A Randomized, Open-Label, Dose Finding, Phase 2 Study to Assess the Pharmacodynamics and Safety of the Anti-FGF23 Antibody, KRN23, in Pediatric Patients With X-linked Hypophosphatemia (XLH)
Phase: PHASE2
Conditions: X-linked Hypophosphatemia
Sponsor: Kyowa Kirin, Inc.

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PPD

CLINICAL STUDY PROTOCOL AMENDMENT  
SUMMARY OF CHANGES AND RATIONALE 
Protocol Amendment 1 
The original version of Protocol UX023-CL201 (dated 24 February 2014) was modified by 
Amendment 1 (dated 07 May 2014) to incorporate changes requested by the Medicines and 
Healthcare Products Regulatory Agency (MHRA). Key changes impacting the conduct of the 
study were: 
 Pregnancy testing (for female subjects of childbearing potential who had experienced 
menarche), contraception requirements, and follow up for pregnancies were 
incorporated into the protocol. Although the study enrolled pre-pubertal subjects of 
Tanner Stage 2 or less, contraception requirements and regular pregnancy testing for 
subjects entering puberty during trial participation was included as an added safety 
precaution, given that burosumab has been found to be associated with premature 
births, embryo/fetal deaths, and abortions in cynomolgus monkeys. 
 Subjects were to be discontinued from study drug if they experienced new or 
clinically significant worsening in mineralization that was considered clinically 
meaningful by the investigator and/or sponsor and was related was to study drug. 
Ectopic mineralization is a characteristic feature of patients with XLH and is also 
related to the current conventional therapy treatment with oral phosphate and active 
forms of vitamin D. It is unknown whether burosumab may increase the risk of 
ectopic mineralization including nephrocalcinosis. 
 The standing height inclusion criterion was broadened from < 25th percentile to 
< 50th percentile to include pediatric XLH subjects with significant bone disease who 
met all other eligibility criteria and who would previously have been excluded from 
participation in the study based on their stature alone.  
Protocol Amendment 2 
Protocol Amendment 1 (dated 07 May 2014) was modified by Protocol Amendment 2 (dated 02 
July 2014) to incorporate changes requested by the US FDA and ECs. Most changes were 
clarifications and adjustments regarding logistical considerations, eg, windows for dosing, visits, 
and assessments; fasting requirements; and the formula to be used for GFR. Key changes 
impacting the conduct of the study were: 
 The number of study sites was increased from 8 to 9. 
 Tanner staging criteria was to be assessed for all subjects, for consistency of data 
collection and to ensure that any subjects with early pubertal status due to underlying 
conditions were identified. 
 Subjects receiving growth hormone therapy within 3 months (previously: 12 months) 
of screening were excluded from the study. 

Protocol Amendment 3 
Protocol Amendment 2 (dated 02 July 2014) was modified by Protocol Amendment 3 (dated 02 
March 2015) to allow for the enrollment of additional study subjects to provide additional safety, 
dose, and efficacy data in the pediatric population. Key changes impacting the conduct of the 
study were: 
 The number of study sites was increased from 9 to 12. 
 Dose Cohort 3 was expanded to include up to 30 subjects for a total study population 
of up to 50 subjects. “Pre-expansion subjects” (n = 36) were fully enrolled under the 
earlier versions of the protocol; Dose Cohort 3 “expansion subjects” (n = 
approximately 15) were to be enrolled under the Amendment 3.  
 Added assessment of changes in rickets severity by the RSS method to complement 
assessments by RGI-C. Methods for blinding of radiographic assessments also were 
added. 
 RSS at the knee of at least 1.5, as determined by a central reader, was required for 
inclusion in the expansion group. Requiring subjects in the expansion group to have 
an RSS of at least 1.5 at the knee increases the probability of seeing a meaningful 
reduction in rickets severity with burosumab. 
 Because the enrollment criteria were adjusted to require a specific level of rickets 
severity, gender-related differences in the severity of skeletal disease were minimized 
and the requirement for gender balance was removed for the expansion group. 
Protocol Amendment 4 
Protocol Amendment 3 (02 March 2015) was modified by Protocol Amendment 4 (dated 
22 April 2015) based on new data. Key changes impacting the conduct of the study were: 
 The upper limit of the target serum phosphorus range was updated to 5.0 mg/dL 
(1.61 mmol/L) from 4.5 mg/dL (1.45 mmol/L). The normal reference serum 
phosphorus range for children aged 5 to 12 years is approximately 3.2 to 6.1 mg/dL 
(1.03 to 1.97 mmol/L). Increasing the upper limit of the target fasting serum 
phosphorus range for this study maintained the target within the low- to mid- normal 
range and would avoid unnecessary fluctuations in dose levels. 
 Dose titration adjustments, whether upward or downward, could be made in 
increments of 0.3 mg/kg for the Q2W regimen (vs 0.1 mg/kg previously) and in 
increments of 0.4 mg/kg for the Q4W regimen (vs 0.2 mg/kg previously). The dose 
increments in the initial version of the protocol were selected to slowly increase the 
dose to prevent any unexpected or exaggerated increases in serum phosphorus. 
Available data showed small proportional increases in serum phosphorus with the 
previous titration scheme, and many dose cycles were required to reach a dose that 
produced serum phosphorus levels in the target range. Therefore, in the absence of 
any safety signal and to allow subjects to achieve their serum phosphorus target range 
earlier, the dose titration scheme was modified. 

 Unscheduled blood draws for peak serum phosphorus measurements could be 
obtained at study visits if titration continues into the Treatment Period to enable 
appropriate dose management. 
 The maximum dose of burosumab in regimen Q2W was increased to 2.0 mg/kg. In 
addition, the maximum allowable dose was capped at 90 mg (for both the Q2W and 
Q4W groups). The target therapeutic goal remained the same, ie, peak serum 
phosphorus levels between 3.5 and 5.0 mg/dL (1.13 and 1.62 mmol/L). This change 
was based on the finding that some subjects needed doses higher than 1.0 mg/dL 
(0.32 mmol/L) to achieve the serum phosphorus target, regardless of whether the dose 
was given at the Q2W or Q4W dose regimen. Approximately half of the subjects in 
the Q4W regimen were already receiving doses above 1.0 mg/dL (0.32 mmol/L) to 
achieve the proposed target serum phosphorus range, and no safety concerns were 
raised. The increases in serum phosphorus were proportional to the dose 
administered, independently of the whether the subject is receiving burosumab 
monthly or biweekly. No cumulative dose effect in the Q2W regimen group was 
observed. The maximum dose was set at 90 mg because there is limited experience in 
adults with burosumab doses above 90 mg. 
 Changes were made in the timing of serum phosphorus, calcium, and 1,25(OH)2D 
measurements at Weeks 48 through 62 to better characterize the longer-term PD 
effects of burosumab by assessing both peak and trough measurements toward the 
end of the study.  
 The dosing window was changed so that subjects will be dosed at Q2W or Q4W 
week intervals (±3 days) and no fewer than 8 days apart (previously: no fewer than 
12 days apart). Adjusting the dosing window provided additional convenience to 
subjects and study sites without impacting safety. 
Protocol Amendment 5 
Protocol UX023-CL201 Amendment 4 (dated 22 April 2015) was modified by Amendment 5 
(dated 28 August 2015) to extend the study duration by adding a treatment extension period, 
apply Q2W dosing for all subjects within the extension period, and adjust the dosing calculation. 
Key changes impacting the conduct of the study were: 
 A 96-week Treatment Extension Period was incorporated into the study design to 
evaluate the long-term safety and efficacy of burosumab. It is expected that the 
maintenance of phosphate control will allow for continued healing of rickets and 
bowing and maximize growth outcomes. Changes in growth and correction of lower 
extremity bowing may take longer to observe than the healing of rickets, and these 
outcomes continued to be followed in the Treatment Extension Period. 
 During the Treatment Extension Period, all subjects receive Q2W administration of 
burosumab. The transition of subjects to Q2W dosing reflects interim Week 40 
findings related to serum phosphorus levels, rickets, and dose. Subjects in the Q2W 
dosing regimen showed a more stable and consistent increase in serum phosphorus 
levels with less fluctuation over time than in subjects who received burosumab Q4W 

for whom serum phosphorus levels increased at the middle of the dose cycle (week 2) 
but tended to return to baseline at the end of the dose interval (week 4). 
 Subjects who had been receiving Q2W dosing continued receiving the same dose 
at the same dose interval.  
 Subjects who had been receiving the Q4W regimen switched to the Q2W regimen 
beginning with the Week 64 dose. The dose was 60% of the most recent monthly 
dose (rounded to the nearest 10 mg), the total dose was approximately 20% higher 
per month compared with the subject’s Q4W dose. 
 Vital signs measurements were required to be performed before any additional 
assessments were completed and after the subject had rested for 5 minutes. A second 
BP measurement was required to be obtained at the end of the study visit after all 
procedures have been performed. 
Protocol Amendment 6 
Protocol UX023-CL201 Amendment 5 (dated 28 August 2015) was modified by Amendment 6 
(dated 07 July 2016) to clarify language and procedures regarding dose adjustment, to add an 
option for non-healthcare provider administration of study drug under certain conditions; to add 
reflexive genetic testing to assess additional genes associated with phenotypes overlapping with 
XLH if initial PHEX mutation analysis is negative or inconclusive; and to clarify or update study 
procedures and assessments. This protocol amendment was implemented at the clinical sites after 
the data cut-off date of 01 December 2016. 
Key changes impacting the conduct of the study were: 
Drug Administration 
 In Section 7.1 and Section 7.2, language and procedures regarding dose adjustment 
were updated and clarified. The information was also reorganized for easier reference 
to dosing for a specific period of the study (eg, Titration Period or Treatment 
Extension Period). Specifically, the protocol states that after the initial dose titration 
is complete, during the Treatment Period and Treatment Extension Period dose 
adjustments may be made in any subject if specific serum phosphorus criteria are met. 
When post-titration dose adjustment is needed, doses should be adjusted in 10 mg 
total dose increments (eg, a 20-mg rounded total dose would be increased to a 30 mg 
total dose). 
 Section 7.4.1 was updated to state that “At the discretion of the investigator and after 
proper training by study personnel in SC injection technique, a subject’s parent or 
non-healthcare provider caregiver may administer burosumab to the subject under the 
supervision of a Home Health (HH) nurse where local regulations permit and where 
logistically feasible. Parents or caregivers will be instructed to follow the directions 
provided in the Instructions for Use. The dosing schedule will remain the same.” 
Inclusion Criteria 

