-up telephone call (TC) 4 weeks (+ 5 days) after the EOS II/ET Visit to collect information on 
whether KRN23 treatment has been started through another mechanism and, if not, any ongoing or new AEs. SAEs, or concomitant medications. 
Appropriate follow-up should continue until all safety concerns, in the Investigator’s opinion, are resolved. If the subject is not continuing KRN23 therapy 
under commercial use or another mechanism at that time, then site personnel will initiate a subsequent Safety Follow-up TC at 8 weeks (+ 5 days) after the 
EOS II/ET Visit to collect information on whether KRN23 treatment has been started through another mechanism and, if not, any ongoing or new AEs, 
SAEs, or concomitant medications. 

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3 TABLE OF CONTENTS 
1 TITLE PAGE .......................................................................................................................1 
2 SYNOPSIS ...........................................................................................................................4 
3 TABLE OF CONTENTS ...................................................................................................22 
4 LIST OF ABBREVIATIONS AND DEFINITION OF TERMS ......................................26 
5 INTRODUCTION .............................................................................................................29 
5.1 Overview of XLH .....................................................................................................30 
5.2 Brief Overview of KRN23 Development .................................................................31 
5.2.1 
Brief Description of KRN23 .......................................................................31 
5.2.1.1 
Mechanism of Action in XLH .....................................................31 
5.2.2 
Nonclinical Studies ......................................................................................31 
5.2.3 
Clinical Studies ............................................................................................33 
5.3 Summary of Overall Risks and Potential Benefits ....................................................34 
5.4 Study Rationale .........................................................................................................34 
5.5 Primary Efficacy Hypothesis ....................................................................................35 
6 STUDY OBJECTIVES ......................................................................................................36 
7 INVESTIGATIONAL PLAN ............................................................................................37 
7.1 Overall Study Design and Plan .................................................................................37 
7.2 Discussion of Study Design, Including Choice of Control Group ............................37 
7.3 Selection of Study Population ...................................................................................38 
7.3.1 
Inclusion Criteria .........................................................................................39 
7.3.2 
Exclusion Criteria ........................................................................................40 
7.3.3 
Removal of Subjects from Therapy or Assessment ....................................42 
7.3.3.1 
Stopping Rules .............................................................................42 
7.4 Treatments .................................................................................................................43 
7.4.1 
Investigational Product ................................................................................43 
7.4.2 
Reference Therapy ......................................................................................44 

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7.4.3 
Selection of Doses and Study Duration .......................................................44 
7.4.3.1 
Study Duration .............................................................................45 
7.4.4 
Method of Assigning Subjects to Treatment Groups ..................................46 
7.4.5 
Blinding .......................................................................................................46 
7.4.6 
Treatment Compliance ................................................................................46 
7.5 Study Procedures and Assessments ..........................................................................46 
7.5.1 
Efficacy Measures .......................................................................................47 
7.5.1.1 
Iliac Crest Bone Biopsy ...............................................................48 
7.5.1.2 
Biochemical Markers ...................................................................48 
7.5.1.3 
Patient Reported Outcomes..........................................................49 
7.5.1.4 
Targeted Radiography and Skeletal Survey .................................50 
7.5.2 
Drug Concentration Measurements .............................................................51 
7.5.3 
Safety Measures & General Assessments ...................................................51 
7.5.3.1 
Medical History ...........................................................................51 
7.5.3.2 
Vital Signs ....................................................................................52 
7.5.3.3 
Weight and Height .......................................................................52 
7.5.3.4 
Physical Examination...................................................................52 
7.5.3.5 
Renal Ultrasound and Glomerular Filtration Rate .......................52 
7.5.3.6 
Echocardiogram ...........................................................................53 
7.5.3.7 
Electrocardiogram ........................................................................53 
7.5.3.8 
Clinical Laboratory Tests for Safety ............................................53 
7.5.3.9 
Pregnancy Testing ........................................................................55 
7.5.3.10 
Prior and Concomitant Therapy ...................................................56 
7.5.3.11 
Adverse Events ............................................................................57 
7.5.4 
Appropriateness of Measures ......................................................................57 
7.6 Statistical Methods and Determination of Sample Size ............................................58 
7.6.1 
Determination of Sample Size .....................................................................59 

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7.6.2 
Analysis Populations ...................................................................................59 
7.6.2.1 
Primary Analysis Set....................................................................59 
7.6.2.2 
Full Analysis Set ..........................................................................59 
7.6.2.3 
Safety Analysis Set ......................................................................59 
7.6.2.4 
Treatment Extension Analysis Set ...............................................59 
7.6.3 
General Principles .......................................................................................59 
7.6.3.1 
Subject Accountability .................................................................60 
7.6.3.2 
Demographic and Baseline Characteristics .................................60 
7.6.3.3 
Baseline ........................................................................................60 
7.6.4 
Efficacy Endpoints and Analyses ................................................................60 
7.6.4.1 
Primary Efficacy Endpoint ..........................................................60 
7.6.4.2 
Key Secondary Endpoint .............................................................61 
7.6.4.3 
Secondary Endpoints ...................................................................61 
7.6.4.4 
Exploratory Endpoints .................................................................62 
7.6.5 
Safety Analyses ...........................................................................................62 
7.6.6 
Interim Analysis ..........................................................................................63 
7.6.7 
Data Monitoring Committee .......................................................................63 
8 STUDY CONDUCT ..........................................................................................................64 
8.1 Ethics .........................................................................................................................64 
8.1.1 
Institutional Review Board or Ethics Committee ........................................64 
8.1.2 
Ethical Conduct of Study ............................................................................64 
8.1.3 
Subject Information and Consent ................................................................64 
8.2 Investigators and Study Administrative Structure ....................................................65 
8.3 Investigational Product Accountability .....................................................................65 
8.4 Data Handling and Record Keeping .........................................................................66 
8.4.1 
Case Report Forms and Source Documents ................................................66 
8.4.2 
Data Quality Assurance ...............................................................................66 

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8.4.3 
Record Retention .........................................................................................67 
8.5 Reporting and Follow-up of Adverse Events ............................................................67 
8.5.1 
Definition of Adverse Events ......................................................................67 
8.5.2 
Severity of Adverse Events .........................................................................68 
8.5.3 
Relationship of Adverse Events to Study Drug ...........................................69 
8.5.4 
Adverse Event Reporting to Ultragenyx .....................................................69 
8.5.4.1 
General .........................................................................................69 
8.5.4.2 
Serious Adverse Events, Serious Adverse Drug Reactions, 
and Requirements for Immediate Reporting ................................70 
8.5.4.3 
Urgent Safety Reporting ..............................................................70 
8.5.4.4 
Adverse Drug Reaction Reporting ...............................................71 
8.5.4.5 
Pregnancy in Subject or Partner ...................................................71 
8.5.4.6 
Review of Safety Data .................................................................72 
8.5.4.7 
Safety Contact Information ..........................................................73 
8.6 Financing and Insurance ...........................................................................................73 
8.7 Publication Policy .....................................................................................................73 
9 REFERENCES ..................................................................................................................74 
10 SIGNATURE PAGE .........................................................................................................78 
 
List of Tables 
Table 2.1: 
Schedule of Events—Screening and Baseline Visits ...........................14 
Table 2.2: 
Schedule of Events—Open Label Treatment Period (Weeks 1 – 
48) ........................................................................................................15 
Table 2.3:  
Schedule of Events – Treatment Extension Period I (Weeks 49-
96), Early Termination, and Safety Follow-up ....................................17 
Table 2.4: 
Schedule of Events – Treatment Extension Period II (Week 97 
– End of Study) Plus Safety Follow-up (Sites in United States 
Only) ....................................................................................................20 
Table 7.5.3.8.1: 
Clinical Laboratory Assessments for Safety ........................................54 

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4 LIST OF ABBREVIATIONS AND DEFINITION OF TERMS 
Abbreviations 
1,25(OH)2D 
1,25-dihydroxyvitamin D 
25(OH)D 
25-hydroxyvitamin D 
ADA 
anti-drug antibodies 
AE 
adverse event 
ALP 
alkaline phosphatase 
AUC 
area under the curve 
BALP 
bone-specific alkaline phosphatase 
BFI 
Brief Fatigue Inventory 
BFI-Q3 
Brief Fatigue Inventory Question 3 (worst fatigue in 24 hours) 
BFR 
bone formation rate 
BPI 
Brief Pain Inventory 
BUN 
blood urea nitrogen 
CBC 
complete blood count 
°C 
CFR 
degrees Celsius 
Code of Federal Regulations 
CKD-EPI 
Chronic Kidney Disease Epidemiology Collaboration 
CRF 
case report form 
CTx 
carboxy-terminal cross-linked telopeptide of type I collagen 
dL 
DMC 
deciliter 
Data Monitoring Committee 
EC 
Ethics Committee 
ECG 
electrocardiogram 
ECHO 
ECLA 
EDC 
echocardiogram 
electrochemiluminescent assay 
electronic data capture 
eGFR 
estimated glomerular filtration rate 
EOS 
End of Study (Visit) 
ET 
Early Termination (Visit) 
EU 
EudraCT 
European Union 
European Union Drug Regulating Authorities Clinical Trials 
FDA 
Food and Drug Administration 
FGF23 
GCP 
fibroblast growth factor 23 
Good Clinical Practice 

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GFR 
glomerular filtration rate 
GLP 
GMP 
Good Laboratory Practice 
Good Manufacturing Practice 
 
HIPAA 
 
Health Insurance Portability and Accountability Act 
Hyp 
IB 
hypophosphatemic 
Investigator’s Brochure 
ICF 
Informed Consent Form 
ICH 
International Conference on Harmonisation of Technical Requirements 
for Pharmaceuticals for Human Use 
iFGF23 
IgG1 
intact FGF23 
immunoglobulin G isotype 1 
IND 
Investigational New Drug (application) 
IRB 
Institutional Review Board 
iPTH 
intact parathyroid hormone 
IV 
intravenous 
kDa 
kilodalton 
kg 
kilogram 
KHK 
L 
Kyowa Hakko Kirin Co. Ltd. 
liter 
LLN 
lower limit of normal 
LVH 
left ventricular hypertrophy 
mAb 
monoclonal antibody 
MAR 
mineral apposition rate 
MLt 
mineralization lag time 
MedDRA 
Medical Dictionary for Regulatory Activities 
mg 
mm Hg 
mmol 
milligram 
millimeters of mercury 
millimole 
MS/BS 
mineralizing surface/bone surface 
NaPi-IIa 
type IIa sodium/phosphate cotransporter  
NaPi-IIc 
type IIc sodium/phosphate cotransporter  
NCI CTCAE 
National Cancer Institute Common Terminology Criteria for Adverse 
Events 
NOAEL 
no observed adverse effect level 
OS/BS 
osteoid surface/bone surface 
O.Th 
osteoid thickness 

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OV/BV 
osteoid volume/bone volume 
P1NP 
procollagen type 1 N-propeptide 
PD 
pharmacodynamic(s) 
PHEX 
Phosphate regulating gene with homology to endopeptidases located on 
the X chromosome 
PK 
pharmacokinetic(s) 
PRO 
patient-reported outcome 
PT 
prothrombin time 
PTT 
partial thromboplastin time 
PTH 
Q4W 
parathyroid hormone 
monthly; every four weeks 
RBC 
red blood cell 
RSI 
Reference Safety Information 
SAE 
serious adverse event 
SAP 
statistical analysis plan 
SC 
subcutaneous 
SSRT 
Study Safety Review Team 
SUSAR 
suspected unexpected serious adverse reactions 
TC 
telephone call 
TmP/GFR 
 
TRP 
ratio of renal tubular maximum reabsorption rate of phosphate to 
glomerular filtration rate 
tubular reabsorption of phosphate 
ULN 
upper limit of normal 
US 
United States 
WBC 
white blood cell 
XLH 
X-linked hypophosphatemia 
 
 
Definition of Terms 
Investigational Product is defined as, “A pharmaceutical form of an active ingredient or 
placebo being tested or used as a reference in a clinical trial, including a product with a 
marketing authorization when used or assembled (formulated or packaged) in a way different 
from the approved form, or when used for an unapproved indication, or when used to gain 
further information about an approved use” (from International Conference on 
Harmonisation of Technical Requirements for Pharmaceuticals for Human Use [ICH] 
Harmonised Tripartite Guideline E6: Guideline for Good Clinical Practice).  
The terms “Investigational Product” and “study drug” may be used interchangeably in the 
protocol. 

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5 INTRODUCTION 
X-linked hypophosphatemia (XLH) is a disorder of hypophosphatemia, renal phosphate 
wasting, and defective bone mineralization caused by inactivating mutations in the PHEX 
gene (phosphate-regulating gene with homologies to endopeptidases on the X chromosome). 
In the absence of functional PHEX, release of fibroblast growth factor 23 (FGF23) by 
osteocytes is greatly increased. Excess circulating FGF23 leads to decreased reabsorption of 
phosphate and reduced 1,25-dihydroxyvitamin D (1,25(OH)2D) production, resulting in 
decreased intestinal absorption of calcium and phosphate. Chronic hypophosphatemia leads 
to defective bone mineralization and consequently to rickets in children and osteomalacia in 
adults, the two major pathologic features of XLH. 
Adult patients with XLH have significant morbidity that increases with age. In adulthood, 
XLH progresses into a disease of persistent and often clinically significant osteomalacia as a 
result of chronic low phosphorus, causing bone and joint pain and pseudofractures in a large 
proportion of patients (Reid et al. 1989). With age, osteoarthritis often develops, in part due 
to degenerative changes resulting from joint misalignment that occurred with childhood 
rickets. Mineralization of tendons/ligaments (enthesopathy) and recurrent dental abscesses 
may also occur. Adults with XLH also have muscle dysfunction, likely due to the importance 
of phosphate in energy metabolism, which may contribute significantly to the fatigue and 
weakness expressed by these patients (Reid et al. 1989), (Veilleux et al. 2012), (Sabbagh et 
al. 2008). 
The current standard of care for XLH in children consists of oral phosphate and vitamin D 
(calcitriol) replacement, which is typically discontinued in adolescence once longitudinal 
bone growth is complete. Treatment can improve rickets but provides limited benefit and 
does not treat the underlying cause (Carpenter et al. 2011). No consensus exists regarding 
treatment of XLH in adults, despite the significant morbidity in many patients. By blocking 
the action of the aberrantly elevated FGF23, phosphorus homeostasis could potentially be 
normalized, offering an effective and safe treatment option for patients with XLH. 
Proof-of-concept studies in a relevant murine model support the use of an anti-FGF23 
monoclonal antibody (mAb) as a treatment for XLH. Experiments in both juvenile and adult 
hypophosphatemic (Hyp) mice provided evidence that treatment with an anti-FGF23 mAb 
normalized or ameliorated many of the characteristic abnormalities associated with XLH  
(Aono et al. 2009), (Aono et al. 2011). KRN23 is a fully human IgG1 mAb that binds to and 
inhibits FGF23. The Sponsor and development partner, Kyowa Hakko Kirin Co. Ltd. (KHK) 
are investigating KRN23 as a potential therapeutic candidate for the treatment of XLH, a 
disease distinguished by high levels of serum FGF23. 
KHK has conducted a series of nonclinical pharmacology, pharmacokinetic (PK), and 
toxicology studies supporting the investigation of KRN23 in adults and children. 
Three clinical studies have been completed in adult patients with XLH: a single dose Phase 1 
safety and tolerability study of KRN23, a repeat dose Phase 1/2 dose escalation study, and an 
associated treatment extension study. An additional open-label long-term extension study is 