 In Section 7.3.1, inclusion criterion #10 was updated to state that sexually active male 
and female subjects must be willing to use 2 highly effective methods of 
contraception during the study. Previously it stated, “an acceptable method.”  
Removal of Subjects 
 In Section 7.3.3, language was added to indicate that orthopedic surgery will be 
permitted during the Treatment Extension Period if recommended by the investigator 
or consulting physician and that subjects who develop hyperparathyroidism may 
remain on study but use of medication to suppress PTH (eg, Sensipar®, cinacalcet, 
calcimimetics) is not permitted at any time. Subjects should be removed from study if 
treatment for hyperparathyroidism becomes medically necessary. 
Study Procedures and Assessments 
 The Schedule of Events was updated to add serum phosphorus and serum 
1,25(OH)2D measurements at Weeks 124 and 148. 
 Section 7.5.3.2 was modified to add a 6MWT assessment at Week 160 and to indicate 
the POSNA-PODCI instrument will be administered at Weeks 88 and 160 but not at 
Weeks 112 and 136. 
 Measurement of pre-dose serum burosumab concentration at Week 24 using 
retrospective samples was added to Section 7.5.4 and the Schedule of Events. 
 The Schedule of Events was updated to indicate post-treatment Tanner staging will be 
performed beginning at Week 64 and every 6 months thereafter during the extension 
phase of the study. 
 Bilateral AP knee X-rays were added at Week 160 to the Schedule of Events and in 
Section 7.5.3.1. In addition, it is noted that beginning at Week 64 and during the 
extension, radiographs will be evaluated for epiphyseal closure, and that RGI-C 
assessment of radiographs will occur at Weeks 88 and 160. 
Genetic Testing 
 Section 7.5.5 was modified to add that genetic testing for mutations in genes 
consistent with syndromes that have 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. 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). The investigator will be 
provided the genetic testing results and will determine when and whether the 
information should be shared with the subject. 
Central Reads of Echocardiograms 
 Section 7.5.5.6 was updated to state that ECHOs will be read centrally rather than 
locally. The central core lab will provide a study specific protocol to be followed by 
the sites to ensure adequate image acquisition for the assessment of mineralization. 

Safety Measures 
 In Section 7.5.5, ECG is listed as a general safety assessment. Previously it was listed 
within the safety assessments for ectopic mineralization. 
 Section 7.5.5.8 was updated to add assessment of lipase in all subjects and specify 
additional laboratory analyses will be performed reflexively if serum amylase levels 
are elevated to ≥ 1.5 times the upper limit of the reference range (ULRR). 
 Language in Section 7.5.5.8 regarding FGF23 assays was updated to indicate testing 
will be performed by a contract laboratory and not the sponsor’s development partner, 
Kyowa Hakko Kirin Pharma, Inc. 
Ethics 
 Section 8.1.2 was 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 GCP guidelines, 
and local ethical and regulatory requirements. 
Statistical Analyses 
 In Section 7.6.4.3, the statistical methodology for the Week 40 analysis was updated 
to include the GEE model rather than the Mixed Model for Repeated Measures. 
Record Retention 
 Section 8.4.3 was 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.  
Definition of Adverse Events 
 In Section 8.5.1, language was added to clarify that hospitalizations planned prior to 
study enrollment (eg, for elective surgeries) are not considered SAEs but 
hospitalizations that occur for pre-existing conditions that are scheduled after study 
enrollment are considered SAEs. 
 
Protocol Amendment 7 
Protocol UX023-CL201 Amendment 6 (dated 07 July 2016) was modified by Amendment 7 
(dated 08 May 2017) to extend the study duration for subjects at study sites in the United States 
(US); to update and clarify end of study procedures globally; and to make other minor 
corrections and edits. Key changes impacting the conduct of the study were: 
Treatment Duration 
 The study treatment period was extended for subjects at study sites in the US for up to 
an additional 56 weeks until September 2018; therefore, the total treatment duration 
varied by region. The study consisted of an individual dose Titration Period (16 
weeks), a Treatment Period (48 weeks), and a Treatment Extension Period I (up to 96 
weeks), for a total treatment duration of up to 160 weeks for subjects at study sites 
outside the US. In the US, the study also included a Treatment Extension Period II 

(up to 56 weeks) until September 2018 for a maximum total treatment duration of up 
to 216 weeks. The total duration of treatment varied for the individual US subjects 
based on their initial time of enrollment but was not to exceed 216 weeks. For 
subjects at study sites in Europe, Week 160 was the final efficacy visit for the study. 
Additional safety follow-up phone calls and visits occurred for certain subjects.  
End of Study Definition, Timing, and Procedures 
 In Section 7.1 and related sections, the description of the study periods was updated 
to indicate that the study duration would vary by region. The study consisted of an 
individual dose Titration Period (16 weeks), a Treatment Period (48 weeks), and a 
Treatment Extension Period I (up to 96 weeks), for a total treatment duration of up to 
160 weeks for subjects at study sites outside the US. For subjects at study sites 
outside the US, the Week 160 visit was their end of study (EOS) efficacy visit 
(referred to as EOSI). In the US, the study also included a Treatment Extension 
Period II (up to 56 weeks) until September 2018, at which time subjects had their 
EOS efficacy visit (referred to as EOS II), for a maximum total treatment duration of 
up to 216 weeks. A safety follow-up telephone call was to occur at 5 weeks (+ 5 days) 
after the EOS (I or II) efficacy visit, and a final safety visit was to occur at 10 weeks 
(± 1 week) after the EOS (I or II) efficacy visit for subjects who were not continuing 
on burosumab treatment through commercial use or another mechanism. The end of 
study was defined as the date of the last protocol-specified procedures (including 
telephone contact) for the last subject in the study. 
Study Drug Administration 
 Sections 7.4.1 and 7.4.6 were updated to indicate that for subjects in the US, after 
proper training by study personnel in subcutaneous injection technique, the subject’s 
parent or caregiver may administer KRN23 to the subject, in the home setting without 
the supervision of a home health nurse during Treatment Extension Period II. Parents 
or caregivers were to be instructed to follow the directions provided in the 
Instructions for Use. The dosing schedule remained the same. Additional instructions 
regarding the timing of the training and implementation of the subject/caregiver 
administration are provided in Section 7.4.6. In addition, in Section 7.4.1, the 
language was updated to indicate that 1.5 mL is the maximum volume that should be 
administered at a single injection site, and that rotation of injections may include 
rotation to a different quadrant of the abdomen. 
Dose Limiting Toxicity 
 In Section 7.5.5.13 the definition of dose limiting toxicity (DLT) for serum 
phosphorus was corrected to be a confirmed serum phosphorus level of ≥ 6.5 mg/dL 
rather than ≥ 6.1 mg/dL. 
Statistical Analyses 
 In Section 7.6.4.5, Treatment Extension Period Analysis, language was updated to 
account for the addition of Treatment Extension Period II. Efficacy analysis was to be 
performed at the completion of Treatment Extension Period I for the overall 
population and a final analysis was to be performed at the end of the study, which is 

defined as the date of the last protocol-specified procedures (including telephone 
contact) for the last subject in the study. 
Pregnancy Testing and Contraception 
 Section 7.5.5.10 and the Schedule of Events were updated to indicate that during 
Treatment Extension Period II, pregnancy testing will be conducted at study site visits 
every 12 weeks for subjects of childbearing potential. In addition, the acceptable 
methods of contraception were updated. 
Anti-Burosumab Antibodies 
 In Section 5.3, Section 7.5.5.9, and the Schedule of Events, the term HAHA (human 
anti-human antibody) in reference to anti- burosumab antibody testing, was replaced 
with the term ADA (anti-drug antibody). 
 

Protocol Number:  UX023-CL201  
Amendment 7  
08 MAY 2017  
 
 
Proprietary and Confidential 
Page 5 
2 SYNOPSIS 
TITLE OF STUDY: 
A Randomized, Open-Label, Dose Finding, Phase 2 Study to Assess the Pharmacodynamics and 
Safety of the anti-FGF23 Antibody, KRN23, in Pediatric Patients with X-linked Hypophosphatemia 
(XLH) 
PROTOCOL NUMBER: 
UX023-CL201 
STUDY SITES: 
Approximately 12 sites globally in the US and EU  
PHASE OF DEVELOPMENT: 
Phase 2 
RATIONALE:  
X-linked hypophosphatemia (XLH) is a disorder of renal phosphate wasting, and the most common 
heritable form of rickets. In XLH patients, high circulating levels of fibroblast growth factor 23 
(FGF23) impair normal phosphate reabsorption in the kidney. Hypophosphatemia and low-normal 
circulating 1,25-dihydroxyvitamin D (1,25(OH)2D) levels are typical biochemical findings.  
Low serum phosphorus levels result in hypomineralization of bone and associated abnormalities 
including rickets, bowing of the legs, and short stature. The current standard of care (SOC) therapy 
consists of multiple daily doses of oral phosphate combined with appropriate doses of active 
vitamin D metabolites. SOC therapy, when taken with a high degree of compliance and monitoring, 
can improve the skeletal disease but often does not fully address the bone and growth abnormalities, 
nor does it target the pathophysiological cause of the disease, renal phosphate wasting induced by high 
FGF23 levels. SOC therapy also requires careful monitoring to avoid potential risks such as 
nephrocalcinosis, hypercalciuria, and hyperparathyroidism. More efficacious, safer, and convenient 
therapies clearly are needed.  
KRN23 is a recombinant fully human monoclonal IgG1 antibody being developed to treat XLH by 
binding and inhibiting FGF23 activity, thereby restoring normal phosphate homeostasis.  Four clinical 
studies have been conducted 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-001), and 
an associated treatment extension study (KRN23 INT-002). An additional open-label long-term 
extension study (UX023-CL203), a double-blind, placebo-controlled, Phase 3 study (UX023-CL303), 
and an open-label, paired bone biopsy Phase 3 study to evaluate changes in osteomalacia at the tissue 
level with KRN23 treatment are ongoing. 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 XLH subjects.  
KRN23 sufficiently increased serum phosphorus levels, such that improvements in bone physiology, 
structure and function would be expected. These data support the initiation of further studies to 
evaluate the therapeutic benefit of KRN23 in children who experience the most severe physical and 
health manifestations associated with XLH. Currently, there are no approved treatments and a high 
unmet medical need in pediatric XLH patients. 
Adults and children with XLH have the same underlying defect but are at a different stage of the 
disease. In childhood, normal phosphorus levels are higher to promote bone formation, whereas 