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ongoing. A randomized, double-blind, placebo-controlled, Phase 3 study is planned in 
symptomatic adults with XLH to establish the efficacy and safety profile of KRN23 
treatment. The study also seeks to establish the beneficial impact of KRN23 treatment on 
functional and patient-reported outcomes (PROs) including pain, stiffness, fatigue, and 
health-related quality of life. The current open-label study will examine the efficacy of 
KRN23 on bone quality and skeletal health, including the effects on osteomalacia at the 
tissue level, and provide an additional assessment of safety. 
5.1 
Overview of XLH 
XLH is a rare genetic disorder that is serious, chronically debilitating and represents an 
unmet medical need. This genetic deficiency is estimated to occur in about 1:20,000 live 
births (Burnett et al. 1964), (Imel et al. 2005). XLH is the most common inherited form of 
rickets and the most common inherited defect in renal tubular phosphate transport. XLH is 
transmitted as an X-linked dominant disorder (Dixon et al. 1998). Mutations resulting in the 
loss of function of PHEX form the genetic basis for XLH (Carpenter et al. 2011). More than 
300 different PHEX gene mutations have been identified in patients with XLH (PHEXdb); 
however, few definitive correlations have been observed between specific mutations and 
phenotypic severity. 
Patients with XLH have hypophosphatemia due to excessive FGF23 levels (Jonsson et al. 
2003), (Yamazaki et al. 2002); however, the precise mechanism by which PHEX disruption 
results in elevated FGF23 is complex and not fully understood (Rowe 2012), (Carpenter et al. 
2011). FGF23 plays an important role as a specific regulator of serum phosphorus; its major 
function is to reduce serum phosphorus levels by inhibiting renal proximal tubular phosphate 
reabsorption (Fukumoto 2008), (Razzaque et al. 2007). FGF23 also decreases serum 
1,25(OH)2D levels by inhibiting 1-alpha-hydroxylase activity in the kidney, thereby 
decreasing intestinal absorption of phosphate and calcium. The actions of FGF23 on the 
tubular reabsorption and intestinal absorption via vitamin D metabolism lead to a decrease in 
serum phosphorus levels. 
Patients with XLH often present during childhood with rickets due to hypophosphatemia and 
frequently develop skeletal abnormalities (e.g. bowed legs), impaired growth, and short adult 
stature (Tenenhouse et al. 2001). As young patients age and progress into adulthood, the 
symptom pattern evolves due to decreased phosphate requirements for bone growth. 
Adult XLH patients suffer from bone pain and osteomalacia, increased risk of bone fractures, 
joint abnormalities and joint pain, enthesopathy, and osteoarthritis (Carpenter et al. 2011). 
No consensus exists regarding treatment of adult patients with XLH (Linglart et al. 2014). 
The use of oral phosphate and vitamin D may be initiated for the treatment of osteomalacia, 
bone/joint pain and pseudofractures in symptomatic patients, although evidence of efficacy is 
limited (Sullivan et al. 1992). This treatment protocol requires frequent and continued 
monitoring of patients. Serum and urine mineral metabolite levels and imaging studies are 
required to assess toxicity and secondary complications, including nephrocalcinosis, 
hypercalciuria, and hyperparathyroidism (Carpenter et al. 2011). 

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5.2 
Brief Overview of KRN23 Development 
A brief overview of existing information on KRN23 is provided below; a comprehensive 
review of the data is contained in the Investigator’s Brochure (IB) provided by Ultragenyx 
Pharmaceutical Inc. (Ultragenyx), which should be reviewed prior to initiating the study.  
5.2.1 
Brief Description of KRN23 
KRN23 is a recombinant human IgG1 mAb that binds to and inhibits the activity of FGF23. 
KRN23 is expressed in Chinese Hamster Ovary dihydrofolate reductase-deficient cells. 
The secreted KRN23 antibody is recovered from the culture medium and purified using a 
series of chromatographic and filtration steps. Based on the amino acid sequence, the 
predicted molecular mass of KRN23 is approximately 140 kilodaltons (kDa). Nonclinical 
studies demonstrated KRN23 possesses high binding affinity to the N-terminal domain of 
FGF23. KRN23 binds to FGF23 from humans, cynomolgus monkeys and rabbits, but not to 
other species tested. 
5.2.1.1 
Mechanism of Action in XLH 
Patients with XLH have hypophosphatemia due to excessive serum FGF23 levels. FGF23 
reduces serum phosphorus levels by two distinct mechanisms of action (Fukumoto 2008), 
(Razzaque et al. 2007), (Yamazaki et al. 2008). The primary mechanism is to inhibit 
phosphate reabsorption in the proximal tubule of the kidney. The secondary mechanism is to 
decrease phosphate absorption by the small intestine through the inhibition of 1,25(OH)2D 
production in the kidney. 
KRN23 has the potential to block or reduce FGF23 action and improve phosphate 
homeostasis in XLH patients. KRN23 binds the amino-terminal domain of FGF23 that 
interacts with the FGF-binding portion of the combination FGFR1/Klotho receptor, 
preventing FGF23 from binding to and signaling from its receptor. Both intact and 
fragmented FGF23 polypeptides are immunoprecipitated with KRN23 (Yamazaki et al. 
2008). By inhibiting FGF23, KRN23 restores tubular reabsorption of phosphate (TmP/GFR) 
from the kidney and increases the production of 1,25(OH)2D that also enhances intestinal 
absorption of phosphate. Both actions increase serum phosphorus levels, which is expected to 
improve bone mineralization and reduce the diverse bone and non-bone manifestations 
associated with hypophosphatemia in XLH patients. Bone histomorphometry is the gold 
standard to evaluate changes in osteomalacia as it allows an assessment of bone quality at the 
tissue level. 
5.2.2 
Nonclinical Studies 
The Hyp mouse is a murine homologue of XLH with a deletion in the 3ꞌ region of the PHEX 
gene (Liu et al. 2007), (Perwad et al. 2005). In addition to hypophosphatemia, rickets, and 
associated developmental abnormalities, these animals display elevated serum FGF23 levels 
and increased expression of FGF23 in the bone. Since KRN23 does not bind murine FGF23, 
the pharmacological effects of murine anti-FGF23 mAbs were examined in juvenile and 

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adult Hyp mice (Aono et al. 2009), (Aono et al. 2011). In juvenile Hyp mice, anti-FGF23 
treatment corrected hypophosphatemia and ameliorated the rachitic bone phenotypes (Aono 
et al. 2009). Histomorphometry of secondary cancellous bones showed improvement in both 
static and dynamic parameters of osteoid accumulation. In adult Hyp mice, anti-FGF23 
treatment increased serum phosphate and 1,25(OH)2D levels, and increased grip strength and 
spontaneous movement (Aono et al. 2011). These studies provide proof-of-concept that 
treatment with antibodies targeting FGF23 may reverse or ameliorate characteristic 
abnormalities associated with XLH. 
KRN23 binds to human, rabbit, and monkey FGF23 with comparable affinities. In a study 
conducted under Good Laboratory Practice (GLP) conditions, KRN23 cross-reactivity was 
evaluated against a full panel of human, rabbit (32 tissues), and cynomolgus monkey 
(33 tissues) tissues by immunohistochemistry. No specific KRN23 staining was observed, 
suggesting untoward direct-effects of KRN23 are not expected in any tissues of normal 
humans, rabbits, or cynomolgus monkeys.  
A series of nonclinical pharmacology, PK, and toxicity studies have been conducted in 
rabbits and cynomolgus monkeys to support the use of KRN23 in adults and children. 
Findings of potential clinical significance and relevance to this protocol are summarized 
below; additional information is provided in the IB.  
• The no observed adverse effect level (NOAEL) in a 40-week toxicity study in adult 
cynomolgus monkeys was 0.03 mg/kg KRN23 for males and 0.3 mg/kg KRN23 for 
females. The NOAEL in a 40-week toxicity study in juvenile cynomolgus monkeys and a 
single-dose study in rabbits was 0.3 mg/kg KRN23. 
• Soft tissue and organ mineralization was a consistent finding associated with prolonged 
and excessive serum phosphate levels including the kidney where nephrocalcinosis was 
observed at the highest dose tested and reversibility of mineralization could not be 
established. 
• The most prominent pharmacologic actions of KRN23 were dose-dependent changes in 
serum inorganic phosphorus and 1,25(OH)2D in rabbits and juvenile, adult, and pregnant 
cynomolgus monkeys. 
• No gross or histopathological abnormalities were observed at the intravenous (IV) 
infusion sites or subcutaneous (SC) injection sites in the 40-week repeat-dose toxicity 
studies in adult and juvenile cynomolgus monkeys.  
• KRN23 demonstrated consistent and predictable PK behavior in both rabbits and 
cynomolgus monkeys based on the results of single- and repeat-dose studies where 
exposure was by either the IV or SC route. 
The NOAEL was the same in juvenile and adult monkeys suggesting no difference in 
sensitivity to the adverse effects of KRN23. The results from single- and repeat-dose 

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toxicology studies in rabbits and juvenile, adult, and pregnant cynomolgus monkeys suggest 
the primary toxicological effects of KRN23 are associated with prolonged and excessive 
antagonism of the normal regulatory actions of FGF23 on renal tubular phosphate 
reabsorption and vitamin D metabolism.  
5.2.3 
Clinical Studies 
Four clinical studies have been completed in adult patients with XLH: a single dose Phase 1 
safety and tolerability study of KRN23 (KRN23-US-02), a single dose Phase 1 safety and 
tolerability study of KRN23 in Japan and Korea (KRN23-001), a repeat dose Phase 1/2 dose 
escalation study (KRN23-INT-002), and an associated treatment extension study 
(KRN23-INT-002). An additional open-label long-term extension study (UX023-CL203) is 
ongoing. A Phase 2 dose-finding, pharmacodynamic (PD) and safety study is also being 
conducted in pediatric XLH patients (UX023-CL201). A confirmatory randomized, 
placebo-controlled Phase 3 safety and efficacy study is being conducted in parallel with this 
study (UX023-CL303). Details of study parameters and available PK, PD, clinical efficacy, 
and safety results are provided in the IB. 
Data from clinical studies to date are consistent with the proposed mechanism of action: that 
KRN23 blocks FGF23 action, leading to a sustained increase in serum phosphorus levels due 
to increased tubular reabsorption of phosphate (TmP/GFR) and increased intestinal 
absorption caused by increased 1,25(OH)2D. Single and repeat-dose clinical studies indicate 
SC administration of KRN23 consistently increased and sustained serum phosphorus levels 
and TmP/GFR, without a major impact on urine calcium levels or vitamin D metabolism. 
The data from the extension study suggest KRN23 could provide sustained increases in 
serum phosphorus levels sufficiently such that improvements in bone physiology, structure, 
and function would be expected.  
Repeated doses of KRN23 up to 1.0 mg/kg were well tolerated by adult XLH subjects 
throughout the Phase 1/2 dose escalation and associated treatment extension study. 
No deaths or life threatening treatment emergent adverse events (AEs) have been reported. 
In the extension study, serious adverse events (SAEs) reported for 3 subjects were unlikely to 
be or were not study drug related: breast cancer, hypertensive crisis, and cervical spinal 
stenosis. Throughout the extension study, treatment-related AEs were reported for 
14 subjects (63.6%) treated with KRN23 and included injection site reaction (5 subjects, 
22.7%), arthralgia (3 subjects, 13.6%), restless legs syndrome (3 subjects, 13.6%), and 
injection site pain (2 subjects, 9.1%). No discernible clinically significant trends of lab 
abnormalities suggestive of a treatment-related adverse effect were noted. Overall, no 
immunogenicity or patterns of dose-limiting toxicity have been associated with KRN23 
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5.3 
Summary of Overall Risks and Potential Benefits 
KRN23, a fully human mAb that binds and inhibits FGF23, is being developed as a potential 
therapeutic candidate for XLH, a rare genetic disease associated with hypophosphatemia and 
elevated levels of FGF23. By blocking the activity of FGF23, KRN23 has the potential to 
restore phosphate, vitamin D, and bone metabolism homeostasis in patients with XLH, 
thereby improving osteomalacia, the pathologic hallmark of XLH in adults. This therapeutic 
approach directly targets the inherent dysregulation in XLH (i.e., excess FGF23). In contrast, 
supplementation therapy with phosphate and/or 1,25(OH)2D, is only partially effective and 
carries a significant burden and risk of ectopic mineralization, particularly nephrocalcinosis. 
Clinical studies to date have demonstrated that KRN23 treatment blocks FGF23 action and 
leads to a sustained increase in serum phosphorus levels due to increased TmP/GFR. 
Increased 1,25(OH)2D was also observed, as expected, based on the inhibition of the excess 
of FGF23. Bone formation and resorption markers also increased. KRN23 was well tolerated 
in the population studied. No major safety concerns were observed; there was no evidence of 
immunogenicity, and no evidence of left ventricular hypertrophy (LVH) based on 
electrocardiogram (ECG), even though FGF23 levels were increased following KRN23 
treatment. Although ectopic mineralization is a known risk related to XLH disease and is 
exacerbated by oral phosphate and/or 1,25(OH)2D supplementation, KRN23 does not appear 
to be associated with progression of cardiac or renal ectopic mineralization beyond the 
natural course of pre-existing disease. 
SC doses of KRN23 in the range from 0.3 to 1.0 mg/kg were able to achieve the desired PD 
effect in adults, which lasted approximately one month, positioning KRN23 as a drug that 
could be administered once-per-month by SC injection, which is a convenient and acceptable 
therapeutic regimen for a chronic condition.  
In conclusion, KRN23 inhibits the effects of FGF23, restoring phosphate, vitamin D, and 
bone metabolism homeostasis. By positively modulating serum phosphorus, it is expected 
that the underlying osteomalacia will be resolved, leading to improved clinical outcomes 
including a reduction in pain, stiffness, fatigue, and fracture risk as well as the impact of 
these factors on the quality of life of adult patients with XLH. To date, KRN23 has a 
favorable safety profile without evidence of increased ectopic mineralization or other 
concerns associated with the excess of FGF23. KRN23 has the potential to be an effective 
and safe treatment option for patients with XLH. 
5.4 
Study Rationale 
XLH is a disorder of hypophosphatemia, renal phosphate wasting, and defective bone 
mineralization caused by inactivating mutations in the PHEX gene (phosphate-regulating 
gene with homologies to endopeptidases on the X chromosome). In the absence of functional 
PHEX, release of FGF23 by osteocytes is greatly increased. Excess circulating FGF23 
signals the kidney tubules to decrease phosphate reabsorption by down-regulating NaPi-IIa 
and NaPi-IIc in the tubular cells and suppressing 1,25(OH)2D production, resulting in 