Protocol Number:  UX023-CL201  
Amendment 7  
08 MAY 2017  
 
 
Proprietary and Confidential 
Page 6 
in adults, the normal range is lower, coincident with reduced demand for bone formation. 
Therefore, smaller, more frequent dosing may be preferred for pediatric hypophosphatemic patients to 
maximize treatment effects without a plateau, drive serum phosphorus levels closer to the normal 
range and minimize the troughs. This Phase 2 study will examine the PD, efficacy, and safety of 
KRN23 administered at multiple doses and dose regimens in pediatric XLH patients.   
The total treatment duration will vary by region. The study will consist of an individual dose Titration 
Period (16 weeks), a Treatment Period (48 weeks), and a Treatment Extension Period I (up to 
96 weeks), for a total treatment duration of up to 160 weeks for subjects at study sites outside the 
United States (US). For subjects at study sites outside the US the Week 160 visit will be their end of 
study (EOS) efficacy visit (referred to as EOS I). In the US, the study will also include a Treatment 
Extension Period II (up to 56 weeks) until September 2018, at which time they will have their EOS 
efficacy visit (referred to as EOS II), for a maximum total treatment duration of up to 216 weeks. 
A safety follow-up telephone call will occur at 5 weeks (+ 5 days) after the EOS (I or II) efficacy visit, 
and a final safety visit will occur at 10 weeks (± 1 week) after the EOS (I or II) efficacy visit for 
subjects that are not continuing on KRN23 treatment through commercial use or another mechanism. 
The end of study is defined as the date of the last protocol-specified procedures (including telephone 
contact) for the last subject in the study. 
The dose response of KRN23 will be evaluated at 3 starting dose levels. Monthly (Q4) and biweekly 
(i.e., every other week; Q2) dosing regimens will also be compared. KRN23 dosing will be 
individually adjusted every 4 weeks as needed, according to serum phosphorus levels. The goal is to 
achieve stable serum phosphorus levels in the target range, while minimizing changes in the calcium 
control system. During Treatment Extension Period I (and II, if applicable), all subjects will receive 
KRN23 at the Q2 dosing regimen. Data collected in this study will establish a KRN23 dose and dose 
regimen for pediatric patients, and provide information about the PD, PK, clinical efficacy and safety 
of KRN23 in children with XLH.      
OBJECTIVES: 
The objectives of the study are to:  
• 
Identify a dose and dosing regimen of KRN23, based on safety and PD effect, in pediatric XLH 
patients     
• 
Establish the safety profile of KRN23 for the treatment of children with XLH including ectopic 
mineralization risk, cardiovascular effects, and immunogenicity profile  
• 
Characterize the PK/PD profile of the KRN23 doses tested in the monthly (Q4) and biweekly (Q2) 
dose regimens in pediatric XLH patients 
• 
Determine the PD effects of KRN23 treatment on markers of bone health in pediatric XLH 
patients 
• 
Obtain a preliminary assessment of the clinical effects of KRN23 on bone health and deformity, 
muscle strength, and motor function 
• 
Obtain a preliminary assessment of the effects of KRN23 on patient-reported outcomes, including 
pain, disability, and quality of life in pediatric XLH patients 
• 
Evaluate the long-term safety and efficacy of KRN23 

Protocol Number:  UX023-CL201  
Amendment 7  
08 MAY 2017  
 
 
Proprietary and Confidential 
Page 7 
STUDY DESIGN AND METHODOLOGY: 
UX023-CL201 is a randomized, multicenter, open-label, dose finding Phase 2 study. The study will 
be conducted in prepubescent children aged 5-12 years with XLH to assess the PD, efficacy, and 
safety of KRN23 administered via subcutaneous (SC) injections monthly (Q4, 28 days) or biweekly 
(Q2, 14 days) for up to 160 weeks for subjects at study sites outside the US and up to 216 weeks (until 
September 2018) for subjects at study sites in the US. The study will consist of an individual dose 
Titration Period (16 weeks), a Treatment Period (48 weeks), and a Treatment Extension Period I (up to 
96 weeks). For subjects at study sites outside the US the Week 160 visit will be their end of study 
efficacy visit (EOS I). In the US, the study will also include a Treatment Extension Period II (up to 
56 weeks) at the end of which the US subjects will have their EOS efficacy visit (referred to as EOS 
II). A safety follow-up telephone call will occur at 5 weeks (+ 5 days) after the EOS (I or II) efficacy 
visit, and a final safety visit will occur at 10 weeks (± 1 week) after the EOS (I or II) efficacy visit for 
subjects that are not continuing on KRN23 treatment through commercial use or another mechanism. 
The end of study is defined as the date of the last protocol-specified procedures (including telephone 
contact) for the last subject in the study. 
The study initially enrolled 36 pediatric subjects with XLH and radiographic evidence of bone disease 
(pre-expansion subjects). The study was expanded to include additional subjects who were required to 
have a level of rickets severity of at least 1.5 points at the knee as defined by the Rickets Severity 
Score (RSS) method for a total of approximately 50 subjects overall. All subjects will discontinue oral 
phosphate and vitamin D metabolite therapy prior to randomization and throughout the duration of the 
study.    
There will be 3 cohorts in this study (n = 10 in cohorts 1 and 2 [pre-expansion subjects] and n = 30 in 
cohort 3 [comprising both pre-expansion and expansion subjects]); each with a Q4 and Q2 dosing 
group (Figure 2.1). Subjects will be randomized 1:1 to the KRN23 Q4 or Q2 dosing regimens within 
each cohort; randomization will be stratified on subject gender. In order to maintain a level of gender 
balance, no more than 20 patients of either sex can be enrolled in the in the pre-expansion group. 
No requirement for gender balance will be applied in the expansion group. The cohorts will be 
enrolled sequentially. The first cohort will examine the lowest starting doses (0.2 mg/kg Q4 and 
0.1 mg/kg Q2) and will be enrolled first.  As an added precautionary measure in this pediatric 
population, the second cohort (0.4 mg/kg Q4 and 0.2 mg/kg Q2) cannot begin dosing until the fourth 
subject in the first cohort completes the Week 4 visit. The third cohort will be administered the highest 
starting doses (0.6 mg/kg Q4 and 0.3 mg/kg Q2).   
 
Dosing During the Titration Period (Weeks 0-16) 
The initial 16-week Titration Period is intended to identify the KRN23 dose required to achieve 
the target peak PD effect. The goal is to identify an individualized KRN23 dose that maintains 
serum phosphorus levels in the target range. The target fasting serum phosphorus range for this study 
is 3.5- 5.0 mg/dL (1.13-1.62 mmol/L), based on the peak PD effect of KRN23. The dose will be 
adjusted every 4 weeks, as needed, based on 2-week post-dose (peak) fasting serum phosphorus levels. 
The KRN23 dose titration scheme (Table 2.1) will be used as a guideline during the Titration Period 
should the peak fasting serum phosphorus level fall outside of the target range.   
 
 
 

Protocol Number:  UX023-CL201  
Amendment 7  
08 MAY 2017  
 
 
Proprietary and Confidential 
Page 8 
Table 2.1: 
KRN23 Dose Titration Scheme 
Serum Phosphorus            
(2 weeks Post-Dose) 
Dose Adjustment1 
< 3.5 mg/dL 2                 
< 1.13 mmol/L 
In 2 weeks, increase dose by 0.3 mg/kg for Q2 OR 0.4 mg/kg for Q43 
3.5 ≤ 4.5 mg/dL 
1.13 – 1.45 mmol/L 
Repeat previous dose 
>4.5 – 5.0 mg/dL 
>1.45 – 1.62 mmol/L 
Repeat previous dose and then repeat serum phosphorus at 2 weeks 
after that dose; determine next dose based on the repeat serum 
phosphorus level. 
> 5.0 mg/dL (1.62 mmol/L) and 
≤ age adjusted ULN 
In 2 weeks, decrease dose by 0.3 mg/kg for Q2 OR  0.4 mg/kg for Q4 
and then repeat serum phosphorus at 2 weeks after that dose3 
> age adjusted ULN 
Skip next 2 doses for Q2 OR skip next dose for Q4, then re-initiate 
dosing at last dose level at which the subject’s peak serum phosphorus 
was in range4   
1 Dose adjustments for subjects assigned to the Q2 regimen will only be made after 2 consecutive peak measurements. 
2 During the Treatment Period, if a subject’s serum phosphorus level has not increased, as defined by a change no greater 
than 0.1 mg/dL, after 2 consecutive dose escalations, even if the target range has not been achieved, then the 
previous dose will be considered that subject’s optimized dose and not escalated further. 
3 If needed, the final dose adjustment increment may be less than 0.3 mg/kg for Q2 or 0.4 mg/kg for Q4 to reach the 
2.0 mg/kg maximum dose  
4The investigator should consult with the medical monitor to determine when and how to titrate up     
 
Dosing During the Treatment Period (Weeks 18-64) 
If the serum phosphorus level is rising but has not yet reached the pre-specified target range by the end 
of the Titration Period, the titration can continue into the Treatment Period until the target range is 
reached, provided there are no safety concerns. For those subjects whose dose titration continues into 
the Treatment Period, 2week post-dose peak serum phosphorus levels may be measured through 
unscheduled blood draws at corresponding study visits (e.g., at Week 18, 26, or 34) and the dose 
titration scheme (Table 2.1) followed until the target range is reached.  
The visit window for HH visits is ± 3 days during the Titration Period and Treatment Period. If at any 
time during dose titration the subject is dosed earlier than the allowable ±3-day window, the previous 
dose should be repeated (i.e., no titration). If a subject is dosed later than the allowable ±3-day 
window, dosing should be determined as if the dosing occurred within the allowable window (i.e., by 
using the most recent post-dose peak serum phosphorus level and the dose titration scheme). 
 
Dosing During Treatment Extension Periods I (Week 66 up to Week 160) and II (Weeks 162 up 
to Week 216) 
During Treatment Extension Periods I (and II, if applicable), all subjects will receive biweekly (Q2) 
administration of KRN23. Subjects in the Q2 dosing regimen during the Treatment Period will 
continue to receive KRN23 at the dose they were receiving at Week 64. At the Week 64 study visit, 
subjects in the Q4 dosing regimen will receive KRN23 at 60% of their established Q4 total dose level 
(rounded to the nearest 10 mg) and continue on that dose biweekly (Q2) through Treatment Extension 
Period I (and II). The visit window for HH visits is ± 5 days during Treatment Extension Period I. 
The window for dosing and biweekly telephone calls from the site during Treatment Extension 
Period II is ± 5 days. 