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decreased intestinal absorption of calcium and phosphate producing hypophosphatemia. 
In adults with XLH, a hallmark of the disease is osteomalacia, a defect in bone 
mineralization due to chronically low serum phosphorus. Osteomalacia is characterized by a 
lack of proper mineralization, a prolonged mineralization process, and an accumulation of 
osteoid tissue. It is also associated with a reduction in bone remodeling and reduced bone 
quality and is a key contributor to the symptoms of bone and joint pain and the non-traumatic 
pseudofractures and reduced quality of life experienced by adults with XLH.  
KRN23 is a recombinant fully human IgG1 monoclonal antibody being developed to treat 
XLH by binding to FGF23 and inhibiting its activity, thereby increasing serum phosphorus 
levels and improving osteomalacia and related symptoms. Bone histomorphometry is the 
gold standard for evaluating changes in osteomalacia, thus it is important to characterize 
changes in bone biopsy parameters in response to KRN23 treatment. Bone biopsy studies in 
adults with XLH receiving oral phosphate and vitamin D therapy have shown incomplete 
healing of osteomalacia (Sullivan et al. 1992). In addition, there are no systematic studies in 
adults to show this regimen improves symptoms or outcomes, and there are concerns about 
the risk of long-term complications, particularly nephrocalcinosis, which increases with dose 
and duration of therapy. More efficacious, safer, and convenient therapies clearly are needed 
for adults who continue to experience XLH-related symptoms and complications. 
A Phase 1 study established the PK profile of KRN23. A Phase 1/2 study and associated 
extension study evaluated the PD of KRN23 on phosphate metabolism and related measures 
of the phosphate-calcium mineral control system. The safety data from these studies have 
shown that KRN23 in single and repeated monthly doses up to 1.0 mg/kg was well tolerated 
by adult subjects with XLH. KRN23 sufficiently increased serum phosphorus levels such that 
improvements in bone physiology, structure, and function would be expected.  
A randomized, double-blind, placebo-controlled Phase 3 study is being conducted to confirm 
the efficacy and safety of KRN23 treatment, and to establish the beneficial impact on 
patient-reported and functional outcomes in adults with XLH. The current open-label study 
will examine the efficacy of KRN23 on bone quality, including the effects on osteomalacia at 
the tissue level, and provide an additional assessment of safety.  During the Treatment 
Extension Periods I and II, additional changes in efficacy outcomes and long-term safety will 
be assessed. 
5.5 
Primary Efficacy Hypothesis 
Treatment with 1.0 mg/kg KRN23 monthly will improve XLH-associated osteomalacia as 
determined by osteoid volume (osteoid volume/bone volume, OV/BV). 

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6 STUDY OBJECTIVES 
Primary Efficacy Objective:   
Establish the effect of KRN23 treatment on improvement in XLH-associated osteomalacia as 
determined osteoid volume/bone volume. 
Secondary Efficacy Objectives: 
The key secondary efficacy objective is to establish the effect of KRN23 treatment on 
increasing serum phosphorus levels in adults with XLH   
Other secondary efficacy objectives are to establish the effect of KRN23 treatment in adults 
with XLH on: 
• Changes from baseline in additional histomorphometric parameters – including osteoid 
thickness (O.Th), osteoid surface/bone surface (OS/BS), and mineralization lag time 
(MLt) 
• Changes from baseline in parameters of bone mineralization including mineral apposition 
rate (MAR), mineralizing surface (MS/BS), bone formation rate (BFR), and others  
• Additional PD markers reflecting the status of phosphorus homeostasis and renal function 
• Bone remodeling as assessed by bone turnover markers 
Exploratory Efficacy Objectives: 
• Examine the effect of KRN23 treatment in adults with XLH on pseudofracture healing 
• PROs assessing skeletal pain and fatigue  
Pharmacokinetic Objective: 
Assess the PK of KRN23 throughout the dosing cycle following the first doses and at steady 
state  
Safety Objective:   
Establish the safety and tolerability profile of KRN23 in the treatment of adults with XLH 
including AEs, ectopic mineralization risk, cardiovascular effects, and immunogenicity 
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7 INVESTIGATIONAL PLAN 
7.1 
Overall Study Design and Plan 
UX023-CL304 is a Phase 3 open-label, single-arm, multicenter study to establish the effects 
of KRN23 on bone quality and osteomalacia associated with XLH. Approximately 14 adult 
subjects with a diagnosis of XLH supported by typical clinical and biochemical features, and 
who have not received oral phosphate and vitamin D therapy in the past two years will be 
enrolled. To ensure a level of gender balance, at least 3 subjects of each sex will be enrolled. 
Iliac crest bone biopsies will be performed at baseline and Week 48 (or ET if applicable). 
Baseline histologic and histomorphometric assessments of the bone biopsy specimens will be 
performed as each biopsy is completed to assess sample quality and confirm the presence of 
osteomalacia in at least 8 subjects. If a subject is determined not to have osteomalacia at the 
time of the initial biopsy, that subject will continue on study but will not undergo the second 
bone biopsy procedure at Week 48. All other assessments will be completed as scheduled. 
The goal of the study is to assess changes in bone quality. Histologic and histomorphometric 
evaluation of iliac crest bone biopsies will be supported by changes in serum phosphorus and 
biochemical markers of bone turnover and additional PD markers associated with 
FGF23-mediated processes. Pseudofractures and PROs will provide additional information 
on KRN23 efficacy. Safety, immunogenicity, and PK of KRN23 will also be evaluated. 
KRN23 will be administered via SC injections monthly (Q4W, 28 days) for 48 weeks. 
Subjects will then continue into an additional 48-week Treatment Extension Period I (until 
Week 96). For subjects at study sites outside of the United States (US), the Week 96 Visit 
will be their End of Study (EOS) efficacy visit (referred to as EOS I).  For subjects at sites in 
the US, treatment will continue for up to an additional 45 weeks  in an open-label Treatment 
Extension Period II, until end of September 2018, at which time they will have their EOS 
efficacy visit (referred to as EOS II).  (The duration of this period will vary for individual 
subjects and will be determined by the time from the start of Week 97 through their EOS II 
Visit).  For subjects not immediately continuing KRN23 treatment under commercial use or 
another mechanism upon completion of study drug treatment or early withdrawal from this 
study, a Safety Follow-up telephone call (TC) will occur 4 weeks (+5 days) after the 
subject’s final study site visit (ie EOS I [non-US subjects], EOS II [US subjects], or Early 
Termination [ET] visit) to collect information on any ongoing or new AEs, SAEs, and 
concomitant medications.  If the subject is not continuing KRN23 therapy under commercial 
use or another mechanism at that time, an additional Safety Follow-up TC will occur at 
8 weeks (+ 5 days) after the subject’s final study site visit. The end of this study is defined as 
the last day that the protocol specified assessments (including telephone contact) are 
conducted for the last subject..   
7.2 
Discussion of Study Design, Including Choice of Control Group 
The study is designed as an open-label, single-arm, multicenter clinical trial intended to 
establish the beneficial impact of KRN23 on bone quality and strengthen the long-term safety 
evaluation of KRN23. The study is being conducted in parallel with a pivotal randomized, 

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double-blind, placebo-controlled Phase 3 efficacy and safety study designed to confirm 
modulation of phosphate homeostasis and establish the impact of KRN23 treatment on 
patient-reported outcomes and functional performance. 
This Phase 3 study will be conducted in subjects most likely to benefit from treatment: adult 
XLH patients with osteomalacia and pain. The sample size and study population are intended 
to characterize KRN23 efficacy as related to bone quality following up to one year of 
treatment in adult XLH patients.  
The protocol consists of multiple study stages, a 48-week Open-Label Treatment Period 
(Weeks 0-48) and an additional 48-week Treatment Extension Period I (Weeks 49-96).  
In the US, the study will also include a Treatment Extension Period II (up to approximately 
45 weeks).  Case reports in XLH and nutritional osteomalacia suggest that healing of 
osteomalacia and resolution of associated symptoms (e.g., pain) are likely to occur within 
3 to 6 months of restoration of phosphorus homeostasis (Kang et al. 2014), (Shikino et al. 
2014), (Chalmers et al. 1967). Therefore, the 12-month duration of the initial Open-Label 
Treatment Period enables a rigorous assessment of improvements in skeletal health 
associated with phosphate control.  
Treatment with oral phosphate and vitamin D metabolites typically stops in adolescence and 
many adults experience long-term complications from the treatment, such as 
hyperparathyroidism and nephrocalcinosis. No consensus exists regarding treatment of adult 
patients with XLH, but symptomatic patients—those with bone or joint pain and/or 
pseudofractures—may be treated with oral phosphate and vitamin D replacement therapy 
(Linglart et al. 2014). However, a double-blind, active-comparator design would be very 
difficult given the differences in the method of administration (oral vs. SC injection for 
KRN23) and the individualized nature of treatment (Linglart et al. 2014), (Carpenter et al. 
2011). Furthermore, bone biopsy assessments and biochemical markers of bone turnover are 
objective, quantitative measures, which will not be impacted by the open-label design of the 
study.  
KRN23 treatment normalizes serum phosphorous levels, directly impacting the 
hypophosphatemia and consequent osteomalacia that is the hallmark of XLH, and the cause 
of the bone abnormalities that result in the clinical signs and symptoms of the disease. 
The primary efficacy variable reflects reduction in osteoid volume after 48 weeks of 
treatment. Secondary variables also address the final goals of therapy in adults with XLH, 
which are to restore skeletal health and thereby reduce the associated pain, fatigue, and 
fracture risk. 
7.3 
Selection of Study Population 
The study will be conducted in approximately 14 adult subjects with XLH 
(aged 18 – 65 years) including at least 8 subjects with a confirmed diagnosis of osteomalacia. 
To ensure a level of gender balance, at least 3 subjects of each sex will be enrolled. 
The inclusion criteria are structured to enroll subjects with a confirmed diagnosis of XLH, 

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presenting with characteristic biochemical and clinical features, including reduced serum 
phosphorus levels, osteomalacia, and pain. 
The Sponsor has taken reasonable measures to ensure the protection and safety of this 
population. Older patients (> 65 years) will be excluded due to frequent comorbidities that 
may make interpretation of the study results more difficult. Patients with evidence of 
hyperparathyroidism indicated by increased serum calcium and iPTH, and/or use of 
calcimimetics will also be excluded. 
7.3.1 
Inclusion Criteria 
Individuals eligible to participate in this study must meet all of the following criteria: 
1) Male or female, aged 18 - 65 years, inclusive 
2) Diagnosis of XLH supported by classic clinical features of adult XLH (such as short 
stature or bowed legs), and at least ONE of the following at Screening: 
• Documented PHEX mutation in either the patient or in a directly related 
family member with appropriate X-linked inheritance  
• Serum iFGF23 level > 30 pg/mL by Kainos assay 
3) Biochemical findings consistent with XLH based on overnight fasting (min. 8 hours):   
• Serum phosphorus < 2.5 mg/dL at Screening 
• TmP/GFR < 2.5 mg/dL at Screening  
4) Presence of skeletal pain attributed to XLH/osteomalacia, as defined by a score of 
≥ 4 on the Brief Pain Inventory question 3 (BPI-Q3, Worst Pain) at Screening. 
(Skeletal pain that, in the opinion of the investigator, is attributed solely to causes 
other than XLH/osteomalacia—for example, back pain or joint pain in the presence of 
severe osteoarthritis by radiograph in that anatomical location—in the absence of any 
skeletal pain likely attributed to XLH/osteomalacia should not be considered for 
eligibility.) 
5) Estimated glomerular filtration rate (eGFR) ≥ 60 mL/min (using the Chronic Kidney 
Disease Epidemiology Collaboration [CKD-EPI] equation) or eGFR of 45 to 
<60 mL/min at Screening with confirmation that the renal insufficiency is not due to 
nephrocalcinosis 
6) Provide written informed consent after the nature of the study has been explained, and 
prior to any research-related procedures. If the subject in a minor, provide written 
assent and have a legally authorized representative willing and able to provide written 
informed consent, after the nature of the study has been explained, and prior to any 
research-related procedures 

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7) Willing to provide access to prior medical records for the collection of biochemical 
and radiographic data and disease history 
8) Females of child-bearing potential must have a negative urine pregnancy test at 
Screening and Baseline and be willing to have additional pregnancy tests during the 
study. Females considered not to be of childbearing potential include those who have 
not experienced menarche, are post-menopausal (defined as having no menses for at 
least 12 months without an alternative medical cause) or are permanently sterile due 
to total hysterectomy, bilateral salpingectomy, or bilateral oophorectomy.   
9) Participants of child‐bearing potential or fertile males with partners of child-bearing 
potential who are sexually active must consent to use a highly effective method of 
contraception as determined by the site Investigator from the period following the 
signing of the informed consent through the final Safety Follow-up TC (as defined in 
Section 7.4.3.1) 
10) Must, in the opinion of the investigator, be willing and able to complete all aspects of 
the study, adhere to the study visit schedule and comply with the assessments 
7.3.2 
Exclusion Criteria 
Individuals who meet any of the following exclusion criteria will not be eligible to participate 
in the study: 
1) Use of any pharmacologic vitamin D metabolite or analog (e.g. calcitriol, 
doxercalciferol, and paricalcitol) within the 2 years prior to Screening 
2) Use of oral phosphate within the 2 years prior to Screening  
3) Use of aluminum hydroxide antacids, acetazolamides, and thiazides within 7 days 
prior to Screening  
4) Use of bisphosphonates in the 2 years prior to Screening 
5) Use of denosumab in the 6 months prior to Screening 
6) Use of teriparatide in the 2 months prior to Screening 
7) Chronic use of systemic corticosteroids defined as more than 10 days in the 2 months 
prior to Screening 
8) Corrected serum calcium level ≥ 10.8 mg/dL (2.7 mmol/L) at Screening 
9) Serum iPTH ≥ 2.5 times the upper limit of normal (ULN) at Screening 

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10) Use of medication to suppress PTH (cinacalcet for example) within 60 days prior to 
Screening 
11) Prothrombin time/Partial thromboplastin time (PT/PTT) outside the normal range at 
Screening 
12) Evidence of any disease or use of anticoagulant medication (such as warfarin, 
heparin, direct thrombin inhibitors, or xabans that, in the opinion of the investigator, 
cannot be discontinued) that may increase the risk of bleeding during the biopsy 
procedure 
13) Pregnant or breastfeeding at Screening or planning to become pregnant (self or 
partner) at any time during the study 
14) Unable or unwilling to withhold prohibited medications throughout the study 
15) Documented dependence on narcotics 
16) Use of KRN23, or any other therapeutic monoclonal antibody within 90 days prior to 
Screening  
17) Use of investigational product or investigational medical device within 30 days prior 
to Screening, or requirement for any investigational agent prior to completion of all 
scheduled study assessments. 
OR, in Japan, use of any investigational product or investigational medical device 
within 4 months prior to Screening, or requirement for any investigational agent prior 
to completion of all scheduled study assessments. 
18) Presence or history of any hypersensitivity, allergic or anaphylactic reactions to any 
monoclonal antibody or KRN23 excipients that, in the judgment of the investigator, 
places the subject at increased risk for adverse effects 
19) History of allergic reaction or adverse reactions to tetracycline or demeclocycline  
20) Prior history of positive test for human immunodeficiency virus antibody, hepatitis B 
surface antigen, and/or hepatitis C antibody 
21) History of recurrent infection (other than dental abscesses, which are known to be 
associated with XLH) or predisposition to infection, or of known immunodeficiency 
22) Presence of malignant neoplasm (except basal cell carcinoma) 
23) Presence of a concurrent disease or condition that would interfere with study 
participation or affect safety  

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24) Presence or history of any condition that, in the view of the investigator, places the 
subject at high risk of poor treatment compliance or of not completing the study 
7.3.3 
Removal of Subjects from Therapy or Assessment 
In accordance with the Declaration of Helsinki, subjects have the right to withdraw from the 
study at any time for any reason. The investigator and Ultragenyx also have the right to 
remove subjects from the study. Ultragenyx must be notified of all subject withdrawals as 
soon as possible. Ultragenyx also reserves the right to discontinue the study at any time for 
either clinical or administrative reasons and to discontinue participation of an individual 
subject or investigator due to poor enrollment or noncompliance, as applicable. 
Subjects may be removed from the study for the following reasons: 
• Occurrence of an unacceptable AE 
• An illness that, in the judgment of the investigator or Ultragenyx, might place the subject 
at risk or invalidate the study  
• Pregnancy in subject 
• At the request of the subject, investigator, or Ultragenyx, for administrative or other 
reasons 
• Protocol deviation or noncompliance 
If the reason for removal of a subject from the study is an AE, the AE and any related test or 
procedure results will be recorded in the source documents and transcribed onto the Case 
Report Form (CRF). Each clinically significant abnormal laboratory value or other clinically 
meaningful abnormality should be followed until the abnormality resolves or until a decision 
is made that it is not likely to resolve. If such abnormalities do not return to normal within 
30 days after the last dose given, their etiology should be identified and Ultragenyx should be 
notified. All unscheduled tests must be reported to Ultragenyx immediately. 
If a subject discontinues from the study prematurely, every reasonable effort should be made 
to perform the Early Termination Visit procedures within four weeks of discontinuation. 
Subjects who discontinue due to SAE will be monitored for safety through the final Safety 
Follow-up TC (as defined in Section 7.4.3.1). 
7.3.3.1 
Stopping Rules 
No formal statistical stopping criteria will be applied for this study. A Data Monitoring 
Committee (DMC) will be constituted for Studies UX023-CL303 and UX023-CL304 and 
will act in an advisory capacity to monitor the safety of KRN23 on a routine basisuntil the 
end of the Treatment Period (Week 48) (Section 7.6.7). The DMC may provide advice to 
Ultragenyx to aid in the determination of whether study enrollment should be paused or if the 
study should be stopped. If the Sponsor deems it appropriate to restart the trial following an 
internal safety review, this will be done only following approval by Regulatory Authorities.  

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During Treatment Extension Periods I and II, safety data will be reviewed by the Ultragenyx 
Study Safety Review Team (SSRT) as described in Section 8.5.4.6. 
Individual subjects who experience any unexpected and possibly, probably, or definitely 
drug-related SAEs (Section 8.5.3) that represent a change in the nature or an increase in 
frequency of the serious event from their prior medical history will be assessed as to whether 
the subject will continue on the study.  
Individual subjects will be monitored for ectopic mineralization (Section 7.5.3). If new or 
clinically significant worsening in mineralization is considered clinically meaningful by the 
investigator and/or sponsor and related to study drug, the subject will be discontinued from 
the study. 
Regulatory Authorities, as well as the Institutional Review Board (IRB)/Ethics Committee 
(EC) will be informed should unexpected and possibly, probably, or definitely drug-related 
SAEs occur. A full clinical evaluation of the event will be performed in order to make a 
decision regarding what actions to take, including whether to recommend stopping the study. 
Regulatory Authorities, as well as IRBs/ECs, will be informed if the study is paused or 
stopped. 
7.4 
Treatments 
The study drug is manufactured, packaged, and labeled according to Good Manufacturing 
Practice (GMP) regulations. The Investigational Product should be securely stored under 
conditions indicated in the IB. 
7.4.1 
Investigational Product 
KRN23 is a sterile, clear, colorless, and preservative-free solution supplied in single-use 
5-mL vials containing 1 mL of KRN23 at a concentration of 30 mg/mL. KRN23 will be 
administered without dilution. All subjects will receive 1.0 mg/kg KRN23 monthly (Q4W, 
28 days), rounded to the nearest 10 mg. The amount of drug administered will be calculated 
based on baseline weight and a 1.0 mg/kg KRN23 dose level (rounded to the nearest 10 mg) 
up to a maximum dose of 90 mg. The dose will remain fixed for the duration of the study, 
provided serum phosphorous levels do not exceed 5.0 mg/dL (1.61 mmol/L) at any time or 
4.5 mg/dL (1.45 mmol/L) on two occasions. The dose will be recalculated if body weight 
changes by more than 20% from the baseline measurement. 
Subjects will receive study drug via SC injection to the abdomen, upper arms, or thighs; the 
injection site will be rotated with each injection. No more than 1.5 mL may be administered 
to a single injection site. If the dose requires more than 1.5 mL, multiple injections must be 
administered, each at a different injection site.  
If serum phosphorus increases above 5.0 mg/dL (1.61 mmol/L) at any time the actual dose 
will be decreased by half. If serum phosphorous increases above the ULN (4.5 mg/dL; 
1.45 mmol/L) but does not exceed 5.0 mg/dL (1.61 mmol/L), the dose will be adjusted only 

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if a second serum phosphorus result exceeds the ULN. Following a downward dose 
adjustment, the investigator together with the medical monitor should determine how and 
when to dose titrate up. Unscheduled serum phosphorus assessments may be necessary. 
Based on the totality of the data from studies INT-001 and INT-002 over a period of 
16 months in which most subjects were treated with 1.0 mg/kg KRN23 and no subject 
experienced an elevation of serum phosphorus that approached the 4.5 mg/dL (1.45 mmol/L) 
threshold, it is considered unlikely that dose adjustment will be necessary. 
Refer to the Study Reference Manual for additional information on dose adjustments. 
7.4.2 
Reference Therapy 
The study is a single-arm, open-label study. All subjects will be on active treatment; no 
reference therapy or placebo will be administered.  
7.4.3 
Selection of Doses and Study Duration  
The goal of therapy in adults with XLH is to increase serum phosphorus sufficiently to allow 
the bone to fully mineralize, and thereby improve bone physiology, structure, and function. 
The level of serum phosphorus needed to restore bone metabolism homeostasis and 
mineralization is not precisely known, but there is a general agreement that increasing serum 
phosphorus above the lower limit of normal (LLN) is an appropriate strategy. Another key 
consideration of the therapeutic goal is related to the safety concerns associated with ectopic 
mineralization, in particular nephrocalcinosis. The risk of nephrocalcinosis with the current 
oral phosphorus and active vitamin D therapy increases with higher doses, and is believed to 
be associated with exacerbated oral phosphate wasting in the urine, and secondary 
hypercalciuria (Goodyer et al. 1987), (Verge et al. 1991), (Sabbagh et al. 2008). 
Although mechanistically KRN23 does not increase urinary phosphorus or calcium, the 
dosing strategy will be conservative, aiming to maintain serum phosphorus above the LLN 
for the majority of a given dose interval without causing hyperphosphatemia.  
The Phase 3 dose is based on PK, PD, clinical, and safety data obtained in previous studies 
(KRN23-US-02, KRN23-INT-001 and KRN23-INT-002). These studies indicate 
normalization of serum phosphorus levels occurs with SC KRN23 doses ranging from 0.3 to 
1.0 mg/dL Q4W. The safety data showed repeated monthly doses up to 1.0 mg/kg were well 
tolerated by adult subjects with XLH.  
Data from KRN23-INT-002, the longest clinical study to date, is the primary basis of the 
dosing strategy. All subjects in the study responded to KRN23 at doses of 0.3, 0.6, and 
1.0 mg/kg by increasing serum phosphorus. After the initial dose-titration period, the 
majority of subjects (60% to 74%) stabilized on an optimal dose of 1.0 mg/kg KRN23 and 
achieved serum phosphorus levels within the normal range. The maximum increase in serum 
phosphorus following KRN23 administration was approximately 1 mg/dL from baseline. 
No hyperphosphatemia (>4.5 mg/dL; 1.45 mmol/L) was detected at any time point. 
Increases in serum phosphorus persisted through much of each treatment interval and 

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throughout the 12 months of treatment; however, serum phosphorus decreased towards the 
end of each dose interval as KRN23 concentrations waned. Importantly, KRN23 
administration increased serum phosphorus without negatively affecting other parameters 
such as iPTH and calcium.  
Based on these data, a KRN23 dose of 1.0 mg/kg (rounded to the nearest 10 mg) 
administered Q4W by the SC route was selected as the dose and regimen expected to be 
therapeutic while maintaining a reasonable safety margin. 
7.4.3.1 
Study Duration 
The planned duration of treatment in this study is 96 weeks for subjects at sites outside of the 
US or up to approximately 141 weeks, until end of September 2018, for subjects at sites in 
the US, or until one of the following occurs:  the subject withdraws consent, the subject is 
discontinued from the study at the discretion of the investigator or Ultragenyx, or the study is 
terminated. The length of the study is intended to define whether KRN23 is effective at 
reducing excess osteoid after 48 weeks. Subjects who complete the Open-Label Treatment 
Period will continue to receive KRN23 for an additional 48 weeks during Treatment 
Extension Period I.   Subjects at study sites outside the US will have their EOS efficacy visit 
(ie, EOS I) at the end of this period. Subjects at US sites will continue KRN23 treatment for 
up to an additional approximately 45 weeks in Treatment Extension Period II. The duration 
of Treatment Extension Period II may vary for individual subjects. For each subject who 
participates in this period, the study site will schedule the EOS efficacy visit (ie, EOS II) to 
take place before 30 September 2018. The duration of the period will be determined by the 
time from the start of Week 97 through the EOS II Visit. 
For subjects not immediately continuing KRN23 treatment under commercial use or another 
mechanism upon completion of study drug treatment or early withdrawal from this study, a 
Safety Follow-up TC will occur 4 weeks (+ 5 days) after their final study site visit (ie, EOS 1 
[non-US subjects], EOS II [US subjects], or ET Visit) to collect information on whether 
KRN23 treatment has been started through another mechanism and, if not, any ongoing or 
new AEs, SAEs, or concomitant medications. If the subject is not continuing KRN23 therapy 
under commercial use or another mechanism at that time, an additional Safety Follow-up TC 
will occur 8 weeks (+ 5 days) after the subject’s final study site visit to collect information on 
whether KRN23 treatment has been started through another mechanism and, if not, any 
ongoing or new AEs, SAEs, or concomitant medications.  
The end of the study is defined as the last day that protocol-specified assessments (including 
telephone contact) are conducted for the last subject. The maximum planned study duration 
(treatment plus safety follow-up) is approximately 149 weeks. 

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7.4.4 
Method of Assigning Subjects to Treatment Groups 
Subjects will be enrolled in the study and sequentially assigned an identification number. 
All subjects will receive active treatment (KRN23); there is only one treatment group in the 
study. 
7.4.5 
Blinding 
The study drug will be administered open-label; no study participants will be blinded to study 
treatment. 
7.4.6 
Treatment Compliance 
Trained personnel will administer study drug by SC injection at the investigational site or 
during home health (HH) visits as indicated in the Schedule of Events for that period 
(Table 2.1, Table 2.2, Table 2.3). Each administration of study drug will be recorded on the 
CRF. If a subject does not receive a dose within 21 days of a scheduled dose, that dose 
should be skipped and the next dose will be administered at the next scheduled dosing visit. 
Doses should be administered no fewer than 14 days apart. 
7.5 
Study Procedures and Assessments 
Potential subjects will come in to the site to sign informed consent and complete the initial 
Screening. Subjects will be contacted by telephone within 1 week of the Screening visit to 
communicate available test results related to eligibility. For patients who do not meet 
eligibility on the basis of the iFGF23 assay, PHEX mutation analysis may be performed 
before baseline. If eligible, tetracycline HCl (or demeclocycline) will be provided to the 
subject with instructions for administration. The bone biopsy should be performed 5 days 
after the last dosing day for tetracycline (or demeclocycline):  The first dose should be given 
on days -20, -19, and -18, and the second dose given on days -8, -7, and -6. Similar telephone 
contacts will be placed to provide instructions for tetracycline (or demeclocycline) labeling 
prior to the Week 48 or, if eligible, the Early Termination (ET) visits. 
All Screening/Baseline assessments and inclusion/exclusion criteria must be satisfied prior to 
dosing. The Baseline visit should occur no more than 31 days following the Screening visit. 
If the Baseline visit (BL) occurs more than 31 days following the Screening Visit, medical 
history and pregnancy status should be re-assessed. The Baseline, Week 48, and Week 96 
(or ET) assessments may be completed in any reasonable order (except where indicated) to 
allow for flexibility in scheduling. Renal ultrasound, ECHO, ECG, and skeletal survey/ 
targeted x-rays may be performed within ± 3 days of indicated clinic visit to accommodate 
scheduling availability. The bone biopsy must be completed on a day with no other 
procedures, and prior to dosing on Day 0. 
During the Open-Label Treatment Period (Weeks 0 – 48), Treatment Extension Period I 
(Weeks 49 – 96), and Treatment Extension Period II (US sites only, Weeks 97 up to 
Weeks 141), subjects will return to the clinic and/or have HH visits as indicated (± 5 days). 