Protocol Number:  UX023-CL201  
Amendment 7  
08 MAY 2017  
 
 
Proprietary and Confidential 
Page 9 
General Dosing Guidelines 
The rounding of doses to the nearest 10 mg will not be applied during the Titration Period 
(Week 0-16). During the Treatment Period and Treatment Extension Period I and II, dose rounding 
will be applied once study sites have obtained appropriate approvals. Calculated doses below 15 mg 
will be adjusted to 15 mg. Calculated doses ≥15 mg will be rounded to the nearest 10 mg up to a 
maximum dose of 90 mg. The total administered dose may differ slightly from the total calculated or 
rounded dose due to rounding of the volume drawn for administration (to the nearest 0.1 mL). 
After the initial dose titration is complete, the dose may be increased at any time during the Treatment 
Period or Treatment Extension Periods I or II if a subject meets the following dose-adjustment criteria: 
1) two consecutive serum phosphorus measurements are below the normal range (3.2-6.1 mg/dL 
[1.03-1.97 mmol/L]); 2) the serum phosphorus level is < 0.5 mg/dL (0.16 mmol/L) above baseline; 
and 3) the subject has not missed a dose of study drug that would account for the decrease in serum 
phosphorus. If the subject has a single serum phosphorus measurement below the normal range and 
criteria 2 and 3 are met, the serum phosphorus measurement should be repeated through an 
unscheduled blood draw within 4 weeks and a dose adjustment made if the serum phosphorus remains 
below the normal range. When post-titration dose adjustment is needed during the Treatment Period or 
Treatment Extension Periods I and II, doses should be adjusted in 10 mg total dose increments (e.g., a 
20 mg rounded total dose would be increased to a 30 mg total dose). The dose level should not exceed 
2.0 mg/kg for either the Q4 regimen or the Q2 regimen. 
If serum phosphorus increases above 5.0 mg/dL (1.62 mmol/L) at any time during the study, the dose 
will be titrated down. During the Titration Period the dose should be titrated down according to the 
dose titration scheme (Table 2.1). During the Treatment Period or Treatment Extension Periods the 
total dose should be decreased by half. Following a dose reduction in a subject, the investigator and 
medical monitor will determine when and how that subject’s dose will be titrated up. 
If a subject does not receive a dose within 10 days of a scheduled dose for the Q2 regimen, that dose 
should be skipped and the next dose will be administered at the next scheduled Q2 dosing visit. If a 
subject does not receive a dose within 21 days of a scheduled dose for the Q4 regimen, that dose 
should be skipped and next dose will be administered at the next scheduled Q4 dosing visit. 
At the end of the Titration Period, the population of approximately 50 subjects will consist of 
essentially two groups of 25 subjects, each with individually optimized dosing of KRN23 at either a 
Q4 week or Q2 week frequency. Analyses of safety and available PD and efficacy data are planned at 
the end of the Titration Period (Week 16) and at Week 24 for pre-expansion subjects. Further analyses 
in the pre-expansion group alone and for the overall population are planned at Week 40 and at 
Week 64 at the end of the Treatment Period to compare treatment outcomes to baseline (pre-dose). 
Analysis of long-term efficacy and safety will be conducted at the completion of Treatment Extension 
Period I (Weeks 64-160), and a final analysis will be performed at study completion (i.e., following 
Treatment Extension Period II and all needed safety follow-up visits). Figure 2.1 provides a schematic 
of the overall study design. 
 
 
 
 
 

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Protocol Number:  UX023-CL201  
Amendment 7  
08 MAY 2017  
 
 
Proprietary and Confidential 
Page 11 
authorized representative after the nature of the study has been explained, and prior to any 
research-related procedures. 
9) 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. 
10) Females who have reached menarche must have a negative pregnancy test at Screening and 
undergo additional pregnancy testing during the study. If sexually active, male and female 
subjects must be willing to use two highly effective methods of contraception for the 
duration of the study. 
Individuals who meet any of the following exclusion criteria will not be eligible to participate in the 
study: 
1) Use of a pharmacologic vitamin D metabolite or analog (e.g. calcitriol, doxercalciferol, 
alfacalcidiol, and paricalcitol) within 14 days prior to Screening Visit 2; washout will take 
place during the Screening Period 
2) Use of oral phosphate within 7 days prior to Screening Visit 2; washout will take place 
during the Screening Period 
3) Use of aluminum hydroxide antacids (e.g. Maalox® and Mylanta®), systemic corticosteroids, 
and thiazides within 7 days prior to Screening Visit 1   
4) Use of growth hormone therapy within 3 months before Screening Visit 1 
5) Use of bisphosphonates for 6 months or more in the 2 years prior to Screening Visit 1 
6) Presence of nephrocalcinosis on renal ultrasound graded ≥ 3 based on the following scale: 
0 = Normal 
1 = Faint hyperechogenic rim around the medullary pyramids 
2 = More intense echogenic rim with echoes faintly filling the entire pyramid 
3 = Uniformly intense echoes throughout the pyramid  
4 = Stone formation: solitary focus of echoes at the tip of the pyramid 
7) Planned or recommended orthopedic surgery, including staples, 8-plates or osteotomy, 
within the clinical trial period 
8) Hypocalcemia or hypercalcemia, defined as serum calcium levels outside the age-adjusted 
normal limits* 
9) Evidence of tertiary hyperparathyroidism as determined by the investigator 
10) Use of medication to suppress PTH (e.g. Sensipar®, cinacalcet, calcimimetics) within 
2 months prior to Screening Visit 1  
11) 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.   
12) Presence of a concurrent disease or condition that would interfere with study participation or 
affect safety  
13) Previously diagnosed with human immunodeficiency virus antibody, hepatitis B surface 

Protocol Number:  UX023-CL201  
Amendment 7  
08 MAY 2017  
 
 
Proprietary and Confidential 
Page 12 
antigen, and/or hepatitis C antibody  
14) History of recurrent infection or predisposition to infection, or of known immunodeficiency 
15) Use of a therapeutic monoclonal antibody within 90 days prior to Screening Visit 1 or 
history of allergic or anaphylactic reactions to any monoclonal antibody 
16) Presence or history of any hypersensitivity to KRN23 excipients that, in the judgment of the 
investigator, places the subject at increased risk for adverse effects. 
17) Use of any 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. 
* Criteria to be determined based on overnight fasting (min. 4 hours) values collected at 
Screening Visit 2 
INVESTIGATIONAL PRODUCT, DOSE AND MODE OF ADMINISTRATION 
KRN23 is a sterile, clear, colorless, and preservative-free solution in single-use 5-mL vials 
containing 1 mL of KRN23 at a concentration of 10 mg/mL or 30 mg/mL. Subjects will receive study 
drug via SC injection to the abdomen, upper arms and thighs; the injection site should be rotated with 
each injection including to a different quadrant of the abdomen. The maximum amount administered 
in a single injection should not exceed 1.5 mL. Subjects will be sequentially enrolled into the cohorts, 
starting with the lowest dose group, and randomized to a dosing regimen (Q2 or Q4) then individually 
titrated to achieve a target overnight (minimum 4 hours) fasting serum phosphorus range of 
3.5- 5.0 mg/dL (1.13-1.62 mmol/L). During Treatment Extension Periods I (and II, if applicable), all 
subjects will receive KRN23 at the Q2 dosing regimen. The amount of KRN23 administered will be 
calculated based on the subject’s weight. Calculated doses below 15 mg will be adjusted to 15 mg. 
Calculated doses ≥15 mg will be rounded to the nearest 10 mg up to a maximum dose of 90 mg. The 
dose level should not exceed 2.0 mg/kg for either the Q4 regimen or the Q2 regimen. After proper 
training, a subject’s parent or non-healthcare provider caregiver may administer KRN23 to the subject. 
REFERENCE THERAPY, DOSE AND MODE OF ADMINISTRATION: 
The study design is open-label; all subjects will receive investigational product. No placebo or 
reference therapy will be administered in this study. 
DURATION OF TREATMENT: 
Treatment duration will vary by region. The study consists of an individual dose Titration Period 
(16 weeks), a Treatment Period (48 weeks), and a Treatment Extension Period I (up to 96 weeks), for 
a total treatment duration of up to 160 weeks for subjects at study sites outside the US. For subjects at 
study sites outside the US the Week 160 visit will be their EOS I visit. In the US, the study will also 
include a Treatment Extension Period II (up to 56 weeks) until September2018 for a maximum total 
treatment duration of up to 216 weeks at which time the subjects will have their EOS II visit. 
The duration of Treatment Extension Period II will vary for individual subjects and will be determined 
by the time from Week 160 through the EOS II visit. 