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Visits designated HH may also be conducted at the investigational site depending on the 
preference of the subject and proximity of the subject to the clinic.  For subjects at sites 
outside of the US, the Week 96 Visit will be their EOS efficacy visit (ie, EOS I).  For sites in 
the US, at the end of Treatment Extension Period II (ie, final study visit before 30 September 
2018), the subjects will have their EOS efficacy visit (ie, EOS II).  
For subjects not immediately continuing KRN23 treatment under commercial use or another 
mechanism upon completion of study drug treatment or early withdrawal from this study, a 
Safety Follow-up TC will occur 4 weeks (+5 days) after their final study site visit (ie, EOS 1 
[non-US subjects], EOS II [US subjects], or ET Visit) to collect information on whether 
KRN23 treatment has been started through another mechanism and, if not, any ongoing or 
new AEs, SAEs, or concomitant medications. If the subject is not continuing KRN23 therapy 
under commercial use or another mechanism at that time, then site personnel will initiate a 
subsequent Safety Follow-up TC 8 weeks (+ 5 days) after the subject’s final study site visit 
to collect information on whether KRN23 treatment has been started through another 
mechanism and, if not, any ongoing or new AEs, SAEs, or concomitant medications. 
The schedule of visits and assessments conducted during Screening and Baseline, and the 
Open-Label Treatment Period are provided in Table 2.1 and Table 2.2. The schedule of visits 
and assessments conducted during the Treatment Extension Periods I and II are provided in 
Table 2.3 and Table 2.4.  Refer to the Study Reference Manual for additional details and a 
recommended schedule and order of specific assessments. 
7.5.1 
Efficacy Measures 
Efficacy will be evaluated by changes in histomorphometric indices of osteomalacia, 
supported by PD markers of phosphate homeostasis and renal function, and patient-reported 
changes in pain and fatigue. Results from baseline assessments will be compared with those 
of post-treatment assessments, with efficacy conclusions based on change from baseline. 
The efficacy variables in this study: OV/BV, O.Th, OS/BS, and MLt, will provide a 
histomorphometric indicator of KRN23 action. The primary efficacy endpoint will be the 
reduction in osteoid volume (OV/BV) based on analysis of iliac crest bone biopsies after 
48 weeks of KRN23 treatment. Osteoid volume (measured as a percentage of total bone 
volume) is the most consistent histomorphometric parameter to quantify the amount of 
osteoid tissue accumulation, which is the hallmark of osteomalacia.  The primary efficacy 
measure will be supported by the key secondary variable, serum phosphorus levels, along 
with multiple secondary and exploratory variables, including additional histomorphometric 
parameters, biochemical markers, and PROs. Secondary and exploratory endpoints and 
associated analyses are described in Section 7.6.4. The following section describes the 
assessments that will be performed throughout the study to derive primary, key secondary, 
secondary, and exploratory variables.  

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7.5.1.1 
Iliac Crest Bone Biopsy 
In adulthood, XLH progresses into a disease of persistent and often clinically significant 
osteomalacia as a result of chronic low serum phosphorus, causing bone and joint pain and 
pseudofractures in a large proportion of patients (Reid et al. 1989). Preclinical and clinical 
data suggest static and dynamic parameters of osteoid accumulation improve significantly 
following anti-FGF23 treatment in the Hyp mouse model (Aono et al. 2009), or 6-9 months 
of supplementation therapy in adults with XLH (Sullivan et al. 1992), (Harrell et al. 1985). 
Therefore, iliac crest bone biopsies will be obtained to assess OV/BV as the primary outcome 
measure in this study; by performing the procedure before and after treatment with KRN23, 
each subject will serve as an individual control.  
A bone biopsy of the iliac crest will be performed to assess OV/BV, O.Th, OS/BS, 
MLt as well as other parameters. Subjects will receive two courses of tetracycline 
(or demeclocycline) label prior to biopsy (see Section 7.5) associated with the Baseline and 
Week 48 (or Early Termination if it occurs between the Week 24 and Week 48) visits. 
Bone biopsy of the trans-iliac crest will be performed by a physician trained and experienced 
in the procedure. Baseline bone biopsies will be qualitatively analyzed in real time to assess 
the presence of osteomalacia. If a subject is determined not to have osteomalacia at the time 
of the initial biopsy, that subject will continue on study but will not undergo the second bone 
biopsy at Week 48/ET.  
Primary and secondary efficacy endpoints derived from these assessments are provided in 
Section 7.6. Refer to the Transiliac Crest Bone Biopsy Manual for detailed instructions on 
bone labeling, biopsy, sample processing, and histomorphometry. 
7.5.1.2 
Biochemical Markers 
Osteomalacia is a hallmark of XLH in adults and results from the underlying mineralization 
defect due to hypophosphatemia. Normalization of bone turnover with improved 
mineralization would be expected to prevent pseudofractures or accelerate their healing. 
Biochemical markers of bone formation will be evaluated as an indicator of changes in bone 
metabolism in response to KRN23 treatment. Skeletal health parameters will be used to 
establish the improvement in biomarkers and modification of pathological features of bone 
disease in XLH.  
7.5.1.2.1 
Serum Phosphorus 
KRN23 binds to and inhibits FGF23. As a phosphaturic hormone, FGF23 plays an important 
role as a specific regulator of serum phosphorus levels. Normalization of serum phosphorus 
directly bears on the hypophosphatemia and consequent osteomalacia that is the hallmark of 
XLH and the cause of the bone abnormalities that result in the clinical signs and symptoms of 
the disease. The key secondary efficacy variable in this study, serum phosphorus levels at the 
mid-point of the dosing cycle, will provide a biochemical indicator of KRN23 action across 
the dosing interval. 

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7.5.1.2.2 
Biochemical Markers of Bone Turnover 
Biochemical markers of bone turnover in serum, including procollagen type 1 N-propeptide 
(P1NP), carboxy-terminal cross-linked telopeptide of type I collagen (CTx), and 
bone-specific alkaline phosphatase (BALP) will be evaluated over time as an indicator of 
changes in bone metabolism in response to KRN23 treatment. Serum samples will be 
collected at the Baseline (Day -2), Week 12, Week 24, Week 48, Week 72, and 
Week 96/EOS I visits and, if applicable, EOS II (or Early Termination) as indicated in the 
Schedules of Events (Table 2.1, Table 2.2, Table 2.3, and Table 2.4).  
7.5.1.2.3 
Additional Pharmacodynamic Markers 
To demonstrate the positive impact of KRN23 on bone metabolism and phosphate 
homeostasis, additional PD markers will be assessed, including serum calcium, 1,25(OH)2D, 
urinary phosphorus, ratio of renal tubular maximum reabsorption rate of phosphate to 
glomerular filtration rate (TmP/GFR), and tubular reabsorption of phosphate (TRP). 
These measures will directly reflect the mechanism by which KRN23 restores phosphorus 
homeostasis by inhibiting excess FGF23.  
Serum samples will be obtained following a minimum overnight fasting time of 8 hours and 
prior to study drug administration (if applicable). Samples should be obtained in the morning 
at approximately the same time for each visit due to known fluctuations in serum 
phosphorous levels associated with circadian rhythm. The time of sample collection will be 
noted on the CRF. 
Two-hour fasting urine collection is required to assess phosphate reabsorption (TmP/GFR 
and TRP) based on simultaneous urine and blood creatinine and phosphorus concentrations. 
Both 2-hr and 24-hr urine will be used for measurements of urinary phosphorus, creatinine 
and calcium.  The duration of fasting time for all PD parameters will be recorded on the 
CRF. 
PD markers will be assessed as specified in the Schedule of Events (Table 2.1, Table 2.2, 
Table 2.3, and Table 2.4). When possible, samples will be used to assess both PD and safety 
parameters to minimize blood draw requirements and patient burden (Section 7.5.3.8).  
7.5.1.3 
Patient Reported Outcomes 
PROs will support the effect of KRN23 on patient benefit and clinical outcomes in this 
population. Adult patients with XLH experience a number of symptoms including bone and 
joint pain due to the underlying osteomalacia and joint pain related to osteoarthritis that often 
develops in adults with XLH as a consequence of the ongoing loading of joints that became 
misaligned during childhood due to XLH rickets and bowing. The BPI and BFI will be used 
to assess the effects of KRN23 treatment on patient-reported and quality of life outcomes. 
PROs will be administered in order of presentation below at Baseline (Week 0) and 
Weeks 12, 24, 36, 48, 72, and 96/EOS I and, if applicable, Q24W during Treatment 
Extension Period II and at EOS II, as indicated in the Schedules of Events (Table 2.1, 

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Table 2.2, Table 2.3, and Table 2.4). PROs will not be administered if a subject terminates 
from the study early (Early Termination).  
7.5.1.3.1 
Brief Pain Inventory 
The short-form BPI is an 11-question, self-reported, pain-specific PRO with a recall period 
of 24 hours that may allow a detailed characterization of the pain experienced by patients 
with XLH. Initially developed to assess pain in cancer patients, the instrument has since been 
validated to characterize non-malignant pain in patients with arthritis or low back pain 
(Keller et al. 2004). The BPI evaluates the condition of all pain over the previous 24 hours. 
Two dimensions are measured: pain severity (worst, least, average, and now) and the impact 
of pain on functioning (pain interference with general activity, walking, work, mood, 
enjoyment of life, relations with others, and sleep). The BPI question 3 (BPI Q3; Worst Pain) 
will be administered at Screening to assess eligibility. The complete short-form BPI will be 
administered at all remaining indicated visits. 
7.5.1.3.2 
 Brief Fatigue Inventory 
The BFI is a self-reported questionnaire consisting of 9 items related to fatigue that are rated 
on a 0 to 10 numerical rating scale with a recall period of 24 hours. As with the BPI, two 
dimensions are measured: fatigue and the interference of fatigue on daily life (activity, mood, 
walking ability, work, relations with others, and enjoyment of life). The BFI was developed 
to evaluate severity of fatigue due to cancer and cancer treatment (Mendoza et al. 1999) and 
has been used in musculoskeletal conditions including osteoarthritis and rheumatoid arthritis 
(Murphy et al. 2010), (Murphy et al. 2013), (Wolfe 2004). The complete BFI will be 
administered at Screening and at all indicated visits.   
7.5.1.4 
Targeted Radiography and Skeletal Survey 
A radiographic skeletal survey will be conducted at baseline to assess healing or resolution of 
current pseudofractures, determine areas of osteomalacia and enthesopathy, and identify the 
number of active fractures/pseudofractures. Standard radiographs will be obtained of the 
chest, lateral spine, right and left hand/wrist, right and left humerus, right and left 
radius/ulna, right and left femur/pelvis, right and left tibia/fibula, and right and left foot.  
During the 48-week long Open-Label Treatment Period, targeted radiography at locations 
identified by the skeletal survey will be taken at Weeks 12, 24, 36, and 48 to monitor 
frequency and healing of pseudofractures and/or fractures. During the Treatment Extension 
Periods I and II (if applicable), targeted radiographs will only be taken at clinic visits 
following newly diagnosed fractures.   
Post-baseline radiographs will be compared to baseline radiographs using a pre-defined list 
of abnormalities by a trained central reader who is blinded to subject data. Existing and new 
pseudofractures will be graded as not healed, partially healed, or fully healed. 

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7.5.2 
Drug Concentration Measurements 
PK samples will be obtained from all subjects throughout the study at indicated time points 
representing the peak and trough exposure levels (Table 2.1, Table 2.2, Table 2.3, and 
Table 2.4). The actual dates and times of study drug administration and sample collection 
will be documented in the CRF. The concentration of KRN23 in human serum will be 
determined using a validated electrochemiluminescent assay (ECLA) method.  
7.5.3 
Safety Measures & General Assessments 
General assessments include medical history, height, and demographics. PHEX mutation 
analysis will be performed for all qualified subjects even if they or a family member has a 
confirmed PHEX mutation. If the initial result for PHEX mutation analysis is negative or 
inconclusive (i.e., No Mutation, Likely Benign, Variant of Uncertain Significance, or 
Possibly Pathogenic) and informed consent is provided by the subject, additional genetic 
testing will be performed to assess mutations in other genes associated with phenotypes 
overlapping with XLH. This testing will include genes for Autosomal Dominant 
Hypophosphatemic Rickets (FGF23), Autosomal Recessive Hypophosphatemic Rickets 
(DMP1, ENPP1), X-Linked Recessive Hypophosphatemic Rickets (CLCN5), Raine 
Syndrome (FAM20C), and Hereditary Hypophosphatemic Rickets with Hypercalciuria 
(SLC34A3). The investigator will communicate any additional genetic testing results to the 
subject. 
Safety will be evaluated by the incidence, frequency and severity of AEs and SAEs, 
including clinically significant changes from baseline to scheduled time points in vital signs, 
weight, physical examination, eGFR, clinical laboratory evaluations (including additional 
KRN23/XLH biochemical parameters of interest), and concomitant medications. Ectopic 
mineralization safety assessments include renal ultrasound, ECHO and ECG. 
The development of anti-KRN23 antibodies (anti-drug antibodies [ADA]) will also be 
assessed. Pregnancy testing will be conducted in females with child-bearing potential.  
7.5.3.1 
Medical History 
General medical information includes subject demographics (date of birth, ethnicity, and sex) 
and a history of major medical illnesses, diagnoses, and surgeries. The review will also 
include a detailed assessment of symptoms and conditions associated with XLH and 
treatment. 
Subjects must be willing to provide access to prior medical records for the collection of 
biochemical and radiographic data, as well as disease history. The specific diagnosis of XLH 
will be recorded, along with date of onset, clinical presentation, and date and method of 
diagnosis. Any available family history of XLH will be noted, including any available 
previous PHEX mutation analysis results for the subject or relevant family members with 
appropriate X-linked inheritance pattern.  

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XLH treatment history and relevant concomitant medications will be recorded (start date, 
stop date, dose, dose regimen). Previous treatments may include calcitriol and oral 
phosphate, calcimimetics or other adjunctive therapy. Medications include investigational, 
prescription, over-the-counter, herbal and nutritional supplements. Any relevant concomitant 
therapy, including physical/occupational therapy will be recorded. Use of pain medications 
will also be recorded. Refer to Section 7.5.3.10.1 for prohibited medications during the study. 
7.5.3.2 
Vital Signs 
Vital signs will include seated systolic blood pressure and diastolic blood pressure measured 
in millimeters of mercury (mm Hg; 2 measurements separated by 15 minutes), heart rate in 
beats per minute, respiration rate in breaths per minute, and temperature in degrees Celsius 
(°C). Vital signs measurements will be obtained at specified visits (Table 2.1, Table 2.2, 
Table 2.3, and Table 2.4) before any additional assessments are completed.  
7.5.3.3 
Weight and Height 
Weight will be obtained using a scale and recorded in kilograms at specified visits 
(Table 2.1, Table 2.2, Table 2.3, and Table 2.4). The measurement obtained at the Baseline 
visit will be used to calculate the appropriate dose of study drug to be administered on a 
mg/kg basis throughout the duration of the study, unless weight changes by more than 20%, 
in which case the dose of study drug should be recalculated according to the new body 
weight. 
Height (in meters) will be obtained using a stadiometer (without shoes) at the Screening Visit 
only. 
7.5.3.4 
Physical Examination 
Complete physical examinations will be performed at specified visits (Table 2.1, Table 2.2, 
Table 2.3, and Table 2.4). Physical examinations will include assessments of general 
appearance; head, eyes, ears, nose, and throat; the cardiovascular, dermatologic, lymphatic, 
respiratory, gastrointestinal, genitourinary, musculoskeletal, and neurologic systems. 
The genitourinary exam scope should be non-invasive and as per age-appropriate standard of 
care, at the Investigator’s discretion based on clinical judgement and/or safety need. If the 
Investigator determines there is no clinical indication for a genitourinary exam, it is not 
necessary to perform. 
7.5.3.5 
Renal Ultrasound and Glomerular Filtration Rate 
Renal ultrasounds will be conducted at Screening and Weeks 24, 48, 72, and 96/EOS I and, if 
applicable, EOS II (or Early Termination), as indicated in the Schedules of Events (Table 2.1, 
Table 2.2, Table 2.3, and Table 2.4). The ultrasound will be interpreted by qualified 
personnel at the investigational site for purposes of inclusion criteria.  

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Results obtained at Screening will serve as baseline data. Baseline and all post-treatment 
renal ultrasounds will be evaluated by a trained central reader blinded to subject data 
to evaluate changes in calcifications and all other renal abnormalities from baseline 
(i.e. screening assessment). Ultrasonographic findings of nephrocalcinosis will be graded on 
a 5-point scale (Patriquin et al. 1986). 
The eGFR will be calculated using the Chronic Kidney Disease Epidemiology 
Collaboration (CKD-EPI) equation (Levey et al. 2009) for determining creatinine clearance. 
Results obtained at screening will serve as baseline data. 
7.5.3.6 
Echocardiogram 
ECHO will be performed Weeks 24, 48, 72, and 96/EOS I and, if applicable, EOS II (or 
Early Termination if not performed within 3 months of termination) as indicated in the 
Schedules of Events (Table 2.1, Table 2.2, Table 2.3, and Table 2.4). The goal is twofold:  
1) assess for evidence of ectopic mineralization in the heart and aorta, and 2) evaluate for 
signs of LVH or cardiac dysfunction. Additional tests may be performed if any abnormalities 
are detected or if medically indicated. ECHO administration procedures will be standardized 
and results will be centrally read. 
7.5.3.7 
Electrocardiogram 
A standardized 12-lead ECG will measure PR, QRS, QT, and QTc at Baseline and Weeks 24, 
48, 72, and 96/EOS I and, if applicable, EOS II (or Early Termination) as indicated in the 
Schedules of Events (Table 2.1, Table 2.2, Table 2.3, and Table 2.4). The goal is to evaluate 
both for LVH changes, as well as for changes in conductivity and intervals. ECG 
administration procedures will be standardized and results will be read centrally by qualified 
personnel blinded to subject data. The ECG results will be assessed for any clinically 
significant abnormality or relevant changes from baseline. 
7.5.3.8 
Clinical Laboratory Tests for Safety 
A comprehensive serum metabolic panel (Chem-20), complete blood count, and urinalysis 
will be used as routine screens to assess KRN23 safety. Screening and Week 48 Day 1 
hematology will include standard tests for risk of bleeding. Certain analytes (i.e., serum 
phosphorus) in the routine Chem-20 panel are also designated as PD/efficacy parameters in 
this study (Section 7.5.1.2.3). Additional KRN23/XLH biochemical parameters of interest 
include serum 1,25(OH)2D, calcium, creatinine, and iPTH; and urinary phosphorus, calcium 
and creatinine.  
Blood and urine samples will be collected at Screening, Baseline, and regular intervals 
throughout the study as indicated in the Schedule of Events (Table 2.1, Table 2.2, Table 2.3, 
and Table 2.4). Fasting for a minimum of 8 hours (overnight) is required prior to each blood 
draw; the duration of fasting will be recorded on the CRF. Twenty-four hour urine collection 
is required to assess urinary phosphorus:creatinine and calcium:creatinine ratios; urinary 
phosphorus, a PD parameter, will also be obtained from 24-hour urine samples.  

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Clinical laboratory parameters to be assessed for safety are provided in Table 7.5.3.8.1. 
See Study Reference Manual for details on sample collection and processing. 
Table 7.5.3.8.1: 
Clinical Laboratory Assessments for Safety 
Chemistry 
Hematology 
Urinalysis 
25(OH) D 
Hematocrit 
Appearance 
1,25(OH)2D 
Hemoglobin 
Color 
Alanine aminotransferase (ALT) 
Platelet count 
pH 
Alkaline phosphatase (ALP) 
Red blood cell (RBC) count 
Specific gravity 
Amylase 
White blood cell (WBC) count 
Ketones 
Aspartate aminotransferase (AST) 
Mean corpuscular volume (MCV) 
Protein  
Bilirubin (direct and total) 
Mean corpuscular hemoglobin (MCH) 
Glucose  
Blood urea nitrogen (BUN) 
MCH concentration 
 
Calcium (total) 
Prothrombin time 
24-hour Urine 
Chloride 
Partial thromboplastin time 
Calcium 
Carbon dioxide (CO2) 
 
Calcium/creatinine 
ratio 
Cholesterol (total) 
 
Creatinine 
Creatinine 
 
Phosphorus/creatinine 
ratio 
Gamma-glutamyl transpeptidase 
(GGT) 
 
Phosphorus 
Glucose 
 
2-hour Urine 
Intact parathyroid hormone (iPTH) 
 
Calcium 
Lactate dehydrogenase (LDH) 
 
Creatinine 
Lipase 
 
Calcium/creatinine 
ratio 
Phosphorus 
 
Phosphorus 
Potassium 
 
TmP/GFR 
Protein (albumin and total) 
 
TRP 
Sodium 
 
Pregnancy test (if 
applicable) 
Uric acid 
 
 
Serum pregnancy test (if applicable) 
 
 

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Subjects who experience a SAE possibly or probably related to study drug or other AE of 
concern may, at the discretion of the investigator (and/or medical monitor), have additional 
blood samples taken for safety laboratory tests. 
7.5.3.8.1 Fibroblast Growth Factor 23 
Serum FGF23 concentrations will be measured using a validated assay. Blood samples will 
be collected at specified visits (Table 2.1, Table 2.2, Table 2.3, and Table 2.4) after a 
minimum overnight fasting time of 8 hours and prior to drug administration (if applicable). 
7.5.3.8.2 
Anti-KRN23 Antibody Testing 
To determine the immunogenicity profile of KRN23 in adults with XLH, blood samples will 
be obtained for anti-KRN23 antibody (ADA) testing at Day 0/Weeks 0, 4, 24,48, 72, and 
96/EOS I and, if applicable, EOS II (or Early Termination), as indicated in the Schedules of 
Events (Table 2.1, Table 2.2, Table 2.3, and Table 2.4).. PK samples will also be obtained on 
days of ADA testing to assess potential neutralizing effects if ADA are detected. The 
formation of anti-KRN23 antibodies in human serum will be determined using a validated 
ECLA and a 3-tiered strategy: screening, specificity confirmation, and titer assays. If the 
development of anti-KRN23 antibodies is suspected in a given subject, samples may be 
obtained at additional time points on a case-by-case basis, if warranted. 
7.5.3.9 
Pregnancy Testing 
Female subjects of childbearing potential will have urine pregnancy tests at the indicated 
visits (Table 2.1, Table 2.2, Table 2.3, and Table 2.4) throughout the duration of the study. 
Female subjects with a positive pregnancy test at Screening will not be enrolled in the study. 
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. 
Pregnancy in subject or partner must be reported (Section 8.5.4.5); pregnant subjects will be 
discontinued from the study.  
Experience with KRN23 in pregnant women is limited. The study drug may involve risks to a 
pregnant female or unborn baby which are currently unknown. Female participants of 
child-bearing potential must consent to use a highly effective method of contraception as 
listed below from the period following the signing of the informed consent through the final 
Safety Follow-up TC (as defined in Section 7.4.3.1). Sexually active male participants with 
female partners of childbearing potential must consent to use a condom with spermicide or 
one of the highly effective methods of contraception listed below from the period following 
the signing of informed consent through the final Safety Follow-up TC (as defined in 
Section 7.4.3.1). 

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Highly effective methods of contraception (CTFG 2014) include: 
• Combined (estrogen and progestogen containing) hormonal contraception associated 
with inhibition of ovulation (e.g. oral, intravaginal, transdermal) 
• Progestogen-only hormonal contraception associated with inhibition of ovulation (e.g. 
oral, injectable, implantable) 
• Intrauterine device (IUD) or intrauterine hormone-releasing system (IUS) 
• Bilateral tubal occlusion 
• Male sterilization, also called vasectomy  
• Sexual abstinence (i.e., refraining from heterosexual intercourse during the entire 
period of risk associated with the study treatments, when this is in line with the 
preferred and usual lifestyle of the subject) 
7.5.3.10 Prior and Concomitant Therapy 
Throughout the study, there should be no significant changes to a subject’s diet or medication 
schedule unless medically indicated. Investigators may prescribe any concomitant 
medications or treatments deemed necessary to provide adequate supportive care, except 
those specified as prohibited medications (Section 7.5.3.10.1). All concomitant medications 
taken during the study will be recorded in the CRF with indication, dose information, and 
dates of administration. Any changes to concomitant medication will also be documented. 
7.5.3.10.1 
Prohibited Medications 
To be eligible for the study, subjects must not have used certain medications for the indicated 
timeframe prior to Screening (Section 7.3.2). The following medications will remain 
prohibited throughout the conduct of the study: 
• Pharmacologic vitamin D metabolites or analogs (e.g. calcitriol, doxercalciferol, and 
paricalcitol) 
• Oral phosphate 
• Aluminum hydroxide antacids, acetazolamides, and thiazides 
• Bisphosphonate therapy (no use in the 2 years prior to Screening) 
• Denosumab therapy (no use in the 6 months prior to Screening) 
• Teriparatide therapy (no use in the 2 months prior to Screening) 
• Initiation of hormone replacement therapy in post-menopausal women (stable doses prior 
to study entry acceptable) 

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• Chronic use of systemic corticosteroids (short courses acceptable if indicated) 
• PTH suppressors (e.g. cinacalcet) 
• Any other mAb therapy (other than study drug; 90-day washout required) 
7.5.3.10.2 
Permitted Medications 
Other than the medications specifically prohibited in this protocol, subjects may receive 
concomitant medications as required. If serum 25-hydroxyvitamin D (25(OH)D) levels fall 
below 20 ng/mL, oral supplementation may be provided. Medications (investigational, 
prescription, over-the-counter, and herbal) and nutritional supplements taken within the 
30 days prior to Screening visit will be reviewed and recorded. 
7.5.3.10.3 
Concomitant Medications/Therapies 
Concomitant medications and therapies will be reviewed and recorded in the subject’s CRF 
at each study visit to the investigational site and during Home Health visits. Medications 
(investigational, prescription, over-the-counter, and herbal) and nutritional supplements taken 
during the 30 days prior to Screening will be reviewed and recorded. Therapies (physical 
therapy, occupational therapy as well as mobility and walking devices, including ankle-foot 
orthosis, braces, cane, crutches, walker, wheelchair etc.) utilized during the 30 days prior to 
Screening will also be reviewed and recorded. At each subsequent visit, change in 
medications and therapies since the previous visit will be recorded. Particular attention will 
be paid to medications used to control pain associated with XLH including changes in dose 
and frequency of administration. Evidence of narcotic dependence is exclusionary and may 
result in subject discontinuation.  
7.5.3.11 Adverse Events 
All AEs will be recorded from the time the subject signs the informed consent through the 
final Safety Follow-up TC (as defined in Section 7.4.3.1). The determination, evaluation, 
reporting, and follow-up of AEs will be performed as outlined in Section 8.5. At each visit, 
subjects will be asked about any new or ongoing AEs since the previous visit. Assessments 
of AEs will occur at each visit to the investigational site and at all Home Health Visits. 
Clinically significant changes from baseline in physical examination findings, vital signs, 
weight, clinical laboratory parameters, renal ultrasounds, eGFR, ECHO and ECGs will be 
recorded as AEs or SAEs, if deemed appropriate by the investigator.  
7.5.4 
Appropriateness of Measures 
Osteomalacia is the hallmark of XLH in adults and results from the underlying 
mineralization defect due to hypophosphatemia. The transiliac crest bone biopsy is a 
well-established tool in research and clinical use for evaluating bone tissue in metabolic bone 
diseases such as renal osteodystrophy, osteomalacia, and osteoporosis. Cellular activity and 
the amount of bone can be accurately quantified by histomorphometry, providing information 

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that cannot be obtained through other imaging or biochemical studies (Sullivan et al. 1992). 
Osteomalacia is characterized by an accumulation of osteoid tissue, reflecting a prolonged 
and defective mineralization process (Arnstein et al. 1967). Specific histomorphometric 
parameters chosen to evaluate changes in osteomalacia with KRN23 treatment include 
osteoid thickness, osteoid surface/bone surface, and osteoid volume/bone volume, which are 
static parameters providing information about the amount of unmineralized bone (Dempster 
et al. 2013). In addition, mineralization lag time, a dynamic modeling parameter representing 
the mean time interval between the formation of osteoid and its subsequent mineralization, 
will be evaluated (Dempster et al. 2013). These parameters showed improvement but not 
normalization with oral phosphate and vitamin D therapy in XLH patients (Sullivan et al. 
1992), (Glorieux et al. 1980), (Harrell et al. 1985). 
Secondary endpoints have been incorporated into the design to support the hypothesis that 
achieving phosphate homeostasis ameliorates defective bone mineralization and metabolism 
and reduces the clinical burden of XLH. Secondary variables have been selected to 
demonstrate an overall improvement in bone health and metabolism to reduce disease burden 
and support the efficacy of KRN23 in this patient population. 
Hypophosphatemia is the cause of the consequent osteomalacia and bone abnormalities that 
result in clinical manifestations of XLH. Serum phosphorus levels serve as a surrogate for the 
final goals of therapy, which are to restore skeletal health, thereby reducing the associated 
pain, fatigue, and fracture risk affecting adult patients with XLH. By positively modulating 
serum phosphorus, the underlying osteomalacia will be resolved, leading to improved clinical 
outcomes.  
PROs have been included in the design to support clinical efficacy and demonstrate patient 
benefit from KRN23 treatment. The BPI has been used to evaluate pain in numerous diseases 
and conditions including cancer bone pain, musculoskeletal pain, and osteoarthritis.  
Similarly, the BFI has been used to evaluate fatigue in musculoskeletal conditions including 
osteoarthritis and rheumatoid arthritis. 
The safety parameters to be evaluated in this study include standard assessments such as 
recording of medical history, AEs and SAEs, physical examination, vital signs, serum 
chemistry, and other routine clinical and laboratory procedures. Additional safety measures 
have been incorporated into the study design to perform a risk assessment of ectopic 
mineralization in this population. PK and ADA samples will also be obtained to gain 
additional information regarding exposure and immunogenicity of KRN23. 
7.6 
Statistical Methods and Determination of Sample Size 
A full description of the analysis details and procedures for handling missing, spurious, or 
unused data will be provided in the Statistical Analysis Plan (SAP).  