Protocol Number:  UX023-CL201  
Amendment 7  
08 MAY 2017  
 
 
Proprietary and Confidential 
Page 13 
CRITERIA FOR EVALUATION: 
Pharmacodynamic*:  
• 
Serum phosphorus  
• 
Serum 1,25(OH)2D   
• 
Urinary phosphorus 
• 
Phosphate reabsorption:  ratio of renal tubular maximum reabsorption rate of phosphate to 
glomerular filtration rate (TmP/GFR), and tubular reabsorption of phosphate (TRP)  
• 
Bone biomarkers:  procollagen type 1 N-propeptide  (P1NP), carboxy-terminal cross-linked 
telopeptide of type I collagen (CTx), bone-specific alkaline phosphatase (BALP) and alkaline 
phosphatase (ALP) 
* Blood and urine to be collected after a minimum overnight fasting time of 4 hours and prior 
to drug administration (if applicable) per dosing regimen 
Efficacy – Bone Health: 
• 
Growth: standing height, sitting height, arm length and leg length will be measured.  
Growth percentiles based on standing height will be derived prior to and following treatment if 
historical data are available  
• 
Severity of rickets and epiphyseal (growth plate) abnormalities:  central readings of 
bilateral posteroanterior (PA) hand/wrist and anteroposterior (AP) knee radiographs using the 
RSS,  a scale developed for nutritional rickets, and a disease-specific qualitative Radiograph 
Global Impression of Change (RGI-C) scoring system  
• 
Lower extremity deformity assessed by intercondylar distance and intermalleolar distance.  
Specific abnormalities related to lower extremity deformity and bowing observed on standing long 
leg films will also be evaluated using the qualitative RGI-C scoring system 
• 
Bone Mineral Density or Content at the cortical and trabecular compartment as assessed by 
XtremeCT of the forearm and tibia (performed at select sites depending on scheduling and 
availability of equipment) 
Efficacy – Clinical Outcomes: 
• 
Walking ability:  Six Minute Walk Test (6MWT) total distance and percent of predicted normal 
distance walked 
• 
Gross motor function: Bruininks-Oseretsky Test of Motor Proficiency – Second Edition (BOT-2) 
subtests to assess running speed, agility and strength   
• 
Muscle strength:  Bilateral hand-held dynamometry (HHD) in the following muscle groups: gross 
grip, knee flexors, knee extensors, hip flexors, hip extensors and hip abductors  
• 
Functional disability and pain:  Pediatric Orthopedic Society of North America Pediatric 
Outcomes Data Collection Instrument (POSNA PODCI) 
• 
Health-Related Quality of Life: SF-10 for Children Health Survey (SF-10) 
 

Protocol Number:  UX023-CL201  
Amendment 7  
08 MAY 2017  
 
 
Proprietary and Confidential 
Page 14 
Pharmacokinetic: 
• 
Serum KRN23 (pre-dose level) 
Safety Assessments: 
Safety will be evaluated by the incidence, frequency, and severity of adverse events (AEs) and serious 
adverse events (SAEs), including clinically significant changes from baseline to scheduled time points.  
General Safety Variables include: 
• 
Vital signs and weight 
• 
Interval history and physical examinations 
• 
GFR (calculated using the Bedside Schwartz equation) 
• 
Chemistry, hematology, and urinalysis, including additional KRN23/XLH biochemical parameters 
of interest (serum 25(OH)D, amylase, creatinine, and FGF23 [total and unbound]) 
• 
Anti-KRN23 antibody testing and dose-limiting toxicities 
• 
Concomitant medications 
• 
ECG 
Ectopic Mineralization Safety Assessments include: 
• 
Renal ultrasound 
• 
ECHO  
• 
Serum calcium, phosphorus and iPTH; urinary calcium and creatinine 
Data Monitoring Committee (DMC)  
An independent DMC that includes members with expertise in metabolic bone disease and the conduct 
of clinical trials in children will act in an advisory capacity to monitor subject safety on a routine basis 
through the end of the Treatment Period (Week 64). The DMC will meet for approximately quarterly 
data reviews. During Treatment Extension Periods I and II, safety data will be reviewed by the 
Ultragenyx Study Safety Review Team (SSRT) on an ongoing basis.    
 
STATISTICAL METHODS: 
A full description of the statistical evaluations will be provided in the Statistical Analysis Plan. 
Sample Size: 
A sample size of at least 10 per cohort will provide at least 90% power to detect a serum phosphorus 
increase from baseline of at least 0.8 mg/dL, assuming a standard deviation of 0.7 mg/dL or smaller, at 
the 2-sided level of significance of 0.05. In addition, a total sample size of 50 subjects (25 subjects per 
Q4 or Q2 regimen) will provide at least 90% power to detect a 0.5 mg/dL difference between the 
two dosing regimens assuming a standard deviation of 0.4 and 2-sided level of significance of 0.05. 

Protocol Number:  UX023-CL201  
Amendment 7  
08 MAY 2017  
 
 
Proprietary and Confidential 
Page 15 
Phosphate and mineral control are adequately powered based on the clinical experience to date with 
KRN23. The degree of powering for bone health will depend on the degree of effect expected, which 
is not known. However, powering for adequate phosphate control should provide the potential for 
improved bone health based on prior experience with oral phosphate replacement therapy. 
In addition, for the RSS endpoint, the expected sample size of 50 subjects will provide at least 90% 
power of rejecting the hypothesis of no change from baseline in knee total score when the true mean 
change is 0.5 with a standard deviation of 0.5, at the 2-sided level of significance of 0.05. 
Pharmacodynamics and Efficacy Analysis: 
Analyses of available PD and efficacy data are planned at the end of the Titration Period (Week 16) 
and at Week 24 for pre-expansion subjects. Further analyses in the pre-expansion group alone and for 
the overall population are planned at Week 40 and at Week 64 at the end of the Treatment Period to 
compare treatment outcomes to baseline (pre-dose). Analyses of long-term efficacy will be conducted 
at the completion of Treatment Extension Period I (Weeks 64-160). A final analysis will be performed 
at study completion (i.e., following Treatment Extension Period II and all needed safety follow-up 
visits).  
Descriptive statistics will be used to summarize the data. For continuous variables, the mean, standard 
error, median, minimum, and maximum will be provided. For discrete data, the frequency and percent 
distributions will be provided. Changes over time and the association of the efficacy with the PD 
variables will be summarized and evaluated. 
Safety Analysis: 
All subjects who receive any amount of study drug will be included in the safety analysis. Safety of 
each cohort and each dose regimen within a cohort will be assessed.  

Protocol Number:  UX023-CL201  
Amendment 7 
08 MAY 2017 
 
 
 
Proprietary and Confidential 
 
 
Page 16 
Table 2.2: 
Schedule of Events – Titration Period Visits 
 
Screening  
Baseline1 
Titration Period 2 
VISIT TYPE/NUMBER 
SV1 
SV21 
V1 
HH3 
V2 
V3 
V4 
V5 
V6 
V7 
V8 
V9 
V10 
WEEK 
W-4 
to -2 
Day -1 
W0 
W1 
W2 
W4 
W6 
W8 
W10 
W12 
W14 
W16 
Informed Consent 
X 
 
 
 
 
 
 
 
 
 
 
 
Inclusion/Exclusion Criteria 
X 
X 
 
 
 
 
 
 
 
 
 
 
Medical History & Demographics 
X 
 
 
 
 
 
 
 
 
 
 
 
Tanner Staging 4 
X 
 
 
 
 
 
 
 
 
 
 
 
PHEX mutation analysis 5 
 
X 
 
 
 
 
 
 
 
 
 
 
PD MEASURES 
Serum Phosphorus 6 
 
X6 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
1,25(OH)2 D 6 
 
 
X 
 
X 
 
 
 
 
 
X 
X 
2-hour urine 6,7 
 
 
X 
 
X 
 
X 
X 
 
 
X 
X 
24-hour urine 8 
 
 
X 
 
 
 
 
 
 
 
 
X 
Bone biomarkers: P1NP, CTx, ALP, 
BALP 6 
 
 
X 
 
 
 
 
 
 
 
 
X 
EFFICACY MEASURES 
Growth (standing height, sitting height, arm 
length and leg length) 
X9 
 
X 
 
 
 
 
 
 
 
 
X 
Bilateral AP knee X-rays1 
X10, 11 
 
 
 
 
 
 
 
 
 
 
 
Bilateral PA hand/wrist X-rays1 
X10 
 
 
 
 
 
 
 
 
 
 
 
Standing long leg X-Ray1 
X10 
 
 
 
 
 
 
 
 
 
 
 
Intercondylar and Intermalleolar distance 
X10 
 
 
 
 
 
 
 
 
 
 
 
XtremeCT of forearm, tibia 12 
 
 
X1 
 
 
 
 
 
 
 
 
 
6MWT, BOT-2, HHD  
X 
 
X1 
 
 
 
 
 
 
 
 
X 
POSNA-PODCI, SF-10 
 
 
X1 
 
 
 
 
 
 
 
 
 
PHARMACOKINETICS 
Serum Pre-Dose KRN2313  
 
 
X 
X14 
X 
X 
 
 
 
X 
X 
X 
SAFETY 
Vital Signs 15 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Weight 
X 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
Physical Examination 
X 
X 
 
 
 
X 
 
X 
 
 
X 
 
Interval History  
 
X 
 
 
X 
X 
 
X 
 
X 
 
X 

Protocol Number:  UX023-CL201  
Amendment 7 
08 MAY 2017 
 
 
 
Proprietary and Confidential 
 
 
Page 17 
 
Screening  
Baseline1 
Titration Period 2 
VISIT TYPE/NUMBER 
SV1 
SV21 
V1 
HH3 
V2 
V3 
V4 
V5 
V6 
V7 
V8 
V9 
V10 
WEEK 
W-4 
to -2 
Day -1 
W0 
W1 
W2 
W4 
W6 
W8 
W10 
W12 
W14 
W16 
Concomitant Medications 
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 
Renal Ultrasound 1 
X 10 
 
 
 
 
 
 
 
 
 
 
X 
ECHO 1 
 
 
X 
 
 
 
 
 
 
 
 
X 
ECG 1 
 
 
X 
 
 
 
 
 
 
 
 
X 
Chemistry, Hematology, Urinalysis 16 
X6 
 
X 
 
 
X 
 
X 
 
 
 
X 
Serum Amylase 
X 
 
X 
 
 
X 
 
X 
 
 
 
X 
Serum 25(OH) D 
X 
 
 
 
 
 
 
 
 
 
 
X 
Serum Calcium 6 
X 
X6 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Serum Creatinine 6 
 
X6 
X 
 
X 
 
X 
X 
 
 
X 
X 
Serum iPTH  
X 
X 
 
 
 
 
 
X 
 
 
 
 
Serum FGF23  13 
X17 
X17 
 
 
 
 
 
X 
 
 
 
X 
Anti-KRN23 antibody (ADA) 13, 18 
 
 
X 
 
 
 
 
 
 
 
 
X 
Pregnancy Test19 
X 
 
X 
 
 
X 
 
X 
 
X 
 
X 
DOSE ADJUSTMENT (AS NEEDED) 
 
 
 
 
 
X 
 
X 
 
X 
 
X 
DRUG ADMINISTRATION20 
 
 
Q2, Q4 
 
Q2 
Q2, 
Q4 
Q2 
Q2, Q4 
Q2 
Q2, Q4 
Q2 
Q2, Q4 
1 
SV2 should be conducted 14 – 35 days following SV1.  SV2 and Baseline visits can be conducted on consecutive days but may be conducted up to 
7 days apart.  Renal ultrasound, ECHO, ECG, and x-rays may be performed within ± 3 days of clinic visit to accommodate scheduling availability.  
XtremeCT may be performed any time between SV1 and Baseline.  Motor function tests (6MWT, BOT-2, HHD) and questionnaires (POSNA-PODCI, 
SF-10) may be completed at either SV2 or Baseline visit, but must be assessed on the same day. All Screening/Baseline assessments and 
inclusion/exclusion criteria based on local lab results must be satisfied prior to randomization and dosing.  
2 
During the Titration Period (Weeks 0 – 16) subjects will return to the clinic for visits at 2 week intervals (± 3 days).   
3 
HH visits may also be conducted at the clinic depending on proximity of the subject to the investigational site and local availability of HH care 
resources.  The visit window is ± 3 days. 
4 
Tanner staging will be performed on all subjects regardless of age.   
5 
PHEX mutation analysis will be performed for all subjects. For any subject with a PHEX mutation analysis result of No Mutation, Likely Benign, 
Variant of Uncertain Significance, or Possibly Pathogenic, additional genetic testing will be performed to assess mutations in other genes associated 
with phenotypes overlapping with XLH. A new blood sample for genetic analysis may be collected if necessary.  