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7.6.1 
Determination of Sample Size 
The study will enroll approximately 14 adult subjects with XLH; baseline histologic and 
histomorphometric assessments of the bone biopsy specimens will be performed as each 
biopsy is completed to assess sample quality and confirm the presence of osteomalacia in at 
least 8 subjects. To ensure a level of gender balance, at least 3 subjects of each sex will be 
enrolled. At least 6 paired biopsy specimens are expected at the end of the study. A reduction 
in excess osteoid is expected to be shown in all subjects with paired biopsies with an 
estimated ≥ 50% reduction from baseline in osteoid thickness. The sample size and study 
duration are believed to be sufficient to enable characterization of KRN23 effects on bone 
tissue and skeletal health.  
Information will be used to support the findings of the larger Phase 3 confirmatory efficacy 
and safety study, where it is adequately powered to evaluate increases in serum phosphorus 
levels across the entire dosing interval and to describe the treatment effect on select 
patient-reported outcomes.  
7.6.2 
Analysis Populations 
7.6.2.1 
Primary Analysis Set 
The primary analysis set will include enrolled subjects with baseline and follow-up 
(Week 48/ET) bone biopsy data.  
7.6.2.2 
Full Analysis Set 
The full analysis set for efficacy is defined as all enrolled subjects who receive at least one 
dose of study drug.  
7.6.2.3 
Safety Analysis Set 
The safety analysis set consists of all enrolled subjects who receive at least one dose of study 
drug. This analysis set will be used for the analyses of all safety endpoints. 
7.6.2.4 
Treatment Extension Analysis Set 
The treatment extension analysis set consists of all enrolled subjects who continued after the 
Open-Label Treatment Period and received at least one dose during the Treatment Extension 
Period I.  This analysis set will be used for the analyses of efficacy and safety endpoints. 
7.6.3 
General Principles 
A general description of the statistical methods to be used to analyze the efficacy and safety 
of the study drug is outlined below. The analyses planned in this protocol will be expanded in 
the SAP to include detailed description. The SAP will be finalized and approved prior to the 

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database lock. Any deviations from the analyses described in the protocol and SAP will be 
noted in the final clinical study report. 
The completeness of the data affects the integrity and accuracy of the final study analysis. 
Therefore, every effort will be made to ensure complete, accurate, and timely data collection, 
and to avoid missing data. In general, only subjects with a post-baseline efficacy evaluation 
will be included for that analysis. Missing data will be treated as missing and no statistical 
imputation method will be used unless stated otherwise. The procedures for handling 
missing, unused, or spurious data, along with the detailed method for analyses, will be 
presented in the SAP. 
The statistical analyses will be reported using summary tables, figures, and data listings. 
For continuous variables, the mean, standard deviation, median, quartile, minimum, and 
maximum will be provided. For discrete data, the frequency and percent distributions will be 
provided.  
7.6.3.1 
Subject Accountability 
The number of subjects who enrolled, complete the treatment period, and discontinue the 
study will be summarized. The reasons for study treatment discontinuation and study 
discontinuation will also be summarized.  
7.6.3.2 
Demographic and Baseline Characteristics 
Demographics (age, gender, race and ethnicity) and other baseline disease characteristics will 
be summarized using descriptive statistics. 
7.6.3.3 
Baseline 
Generally, for parameters/assessments scheduled to be performed on the same day as the first 
study treatment, the baseline value is the last value measured before the first administration 
of study treatment on that day. For parameters/assessments not scheduled to be performed 
(or scheduled but not performed) on the same day as the first administration of study 
treatment, the baseline value is the value from the screening period measured closest to the 
day of first administration of study treatment.  
7.6.4 
Efficacy Endpoints and Analyses 
In general, observed values at baseline and end of study, change from baseline, and percent 
changes from baseline at end of study will be summarized. The detailed statistical approaches 
on analysis of primary and secondary endpoints will be described in the SAP. 
7.6.4.1 
Primary Efficacy Endpoint 
The primary endpoint is the percent change from baseline at Week 48 in osteoid volume 
(osteoid volume/bone volume, OV/BV). 

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The primary analysis will be performed using the primary analysis set. OV/BV at baseline, 
48 Weeks, and the percent change from baseline at 48 Weeks will be summarized.  
7.6.4.2 
Key Secondary Endpoint 
The key secondary efficacy endpoint is the proportion of subjects achieving mean serum 
phosphorus levels above the LLN (2.5 mg/dL [0.81 mmol/L]) at the mid-point of the dose 
interval (i.e., Weeks 2, 6, 14, and 22), as averaged across dose cycles between baseline and 
Week 24.  
7.6.4.3 
Secondary Endpoints 
The secondary efficacy endpoints will compare the effects of treatment with KRN23 on the 
following: 
• Percent changes from baseline in additional histomorphometric parameters – including 
osteoid thickness (O.Th), osteoid surface/bone surface (OS/BS), and mineralization lag 
time (MLt) 
• Changes from baseline in MAR, MS/BS, BFR and additional measures of bone formation 
and remodeling 
• Additional measures to assess serum phosphorus levels between baseline and Week 24 
include: 
o 
Proportion of subjects achieving mean serum phosphorus levels above the LLN 
(2.5 mg/dL [0.81 mmol/L] at the end of the dosing cycle (4 weeks after dosing), 
as averaged across dose cycles  
o 
Mid-point of dosing cycle:  mean change from baseline, and percent change from 
baseline averaged across dose cycles 
o 
End of dosing cycle: mean change from baseline, and percent change from 
baseline averaged across dose cycles 
o 
Cumulative exposure: area under the curve (AUC) 
• Change from baseline over time in serum 1,25(OH)2D, urinary phosphorus, TmP/GFR, 
and TRP 
• Change and percent change from baseline over time in serum bone turnover markers, 
including P1NP, CTx-I, and BALP 
Additional analyses of serum phosphorus including observed values, change from baseline, 
percent change from baseline over time, and area under the curve will be summarized. 

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Similar analyses will be performed for 1,25(OH)2D, urinary phosphorus, TmP/GFR, and 
TRP. 
In general, observed values at baseline and end of study, and percent changes from baseline 
to end of the study for bone quality parameters and bone turnover markers will be 
summarized.  
Correlations may be used to assess the relationship between bone turnover markers and 
selected histomorphometric indices. 
7.6.4.4 
Exploratory Endpoints 
The following exploratory endpoints will be examined: 
• Healing of active pseudofractures and/or fractures, as defined by skeletal survey at 
baseline and subsequent targeted radiography  
• Change from baseline in BPI Pain Severity and in Pain Interference scores over time 
• Change from baseline over time in BFI Q3-Worst Fatigue Score  
• Change from baseline over time in BFI Global Fatigue score, calculated by averaging all 
9 items on the BFI 
7.6.5 
Safety Analyses 
Safety will be evaluated by the incidence, frequency and severity of AEs and SAEs, 
including clinically significant changes from baseline to scheduled time points in vital signs 
and weight, physical examinations, eGFR, chemistry, hematology, urinalysis, 
immunogenicity, and concomitant medications. Additional safety parameters to assess the 
risk of ectopic mineralization include renal ultrasound, ECHO and ECG findings. Safety 
analysis will be performed using the safety analysis set. 
All AEs will be coded using the Medical Dictionary for Regulatory Activities (MedDRA). 
The incidence and frequency of AEs will be summarized by System Organ Class, Preferred 
Term, relationship to study drug, and severity. All reported AEs with onset during the 
treatment (i.e. treatment-emergent AEs) will be included in the analysis. For each AE, the 
percentage of subjects who experienced at least 1 occurrence of the given event will be 
summarized. Special attention will be given to those subjects who died, discontinued 
treatment due to an AE, or experienced a SAE (e.g. summaries, listings, and narrative 
preparation may be provided, as appropriate). 
Clinical laboratory data will be summarized by the type of laboratory test. Reference ranges 
and markedly abnormal results (specified in the SAP) will be used in the summary of 
laboratory data. The frequency and percentage of subjects who experience abnormal clinical 
laboratory results (i.e. outside of reference ranges) and/or clinically significant abnormalities 

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(as determined by the investigator) will be presented for each clinical laboratory 
measurement. 
The SAP will provide additional details on the planned safety analyses. 
7.6.6 
Interim Analysis 
Administrative analyses may be performed at any time during the study at the discretion of 
the Sponsor.  
7.6.7 
Data Monitoring Committee 
An independent DMC constituted for the double-blind, placebo-controlled Phase 3 study 
(UX023-CL303) includes members with expertise in metabolic bone disease. This DMC will 
act in an advisory capacity to monitor subject safety for both the UX023-CL303 and 
UX023-CL304 studies through the end of the Treatment Period (Week 48). A review of 
safety data will be conducted by the DMC periodically. Ad hoc meetings will be held if 
indicated based on observed events. The roles and responsibilities of the DMC will be 
defined in the DMC Charter.  During Treatment Extension Periods I and II, safety data will 
be reviewed by the SSRT on an ongoing basis.   

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8 STUDY CONDUCT 
8.1 
Ethics 
8.1.1 
Institutional Review Board or Ethics Committee 
The IRB/EC must be a properly constituted board or committee operating in accordance with 
21 CFR Part 56, "Institutional Review Boards." This protocol, any protocol amendments, and 
the associated informed consent forms (ICFs) must be submitted to the IRB/EC for review 
and must be approved before screening of any subject into the study. Study drug may not be 
shipped to the investigator until Ultragenyx or its designee has received a copy of the letter or 
certificate of approval from the IRB/EC for the protocol and any protocol amendments, as 
applicable. 
All subject recruitment and/or advertising information must be submitted to the IRB/EC and 
Ultragenyx or its designee for review and approval prior to implementation. IRB/EC 
approval of any protocol amendments must be received before any of the changes outlined in 
the amendments are put into effect, except when the amendment has been enacted to protect 
subject safety. In such cases, the chair of the IRB/EC should be notified immediately and the 
amendment forwarded to the IRB/EC for review and approval. 
8.1.2 
Ethical Conduct of Study 
This protocol is written in accordance with the principles established by the 18th World 
Medical Association General Assembly (Helsinki, 1964) and subsequent amendments and 
clarifications adopted by the General Assemblies. The sponsor and investigator will make 
every effort to assure the study described in this protocol is conducted in full conformance 
with those principles, current FDA regulations, ICH Good Clinical Practices (GCP) 
guidelines, and local ethical and regulatory requirements. Should a conflict arise, the sponsor 
and investigator will follow whichever law or guideline affords the greater protection to the 
individual subject. The investigator will also make sure he or she is thoroughly familiar with 
the appropriate administration and potential risks of administration of the study drug, as 
described in this protocol and the IB, prior to the initiation of the study. 
8.1.3 
Subject Information and Consent 
Appropriate forms for documenting written informed consent will be provided by the 
investigator and reviewed and approved by Ultragenyx or its designee before submission to 
the IRB/EC. Ultragenyx or its designee must receive a copy of the IRB/EC's approval of the 
ICF before the shipment of study drug to the study site. 
It is the investigator's responsibility to obtain signed written informed consent from each 
potential study subject prior to the conduct of any study procedures. This written informed 
consent will be obtained after the methods, objectives, requirements, and potential risks of 
the study have been fully explained to each potential subject. The investigator must explain 

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to each subject that the subject is completely free to refuse to enter the study or to withdraw 
from it at any time.  
The method of obtaining and documenting informed consent and the contents of the ICF will 
comply with ICH GCP guidelines, the requirements of 21 CFR Part 50, “Protection of 
Human Subjects,” the Health Insurance Portability and Accountability Act (HIPAA) 
regulations, and all other applicable regulatory requirements. Subjects will be given a copy of 
the signed ICF and will be provided any new information during the course of the study that 
might affect their continued participation in the study. The investigator or a qualified 
designee will be available to answer each subject's questions throughout the study, and all of 
the subject's questions must be answered to the subject's satisfaction. If the protocol is 
amended and the ICF is revised, each subject will be required to provide written informed 
consent again using the revised ICF. 
Receipt of written informed consent will be documented in each potential subject’s CRF. 
The signed ICF will remain in each subject's study file and must be available to the study 
monitor(s) at all times. 
8.2 
Investigators and Study Administrative Structure 
Each investigator must provide Ultragenyx and/or its designee a completed and signed 
Form FDA 1572 and a Financial Disclosure Form. All sub-investigators must be listed on 
Form FDA 1572 and Financial Disclosure Forms must be completed for all sub-investigators 
listed on Form FDA 1572. 
Ultragenyx and/or its designee will be responsible for managing and monitoring the clinical 
trial to ensure compliance with FDA and ICH GCP guidelines. Ultragenyx's trained 
designated representative (the monitor) will conduct regular visits to the clinical site, to 
perform source document verification. The monitor will verify the investigator's ongoing 
qualifications, inspect clinical site facilities, and inspect study records, including proof of 
IRB/EC review, with the stipulation that subject confidentiality will be maintained in 
accordance with local and federal regulations, including HIPAA requirements. 
A Coordinating Investigator will be identified for multicenter trials. The Coordinating 
Investigator will be selected on the basis of active participation in the trial, thorough 
knowledge of the therapeutic area being studied, and the ability to interpret data. 
The Coordinating Investigator will read and sign the Clinical Study Report (CSR). 
8.3 
Investigational Product Accountability 
While at the clinical site, study drug must be stored in a secure limited access location at 
controlled temperature as described in the IB and according to product packaging. 
The storage facility must be available for inspection by the study monitor at any time during 
the study. 

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A drug accountability record must be maintained for all study drug received, dispensed, 
returned, and/or lost during the study. This record must be kept current and made available to 
the study monitor for inspection. Following the close-out of the study, all unused study drug 
must be returned to Ultragenyx and/or its designee unless other instructions have been 
provided for final disposition of the study drug. 
8.4 
Data Handling and Record Keeping 
8.4.1 
Case Report Forms and Source Documents 
The investigator is required to initiate and maintain, for each subject, an adequate and 
accurate case history that records all observations and other data related to the study for that 
subject. A validated electronic data capture (EDC) system will be used for entry of the data 
into electronic CRFs. Data must be recorded on CRFs approved by Ultragenyx or its 
designee. All information recorded on CRFs for this study must be consistent with the 
subject's source documentation. 
Initial data entry and any changes to the data will be made only by Ultragenyx-
authorized users, and data entries and changes will be captured in an electronic audit trail. 
An explanation of any data change should be recorded in the CRF. All data entered in to the 
CRF must be verifiable; therefore, CRFs will be routinely checked for accuracy, 
completeness, and clarity and will be cross-checked for consistency with source documents, 
including laboratory test reports and other subject records by Ultragenyx or its designee. 
The investigator must allow direct access to all source documents. 
8.4.2 
Data Quality Assurance 
Monitoring and auditing procedures developed by Ultragenyx and/or its designee will be 
implemented to ensure compliance with FDA and ICH GCP guidelines. Ultragenyx's 
designated representative (the monitor) will contact the investigator and conduct regular 
visits to the study site. The monitor will be expected and allowed to verify the investigator's 
qualifications, to inspect clinical site facilities, and to inspect study records, including proof 
of IRB/EC review, with the stipulation that subject confidentiality will be maintained in 
accordance with local and federal regulations, including HIPAA requirements. The monitor 
will also be responsible for confirming adherence to the study protocol, inspecting CRFs and 
source documents, and ensuring the integrity of the data. CRFs will be checked for accuracy, 
completeness, and clarity and will be cross-checked for consistency with source documents 
including progress notes, laboratory test reports and other subject records. Instances of 
missing or uninterruptable data will be resolved in coordination with the investigator. 
The monitor will also investigate any questions concerning adherence to regulatory 
requirements. Any administrative concerns will be clarified and followed. The monitor will 
maintain contact with the site through frequent direct communications with the study site by 
e-mail, telephone, facsimile, and/or mail. The investigator and all other site personnel agree 

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to cooperate fully with the monitor and will work in good faith with the monitor to resolve 
any and all questions raised and any and all issues identified by the monitor. 
The investigator understands that regulatory authorities, the IRB/EC, and/or Ultragenyx or its 
designees have the right to access all CRFs, source documents, and other study 
documentation for on-site audit or inspection and will retain this right from the start of the 
study to at least two years after the last approval of a marketing application or for at least two 
years after clinical development of the study drug for the indication being studied has been 
discontinued. The investigator is required to guaranty access to these documents and to 
cooperate with and support such audits and inspections. 
8.4.3 
Record Retention 
All study records must be retained for at least 25 years after the end of the clinical trial or in 
accordance with national law. Subject files and other source data must be kept for the 
maximum period of time permitted by the hospital, institution or private practice, but not less 
than 25 years. Ultragenyx must be notified and will assist with retention should the 
Investigator/institution be unable to continue maintenance of subject files for the full 
25 years. All study records must be stored in a secure and safe facility. 
8.5 
Reporting and Follow-up of Adverse Events 
8.5.1 
Definition of Adverse Events 
An AE is defined as any untoward medical occurrence associated with the use of a drug in 
humans, whether or not considered drug related. 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. 
A suspected adverse reaction is any AE for which there is a reasonable possibility that the 
drug caused the AE. For the purposes of expedited safety reporting, “reasonable possibility” 
means there is evidence to suggest a causal relationship between the drug and the AE. 
Suspected adverse reaction implies a lesser degree of certainty about causality than adverse 
reaction, which means any AE caused by a drug. 
Life-threatening AE or life-threatening suspected adverse reaction is an AE or suspected 
adverse reaction that, in the view of either the investigator or Ultragenyx, places the patient 
or subject at immediate risk of death. It does not include an AE or suspected adverse reaction 
that, had it occurred in a more severe form, might have caused death. 
An AE or suspected adverse reaction is considered “unexpected” if it is not listed in the 
current Investigators Brochure’s Reference Safety Information (RSI) or is not listed at the 
specificity or severity that has been observed.  

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An SAE or serious suspected adverse reaction is an AE or suspected adverse reaction that at 
any dose, in the view of either the investigator or Ultragenyx, results in any of the following 
outcomes: 
• Death 
• A life-threatening AE 
• Inpatient hospitalization or prolongation of existing hospitalization 
• Persistent or significant incapacity or disability (substantial disruption of the ability to 
conduct normal life functions) 
• A congenital anomaly/birth defect 
• Note that hospitalizations planned prior to study enrollment (e.g. for elective surgeries) 
are not considered SAEs. Hospitalizations that occur for pre-existing conditions that are 
scheduled after study enrollment are considered SAEs.  
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 outcomes listed in the definition. 
8.5.2 
Severity of Adverse Events 
Wherever possible, the severity of all AEs will be graded using the NCI CTCAE version 
4.03. The majority of AEs can be graded using this system. 
If an AE cannot be graded using the CTCAE criteria, it should be graded as mild, moderate, 
severe, life-threatening, or death using the following definitions.  
• Mild (Grade 1): Awareness of signs or symptoms, but easily tolerated and of a minor 
irritant type, causing no loss of time from normal activities. Symptoms do not require 
therapy or a medical evaluation; signs and symptoms are transient. 
• Moderate (Grade 2): Events introduce a low level of inconvenience or concern to the 
participant and may interfere with daily activities, but are usually improved by simple 
therapeutic measures; moderate experiences may cause some interference with 
functioning. 
• Severe (Grade 3): Events interrupt the participant’s normal daily activities and generally 
require systemic drug therapy or other treatment; they are usually incapacitating. 
• Life-threatening (Grade 4): Events that place the participant at immediate risk of death or 
are disabling. 
• Death (Grade 5): Events that result in death. 
To make sure there is no confusion or misunderstanding of the difference between the terms 
"serious" and "severe," which are not synonymous, the following note of clarification is 

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provided. The term "severe" is often used to describe the intensity (severity) of a specific 
event (as in mild, moderate, or severe myocardial infarction); the event itself, however, may 
be of relatively minor medical significance (such as severe headache). This is not the same as 
"serious" which is based on subject/event outcome or action criteria usually associated with 
events that pose a threat to a subject's life or functioning. Seriousness (not severity) serves as 
a guide for defining regulatory reporting obligations. 
8.5.3 
Relationship of Adverse Events to Study Drug 
The investigator will assess the potential relationship of the AE to study drug using the 
following descriptions. 
Categories of attributions for “Unrelated” events: 
• Unrelated:  This category applies to an AE that is clearly not related to the 
investigational agent/procedure, beyond a reasonable doubt. 
• Unlikely Related:  This category applied to an AE that is doubtfully related to the 
investigational agent/procedure. 
Categories of attributions for “Related” events: 
• Possibly Related: This category applies to an AE that may be related to the 
investigational agent/procedure. 
• Probably Related: This category applies to an AE that is likely related to the 
investigational agent/procedure.  
• Definitely Related: This category applies to an AE that is clearly related to the 
investigational agent/procedure. 
For the purposes of reporting to regulatory agencies, AEs deemed as Definitely, Probably or 
Possibly Related will be considered Related and those deemed Unrelated or Unlikely Related 
will be considered Unrelated. 
8.5.4 
Adverse Event Reporting to Ultragenyx 
8.5.4.1 
General 
All AEs (i.e. any new or worsening in severity or frequency of a preexisting condition) with 
onset after the subject signs consent for study participation must be promptly documented on 
the AE eCRF via the EDC system. The Principal Investigator is responsible for evaluating all 
AEs, obtaining supporting documents, and ensuring documentation of the event is adequate. 
Details of the AE must include severity, relationship to study drug, duration, and outcome.  

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All AEs will be collected from the time the subject signs informed consent through the final 
Safety Follow-up TC (as defined in Section 7.4.3.1). In addition, the Investigator should 
report any AE that occurs after this time period that is believed to have a reasonable 
possibility of being associated with study drug.  
AEs ongoing at the final Safety Follow-up TC should have a comment in the source 
document by the Investigator whether the event has recovered, recovered with sequelae, or 
stabilized. 
8.5.4.2 
Serious Adverse Events, Serious Adverse Drug Reactions, and Requirements 
for Immediate Reporting 
Any SAE that occurs at any time during the study, including a clinically significantly 
abnormal laboratory test result that is considered serious, must be reported within 24 hours of 
knowledge of the event to Ultragenyx or its designee. These requirements apply equally to all 
subjects, regardless of the study phase or the at-risk subject's treatment assignment or dosage. 
The reporting requirement for SAEs is from the time of signing of the ICF through the final 
Safety Follow-up TC.  
SAEs will be reported by completing and submitting SAE report forms to Ultragenyx or its 
designee. Initial SAE reports must be followed by detailed descriptions. These should include 
copies of hospital case records and other documents when requested. Telephone reports must 
be confirmed promptly by facsimile. Follow-up SAE information must be submitted in a 
timely manner as additional information becomes available. All SAEs regardless of 
relationship to study drug must be followed to resolution or stabilization if improvement is 
not expected. 
A death occurring during the study, during the per-protocol follow-up period, or through the 
final Safety Follow-up TC (as defined in Section 7.4.3.1) must be reported to Ultragenyx or 
its designee within 24 hours of knowledge of the death whether or not it is considered 
treatment-related.  
The investigator also must notify the IRB/EC of the occurrence of the SAE, in writing, as 
soon as is practicable and in accordance with IRB/EC requirements and local law. A copy of 
this notification must be provided to Ultragenyx or its designee. 
8.5.4.3 
Urgent Safety Reporting 
The regulations governing clinical studies state that the sponsor and investigator are required 
to take appropriate urgent safety measures to protect subjects against any immediate hazards 
that may affect the safety of subjects, and that the appropriate regulatory bodies should be 
notified according to their respective regulations. According to the European Union (EU) 
Clinical Trial Directive 2001/20/EC, “…in the light of the circumstances, notably the 
occurrence of any new event relating to the conduct of the trial or the development of the 
investigational medicinal product where that new event is likely to affect the safety of the 
subjects, the sponsor and the investigator shall take appropriate urgent safety measures to 

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protect the subjects against any immediate hazard. The sponsor shall forthwith inform the 
competent authorities of those new events and the measures taken and shall ensure that the 
Ethics Committee (EC) is notified at the same time.”  The reporting period for urgent safety 
issues is the period from the signing of the ICF through the final Safety Follow-up TC (as 
defined in Section 7.4.3.1). Investigators are required to report any urgent safety measures to 
Ultragenyx within 24 hours. 
8.5.4.4 
Adverse Drug Reaction Reporting 
Ultragenyx or its designee will submit suspected unexpected serious adverse reactions 
(SUSAR) to appropriate Regulatory Authorities (including Competent Authorities in all 
Member States concerned), Ethics Committees, and Investigators as per local laws and 
regulations. Fatal and life-threatening SUSARs will be submitted no later than 7-calendar 
days of first knowledge of the event and follow-up information submitted within an 
additional eight (8) days. All other SUSARs will be submitted within 15-calendar days of 
first knowledge of the event.  
Principal Investigators are required to report any urgent safety matters to Ultragenyx or its 
designee within 24 hours. Ultragenyx or its designee will inform the Regulatory Authorities, 
Ethics Committees, and Investigators of any events (e.g. change to the safety profile of 
KRN23, major safety findings) that may occur during the clinical trial that do not fall within 
the definition of a SUSAR but may affect the safety of subjects participating in the clinical 
trials, as required, in accordance with applicable laws and regulations. The reporting period 
for urgent safety issues is the period from the signing of the ICF through the final Safety 
Follow-up TC (as defined in Section 7.4.3.1). 
The investigator will notify the IRBs/Research Ethics Boards (REB)/ECs of SAEs and urgent 
safety matters, in accordance with IRB/REB/EC requirements and local laws and regulations. 
A copy of this notification must be provided to Ultragenyx or its designee.  
Non-SUSARs will be maintained in the Ultragenyx safety database and provided in annual 
and/or periodic reports as per local laws and regulations. Ultragenyx or its designee will 
prepare and submit annual safety reports and/or other aggregate periodic summary reports to 
Regulatory Authorities and Ethics Committees, as per local laws and regulations. 
8.5.4.5 
Pregnancy in Subject or Partner 
Pregnancies in subjects or partners must be reported within 24 hours of knowledge of the 
event to Ultragenyx or its designee. The reporting period for pregnancies is the period 
from the signing of the ICF through the final Safety Follow-up TC (as defined in 
Section 7.4.3.1). 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. Refer to the Study Reference Manual for details on the reporting 

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procedures to follow in the event of pregnancy. Pregnancy-associated SAEs will be 
processed and submitted, as necessary, as per the SUSAR reporting process (Section 8.5.4.4). 
8.5.4.6 
Review of Safety Data 
The Ultragenyx SSRT, Medical Monitor, and Investigator(s) will actively review safety data 
during the course of the study. Subsequent safety data review by the SSRT will occur 
approximately quarterly or more frequently, as needed.  Safety data for review will, at a 
minimum, include listings of all SAEs, treatment-emergent AEs, grade 2 or greater 
laboratory values, deaths, and AEs leading to study discontinuation. 
To facilitate prompt risk mitigation activities, the SSRT will immediately evaluate:  
• Any observations that may materially influence the risk-benefit analysis of KRN23 
• Any significant safety issues that have been identified from cumulative data  
• Any actions taken by any country’s Regulatory Authority due to safety issues 
 
Potential safety signals identified during the SSRT reviews or any other process during the 
conduct of the study will be escalated to the appropriate internal Ultragenyx safety governing 
bodies. Any action indicated by Ultragenyx safety governing bodies will be communicated 
accordingly to all stakeholders, e.g. Regulatory Authorities, Ethics Committees, and 
Investigators. 
An independent DMC will act in an advisory capacity to monitor subject safety through the 
end of the Treatment Period (Week 48). The DMC may meet on a routine basis, or as needed, 
to review aggregate safety data and provide advice regarding the safety of subjects and the 
continuing scientific validity of the study. The DMC may also be asked to review SUSARs 
that represent changes in the nature or an increase in the frequency of events and may 
provide recommendations regarding continued subject participation. 
Potential safety signals identified during the DMC reviews or any other process during the 
conduct of the study will be escalated to the appropriate internal Ultragenyx safety governing 
bodies. Any action indicated by Ultragenyx safety governing bodies will be communicated 
accordingly to all stakeholders, e.g. Regulatory Authorities, ECs, IRBs, and Investigators. 

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8.5.4.7 
Safety Contact Information 
Drug Safety 
Medical Monitor 
PrimeVigilance 
Fax:     
     
e-mail: 
 
  
 MD, PharmD 
Premier Research 
Mobile:  
 
Office:  
 
24-Hr Emergency Phone number for US and 
Canada:             
 
24-Hr Emergency Phone number for Europe, 
Japan, Korea:   
 
 
8.6 
Financing and Insurance 
Financing and insurance for this clinical trial will be addressed in clinical trial agreements 
with the study site. 
8.7 
Publication Policy 
Any publication or presentation by the investigator and/or the Institution based on data or 
results resulting from the Ultragenyx study shall only be done in strict accordance with the 
Publication section in the Clinical Trial Agreement executed between Ultragenyx or its 
designee and the Institution and/or the investigator. 

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