Protocol Number:  UX023-CL201  
Amendment 7 
08 MAY 2017 
 
 
 
Proprietary and Confidential 
 
 
Page 18 
6 
Blood and urine to be collected after a minimum overnight fasting time of 4 hours and prior to drug administration (if applicable) per dosing regimen.  
Record fasting duration on CRF. At SV2, local lab values will be used to confirm eligibility. Baseline visit samples will be sent to the central lab for 
data analysis.   
7 
2-hour urine collections for urinary calcium, phosphorous, and creatinine and calculation of TmP/GFR and TRP 
8 
24-hour urine collections for urinary phosphorus, calcium, and creatinine 
9 
At Screening Visit 1, only standing height is required to confirm eligibility. 
10 
Screening results will be treated as baseline data 
11 
For the expansion subjects, screening knee x-rays must be read centrally for determination of eligibility   
12 
Performed at select sites based on scheduling and availability of equipment 
13 
If there is a technical or operational issue obtaining results for PK, FGF23, or ADA, an additional blood sample may be obtained at the next suitable 
clinic visit. 
14 
Serum KRN23 samples will be taken at W1 for subjects enrolled in Cohorts 2 and 3 only. 
15 
Vital sign measurements consist of seated systolic/diastolic BP measured in millimeters of mercury (mm Hg), HR (beats per minute), respiration rate 
(breaths per minute), and temperature in degrees Celsius (°C).  Obtain at the beginning of each visit before any additional assessments are completed 
and after the subject has rested for 5 minutes.  A second BP measurement should be obtained at the end of the study visit after all procedures have been 
performed.   
16 
Serum chemistry panels may include PD parameters (i.e. serum phosphorus and ALP), and safety parameters of interest (i.e. calcium) to avoid 
duplication of testing. See Table 7.5.5.8.1 for complete list of Clinical Laboratory Assessments for Safety. 
17 
If confirmation of XLH diagnosis is based on FGF23, the results may be communicated by telephone to the potential subject with instructions to begin 
washout of prohibited medications. If subject or directly related family member with appropriate X-linked inheritance has a confirmed PHEX mutation, 
samples for FGF23 analysis will be obtained at SV2 only and used as baseline values.  If subject or qualified directly related family member does NOT 
have a confirmed PHEX mutation, FGF23 levels will be obtained at SV1 to determine eligibility and at SV2 to obtain a baseline value.     
18 
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. 
19 
Pregnancy testing will be performed on any female subject of childbearing potential who has experienced menarche.  
20 
Subjects will be dosed at either Q2 (± 3 days and no fewer than 8 days apart) or Q4 week intervals (± 3 days and no fewer than 12 days apart). Subjects 
should be observed for 3-4 hours following the first dose of study drug. Subjects should be observed for 30 minutes following subsequent doses of study 
drug.  
 

Protocol Number:  UX023-CL201  
Amendment 7 
08 MAY 2017 
 
 
 
Proprietary and Confidential 
 
 
Page 19 
Table 2.3: 
Schedule of Events –Treatment Period Visits (Weeks 18 – 40) 
 
Treatment Period 21 
VISIT TYPE/NUMBER 
HH 22 
V11 
V12 
HH 
V13 
V14 
HH 
V15 
V16 
HH 
V17 
V18 
HH 
V19 
V20 
V21 
V22 37 
WEEK 
W18 
W20 
W22 
W24 
W26 
W28 
W30 
W32 
W34 
W36 
W38 
W40 
PD MEASURES 
Serum Phosphorus 23 
 
X 
X 
X 
 
X 
X 
X 
 
X 
X 
X 
1,25(OH)2 D 23 
 
 
 
 
 
X 
 
 
 
 
X 
X 
2-hour urine 23,24 
 
 
 
X 
 
 
 
 
 
 
X 
X 
24-hour urine 25 
 
 
 
 
 
 
 
 
 
 
 
X 
Bone biomarkers: P1NP, CTx, ALP, 
BALP 23 
 
 
 
 
 
 
 
 
 
 
 
X 
EFFICACY MEASURES 
Growth (standing height, sitting height, 
arm length and leg length) 
 
 
 
X 
 
 
 
 
 
 
 
X 
Bilateral PA hand/wrist and AP knee 
X-ray 
 
 
 
 
 
 
 
 
 
 
 
X 
Intercondylar and Intermalleolar distance 
 
 
 
 
 
 
 
 
 
 
 
X 
XtremeCT of forearm, tibia 26 
 
 
 
 
 
 
 
 
 
 
 
 
6MWT, BOT-2, HHD  
 
 
 
X 
 
 
 
 
 
 
 
X 
POSNA-PODCI, SF-10 
 
 
 
X 
 
 
 
 
 
 
 
X 
PHARMACOKINETICS 
Serum Pre-Dose KRN2327 
 
 
 
X 28 
 
 
 
 
 
X 
X 
X 
SAFETY 
Vital Signs 29 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Weight 
 
X 
 
X 
 
X 
 
X 
 
X 
X 
X 
Physical Examination 
 
X 
 
 
 
 
 
X 
 
 
 
X 
Tanner Staging 
 
 
 
 
 
 
 
 
 
 
 
 
Interval History  
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
Concomitant Medications 
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 
Renal Ultrasound 
 
 
 
 
 
 
 
 
 
 
 
X 
ECHO 
 
 
 
 
 
 
 
 
 
 
 
X 

Protocol Number:  UX023-CL201  
Amendment 7 
08 MAY 2017 
 
 
 
Proprietary and Confidential 
 
 
Page 20 
 
Treatment Period 21 
VISIT TYPE/NUMBER 
HH 22 
V11 
V12 
HH 
V13 
V14 
HH 
V15 
V16 
HH 
V17 
V18 
HH 
V19 
V20 
V21 
V22 37 
WEEK 
W18 
W20 
W22 
W24 
W26 
W28 
W30 
W32 
W34 
W36 
W38 
W40 
ECG 
 
 
 
 
 
 
 
 
 
 
 
X 
Chemistry, Hematology, Urinalysis 30 
 
 
 
X 
 
 
 
 
 
 
 
X 
Serum Amylase31 
 
 
 
X 
 
 
 
 
 
 
 
X 
Serum Lipase32 
 
 
 
 
 
 
 
 
 
 
 
X 
Serum 25(OH) D 
 
 
 
 
 
 
 
X 
 
 
 
 
Serum Calcium 23 
 
X 
X 
X 
 
X 
X 
X 
 
X 
X 
X 
Serum Creatinine 23 
 
 
 
X 
 
 
 
 
 
 
X 
X 
Serum iPTH  
 
X 
 
 
 
X 
 
 
 
X 
 
 
Serum FGF23 27 
 
 
 
 
 
X 
 
 
 
 
X 
 
Anti-KRN23 antibody (ADA) 27, 33 
 
 
 
X 
 
 
 
 
 
X 
 
 
Pregnancy Test 34 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
DOSE ADJUSTMENT (AS NEEDED)35 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
DRUG ADMINISTRATION 36 
Q2 
Q2 Q4 
Q2 
Q2 Q4 
Q2 
Q2 Q4 
Q2 
Q2 Q4 
Q2 
Q2 Q4 
Q2 
Q2, Q4 
21 
During the Treatment Period (Weeks 16 – 40) clinic visits will occur at 4 week intervals (± 3 days).   
22 
HH visits may also be conducted at the clinic depending on proximity of the subject to the investigational site and local availability of HH care 
resources.  The visit window is ± 3 days. 
23 
Blood and urine to be collected after a minimum overnight fasting time of 4 hours and prior to drug administration (if applicable) per dosing regimen. 
Peak serum phosphorus may be collected as an unscheduled lab if required (to assist in dose titration) at Week 18, 26 and 34. 
24 
2-hour urine collections for urinary calcium, phosphorous, and creatinine and calculation of TmP/GFR and TRP 
25 
24-hour urine collections for urinary phosphorus, calcium, and creatinine 
26 
Performed at select sites based on scheduling and availability of equipment 
27 
If there is a technical or operational issue obtaining results for PK, FGF23, or ADA, an additional blood sample may be obtained at the next suitable 
clinic visit. 
28 
Week 24 pre-dose serum KRN23 concentration will be retrospectively tested on subjects’ previously collected samples, if available. 
29 
Vital sign measurements consist of seated systolic/diastolic BP measured in millimeters of mercury (mm Hg), HR (beats per minute), respiration rate 
(breaths per minute), and temperature in degrees Celsius (°C).  Obtain at the beginning of each visit before any additional assessments are completed 
and after the subject has rested for 5 minutes.  A second BP measurement should be obtained at the end of the study visit after all procedures have been 
performed. 

Protocol Number:  UX023-CL201  
Amendment 7 
08 MAY 2017 
 
 
 
Proprietary and Confidential 
 
 
Page 21 
30 
Serum chemistry panels may include PD parameters (i.e., serum phosphorus and ALP), and safety parameters of interest (i.e., calcium) to avoid 
duplication of testing. See Table 7.5.5.8.1 for complete list of Clinical Laboratory Assessments for Safety.  
31 
Reflexive assessment of amylase isoenzymes will be performed if the serum amylase level is elevated to ≥1.5 times the upper limit of the reference 
range (ULRR) beginning at Week 40 or the first scheduled time point after appropriate approvals are obtained. 
32 
Serum lipase will be assessed as part of the serum chemistry panel beginning at Week 40 or the first scheduled time point after appropriate approvals are 
obtained. 
33 
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.  
34 
Pregnancy testing will be performed on any female subject of childbearing potential who has experienced menarche. 
35 
Dose adjustments may be made at visits W20, W24, W28, W32, W36, W40 if required when following the KRN23 Dose Titration Scheme Table 2.1) 
36 
Subjects will be dosed at either Q2 (± 3 days and no fewer than 8 days apart) or Q4 week intervals (± 3 days and no fewer than 12 days apart). Subjects 
should be observed for 3-4 hours following the first dose of study drug. Subjects should be observed for 30 minutes following subsequent doses of study 
drug. 
37 
The Week 40 visit may be up to 2 days in duration due to the volume of testing; required blood draws may be split across the 2 days 
 

Protocol Number:  UX023-CL201  
Amendment 7 
08 MAY 2017 
 
 
 
Proprietary and Confidential 
 
 
Page 22 
Table 2.4: 
Schedule of Events –Treatment Period Visits (Weeks 42 – 64) 
 
Treatment Period 38 
VISIT TYPE/NUMBER 
HH 39 
V23 
HH 
V24 
 V25 
HH 
V26 
HH 
V27 
HH 
V28 
HH 
V29 
V30 
HH 
V31 
HH 
V32 
HH 
V33 
V34 
WEEK 
W42 
W44 
W46 
W48 
W50 
W52 
W54 
W56 
W58 
W60 
W62 
W6453 
PD MEASURES 
Serum Phosphorus 40 
 
 
X 
X 
 
 
X 
X 
 
 
X 
X 
1,25(OH)2 D 40 
 
 
 
 
 
 
X 
X 
 
 
X 
X 
2-hour urine 40, 41 
 
 
 
 
 
 
 
 
 
 
 
X 
24-hour urine 42 
 
 
 
 
 
 
 
 
 
 
 
X 
Bone biomarkers: P1NP, CTx, ALP, 
BALP 40 
 
 
 
 
 
 
 
 
 
 
 
X 
EFFICACY MEASURES 
Growth (standing height, sitting height, 
arm length and leg length) 
 
 
 
 
 
 
 
X 
 
 
 
X 
Bilateral PA hand/wrist and AP knee X-
ray 
 
 
 
 
 
 
 
 
 
 
 
X 
Standing long leg X-ray 
 
 
 
 
 
 
 
 
 
 
 
X 
Intercondylar and Intermalleolar distance 
 
 
 
 
 
 
 
 
 
 
 
X 
XtremeCT of forearm, tibia 43 
 
 
 
 
 
 
 
 
 
 
 
X 
6MWT, BOT-2, HHD  
 
 
 
 
 
 
 
 
 
 
 
X 
POSNA-PODCI, SF-10 
 
 
 
 
 
 
 
 
 
 
 
X 
PHARMACOKINETICS 
Serum Pre-DoseKRN23 44 
 
 
 
 
 
 
 
X 
 
 
 
X 
SAFETY 
Vital Signs 45 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Weight 
 
 
X 
 
 
 
 
X 
 
 
 
X 
Physical Examination 
 
 
X 
 
 
 
 
X 
 
 
 
X 
Tanner Staging 
 
 
 
 
 
 
 
 
 
 
 
X 
Interval History  
 
 
X 
 
 
 
 
X 
 
 
 
X 
Concomitant Medications 
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 
Renal Ultrasound 
 
 
 
 
 
 
 
 
 
 
 
X 

Protocol Number:  UX023-CL201  
Amendment 7 
08 MAY 2017 
 
 
 
Proprietary and Confidential 
 
 
Page 23 
 
Treatment Period 38 
VISIT TYPE/NUMBER 
HH 39 
V23 
HH 
V24 
 V25 
HH 
V26 
HH 
V27 
HH 
V28 
HH 
V29 
V30 
HH 
V31 
HH 
V32 
HH 
V33 
V34 
WEEK 
W42 
W44 
W46 
W48 
W50 
W52 
W54 
W56 
W58 
W60 
W62 
W6453 
ECHO 
 
 
 
 
 
 
 
 
 
 
 
X 
ECG 
 
 
 
 
 
 
 
 
 
 
 
X 
Chemistry, Hematology, Urinalysis 46 
 
 
X 
 
 
 
 
X 
 
 
 
X 
Serum Amylase47 
 
 
X 
 
 
 
 
X 
 
 
 
X 
Serum Lipase48 
 
 
X 
 
 
 
 
X 
 
 
 
X 
Serum 25(OH) D 
 
 
X 
 
 
 
 
 
 
 
 
X 
Serum Calcium 40 
 
 
X 
X 
 
 
X 
X 
 
 
X 
X 
Serum Creatinine 40 
 
 
 
 
 
 
 
 
 
 
 
X 
Serum iPTH  
 
 
X 
 
 
 
 
X 
 
 
 
X 
Serum FGF23 44 
 
 
 
 
 
 
 
 
 
 
 
X 
Anti-KRN23 antibody (ADA) 43,49 
 
 
 
 
 
 
 
X 
 
 
 
X 
Pregnancy Test 50 
 
 
X 
 
 
X 
 
X 
 
X 
 
X 
DOSE ADJUSTMENT (AS NEEDED)51 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
DRUG ADMINISTRATION
 52 
Q2 
Q2 Q4 
Q2 
Q2 Q4 
Q2 
Q2 Q4 
Q2 
Q2 Q4 
Q2 
Q2 
Q4 
Q2 
Q2 
38 
During the Treatment Period (Weeks 40-64) clinic visits will occur at approximately 8-week intervals (± 3 days).     
39 
HH visits may also be conducted at the clinic depending on proximity of the subject to the investigational site and local availability of HH care 
resources.  The visit window is ± 3 days. 
40 
Blood and urine to be collected after a minimum overnight fasting time of 4 hours and prior to drug administration (if applicable) per dosing regimen. 
Peak serum phosphorus may be collected as an unscheduled lab if required (to assist in dose titration). 
41 
2-hour urine collections for urinary calcium, phosphorous, and creatinine and calculation of TmP/GFR and TRP 
42 
24-hour urine collections for urinary phosphorus, calcium, and creatinine  
43 
Performed at select sites based on scheduling and availability of equipment 
44 
If there is a technical or operational issue obtaining results for PK, FGF23 or ADA, an additional blood sample may be obtained at the next suitable 
clinic visit. 
45 
Vital sign measurements consist of seated systolic/diastolic BP measured in millimeters of mercury (mm Hg), HR (beats per minute), respiration rate 
(breaths per minute), and temperature in degrees Celsius (°C).  Obtain at the beginning of each visit before any additional assessments are completed 

Protocol Number:  UX023-CL201  
Amendment 7 
08 MAY 2017 
 
 
 
Proprietary and Confidential 
 
 
Page 24 
and after the subject has rested for 5 minutes.  A second BP measurement should be obtained at the end of the study visit after all procedures have been 
performed. 
46 
Serum chemistry panels may include PD parameters (i.e. serum phosphorus and ALP), and safety parameters of interest (i.e. calcium) to avoid 
duplication of testing. See Table 7.5.5.8.1 for complete list of Clinical Laboratory Assessments for Safety.  
47 
Reflexive assessment of amylase isoenzymes will be performed if the serum amylase level is elevated to ≥1.5 times the upper limit of the reference 
range (ULRR) beginning at Week 40 or the first scheduled time point after appropriate approvals are obtained. 
48 
Serum lipase will be assessed as part of the serum chemistry panel beginning at Week 40 or the first scheduled time point after appropriate approvals are 
obtained. 
49 
If the development of anti-KRN23 antibodies is suspected in a given subject, samples may be obtained at additional time points, and may include 
additional blood volume required to perform a neutralization assay on a case-by-case basis, if warranted. 
50 
Pregnancy testing will be performed on any female subject of childbearing potential who has experienced menarche. 
51 
Post-titration dose escalation during the Treatment Period will occur only for subjects who meet the following criteria: 1) two consecutive serum 
phosphorus measurements are below the normal range (3.2-6.1 mg/dL [1.03-1.97 mmol/L]); 2) serum phosphorus has increased by < 0.5 mg/dL from 
baseline; and 3) the subject has not missed a dose of study drug that would account for the decrease in serum phosphorus. If the subject has single serum 
phosphorus measurement below the normal range and criteria 2 and 3 are met, the serum phosphorus measurement should be repeated through an 
unscheduled blood draw within 4 weeks and a dose adjustment made if the serum phosphorus remains below the normal range. 
52 
Subjects will be dosed at either Q2 (± 3 days and no fewer than 8 days apart) or Q4 week intervals (± 3 days and no fewer than 12 days apart). Subjects 
should be observed for 3-4 hours following the first dose of study drug. Subjects should be observed for 30 minutes following subsequent doses of study 
drug. Dosing will continue Q2 between the Week 64 and Week 74 study visits. 
53 
The Week 64 visit may be up to 2 days in duration due to the volume of testing; required blood draws may be split across the 2 days. 
 

Protocol Number:  UX023-CL201  
Amendment 7 
08 MAY 2017 
 
 
 
Proprietary and Confidential 
 
 
Page 25 
Table 2.5: 
Schedule of Events –Treatment Extension Period I Visits (Weeks 66 – 160) 
 
 
 
 
Treatment Extension Period I54 
Safety 
follow 
up TC71 
Safety 
follow 
up 
visit72 
VISIT TYPE/NUMBER 
HH55 
 
HH 
V36 
HH 
V37 
HH 
V39 
HH 
V40 
HH 
V41 
 
V46 
HH 
V52 
 
V58 
HH 
V64 
 
V70 
HH 
V76 
 
V80 
 
V82 
V83 
(EU) 
V84 
(EU) 
 
Q2 
W68 
W7
0 
W7
4 
W7
6 
W7
8 
W8869 
W10
0 
W11269 
W124 
W1366
9 
W148 
W156 
W16069 
(EOS 
I)70 
W165 
W170 
PD MEASURES 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Serum Phosphorus56,57 
 
X57 
 
X57 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
1,25(OH)2D56,57 
 
X57 
 
X57 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
2-hour urine56,58  
 
 
 
 
 
 
X 
 
X 
 
X 
 
 
X 
 
 
24-hour urine59 
 
 
 
 
 
 
X 
 
X 
 
X 
 
 
X 
 
 
Bone biomarkers: 
ALP56 
 
 
 
 
 
 
X 
 
X 
 
X 
 
 
X 
 
 
EFFICACY MEASURES 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Growth (standing 
height, sitting height, 
arm length and leg 
length) 
 
 
 
 
 
 
X 
 
X 
 
X 
 
 
X 
 
 
Bilateral PA hand/wrist 
X-ray 
 
 
 
 
 
 
X 
 
 
 
 
 
 
X 
 
 
Bilateral AP knee X-ray 
 
 
 
 
 
 
X 
 
 
 
 
 
 
X 
 
 
Standing long leg X-ray 
 
 
 
 
 
 
X 
 
 
 
 
 
 
X 
 
 
XtremeCT of forearm, 
tibia  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
6MWT 
 
 
 
 
 
 
X 
 
 
 
 
 
 
X 
 
 
POSNA-PODCI, SF-10 
 
 
 
 
 
 
X 
 
 
 
 
 
 
X 
 
 
BOT-2 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

Protocol Number:  UX023-CL201  
Amendment 7 
08 MAY 2017 
 
 
 
Proprietary and Confidential 
 
 
Page 26 
 
 
 
Treatment Extension Period I54 
Safety 
follow 
up TC71 
Safety 
follow 
up 
visit72 
VISIT TYPE/NUMBER 
HH55 
 
HH 
V36 
HH 
V37 
HH 
V39 
HH 
V40 
HH 
V41 
 
V46 
HH 
V52 
 
V58 
HH 
V64 
 
V70 
HH 
V76 
 
V80 
 
V82 
V83 
(EU) 
V84 
(EU) 
 
Q2 
W68 
W7
0 
W7
4 
W7
6 
W7
8 
W8869 
W10
0 
W11269 
W124 
W1366
9 
W148 
W156 
W16069 
(EOS 
I)70 
W165 
W170 
HHD 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
PHARMACOKINETICS 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Serum Pre-DoseKRN23 
60 
 
 
 
 
 
 
X 
 
X 
 
X 
 
 
X 
 
 
SAFETY 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Vital Signs61 
X61 
X 
 
 
X 
 
X 
X 
X 
 
X 
 
X 
X 
 
X 
Weight 
 
 
 
 
 
 
X 
 
X 
 
X 
 
X 
X 
 
 
Physical Examination 
 
 
 
 
 
 
X 
 
X 
 
X 
 
 
X 
 
X 
Tanner Staging 
 
 
 
 
 
 
X 
 
X 
 
X 
 
 
X 
 
 
Interval History  
 
 
 
 
 
 
X 
 
X 
 
X 
 
 
X 
 
 
Concomitant 
Medications 
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 
Renal Ultrasound 
 
 
 
 
 
 
X 
 
X 
 
X 
 
 
X 
 
 
ECHO 
 
 
 
 
 
 
X 
 
X 
 
X 
 
 
X 
 
 
ECG 
 
 
 
 
 
 
X 
 
X 
 
X 
 
 
X 
 
 
Chemistry, 
Hematology, 
Urinalysis62  
 
 
 
 
 
 
X 
 
X 
 
X 
 
 
X 
 
X 
Serum Amylase63 
 
 
 
 
 
 
X 
 
X 
 
X 
 
 
X 
 
X 
Serum Lipase64 
 
 
 
 
 
 
X 
 
X 
 
X 
 
 
X 
 
X 
Serum 25(OH) D 
 
 
 
 
 
 
X 
 
X 
 
X 
 
 
X 
 
 

Protocol Number:  UX023-CL201  
Amendment 7 
08 MAY 2017 
 
 
 
Proprietary and Confidential 
 
 
Page 27 
 
 
 
Treatment Extension Period I54 
Safety 
follow 
up TC71 
Safety 
follow 
up 
visit72 
VISIT TYPE/NUMBER 
HH55 
 
HH 
V36 
HH 
V37 
HH 
V39 
HH 
V40 
HH 
V41 
 
V46 
HH 
V52 
 
V58 
HH 
V64 
 
V70 
HH 
V76 
 
V80 
 
V82 
V83 
(EU) 
V84 
(EU) 
 
Q2 
W68 
W7
0 
W7
4 
W7
6 
W7
8 
W8869 
W10
0 
W11269 
W124 
W1366
9 
W148 
W156 
W16069 
(EOS 
I)70 
W165 
W170 
Serum Calcium56, 57 
 
X 
 
X 
 
X 
X 
 
X 
 
X 
 
 
X 
 
X 
Serum Creatinine56 
 
 
 
 
 
 
X 
 
X 
 
X 
 
 
X 
 
 
Serum iPTH  
 
 
 
 
 
 
X 
 
X 
 
X 
 
 
X 
 
 
Serum FGF2360 
 
 
 
 
 
 
X 
 
X 
 
X 
 
 
X 
 
X 
Anti-KRN23 antibody 
(ADA)60,65  
 
 
 
 
 
 
X 
 
X 
 
X 
 
 
X 
 
 
Pregnancy Test66 
X 
X 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
DOSE TITRATION67 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X67 
 
 
DRUG 
ADMINISTRATION68 
Q2 
Q2 
Q2 
Q2 
Q2 
Q2 
Q2 
Q2 
Q2 
Q2 
Q2 
Q2 
Q2 
Q268 
 
 
 
54 
During the Treatment Extension Period (Weeks 66-160) clinic visits will occur at approximately 24-week intervals (± 5 days) 
55 
In addition to the specific visits noted, HH visits will be conducted every 2 weeks (i.e., starting at Week 66), for administration of study drug (Q2) and 
reporting of concomitant medications and adverse events. The visit window is ± 5 days. HH visits may also be conducted at the clinic depending on 
proximity of the subject to the investigational site and local availability of HH care resources.   
56 
Blood and urine to be collected after a minimum overnight fasting time of 4 hours and prior to drug administration (if applicable) per dosing regimen. 
Peak serum phosphorus may be collected as an unscheduled lab if necessary. 
57 
Blood collection for assessment of serum phosphorus, 1,25(OH)2D, and serum calcium will be collected at Weeks 68 and Week 74 only for the subjects 
transitioning from Q4 to Q2 dosing.  
58 
2-hour urine collections for urinary calcium, phosphorous, and creatinine and calculation of TmP/GFR and TRP 
59 
24-hour urine collections for urinary phosphorus, calcium, and creatinine 
60 
If there is a technical or operational issue obtaining results for PK, FGF23, or ADA, an additional blood sample may be obtained at the next suitable 
clinic visit.  
61 
Vital sign measurements consist of seated systolic/diastolic BP measured in millimeters of mercury (mm Hg), HR (beats per minute), respiration rate 
(breaths per minute), and temperature in degrees Celsius (°C).  Obtain at the beginning of each visit before any additional assessments are completed 

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and after the subject has rested for 5 minutes.  A second BP measurement should be obtained at the end of the study visit after all procedures have been 
performed. At HH visits during Weeks 66-160, vital signs will be measured every 4 weeks starting at Week 68. 
62 
Serum chemistry panels may include PD parameters (i.e. serum phosphorus and ALP), and safety parameters of interest (i.e. calcium) to avoid 
duplication of testing. See Table 7.5.5.8.1 for complete listing of Clinical Laboratory Assessments for Safety. 
63 
Reflexive assessment of amylase isoenzymes will be performed if the serum amylase level is elevated to ≥1.5 times the upper limit of the reference 
range (ULRR) beginning at Week 40 or the first scheduled time point after appropriate approvals are obtained. 
64 
Serum lipase will be assessed as part of the serum chemistry panel beginning at Week 40 or the first scheduled time point after appropriate approvals are 
obtained.  
65 
If the development of anti-KRN23 antibodies is suspected in a given subject, samples may be obtained at additional time points, and may include 
additional blood volume required to perform a neutralization assay on a case-by-case basis, if warranted. 
66 
Pregnancy testing will be performed on any female subject of childbearing potential who has experienced menarche. A urine pregnancy test will be 
given every 4-6 weeks at HH visits in addition to those visits indicated. 
67 
Dose titration during the Treatment Extension Period will apply only to subjects meeting the following criteria: 1) two consecutive serum phosphorus 
measurements are below the normal range (3.2-6.1 mg/dL [1.03-1.97 mmol/L]); 2) serum phosphorus has increased by < 0.5 mg/dL from baseline; and 
3) the subject has not missed a dose of study drug that would account for the decrease in serum phosphorus. If the subject has single serum phosphorus 
measurement below the normal range and criteria 2 and 3 are met, the serum phosphorus measurement should be repeated through an unscheduled blood 
draw within 4 weeks and a dose adjustment made if the serum phosphorus remains below the normal range. 
68 
Subjects will be dosed at Q2 week intervals (± 5 days and no fewer than 8 days apart). Subjects should be observed for 3-4 hours following the first dose 
of study drug. Subjects should be observed for 30 minutes following subsequent doses of study drug. For subjects outside the US, no study drug will be 
administered at the Week 160/EOS I visit. 
69 
The Week 88, 112, 136, and 160/EOS I visits may be up to 2 days in duration due to the volume of testing; required blood draws may be split across the 
2 days. 
70 
For subjects at study sites outside the US, the Week 160 visit will be their End of Study efficacy visit (EOS I). No study drug will be administered under 
the current protocol. 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 EOS I assessments.  
71 
To be completed for those subjects at sites outside the US who complete EOS I and do not continue on KRN23 treatment immediately through 
commercial use or through another mechanism. Site personnel will initiate a safety follow-up telephone call at 5 weeks (+ 5 days) after the EOS I visit 
to collect information on whether KRN23 has been started through another mechanism and, if not, any ongoing or new AEs, serious AEs, or 
concomitant medications.  
72 
An additional safety visit will take place 10 weeks ±1 week after the EOS I visit for those subjects who discontinue treatment before Week 160 or for 
those subjects at sites outside the US who complete EOS I and do not continue on KRN23 through commercial use or another mechanism. This safety 
visit will not occur for subjects in the US who continue into Treatment Extension Period II or subjects who complete EOS I and are documented to be 
continuing on KRN23 on commercial use or through another mechanism.  Every reasonable effort should be made to have subjects return to the clinic 
for the final safety visit; however, subjects who are unable to return to the clinic for the final safety visit will be given the option of having a final safety 
telephone call for the collection of any ongoing or new AEs, serious AEs, or concomitant medications.  

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Table 2.6: 
Schedule of Events–Treatment Extension Period II Visits (Week 162 – End of Study)73 
 
Q2W 
Q12W 
Q24W 
EOS II  Visit86 
ET Visit87 
Safety Follow 
Up TC 88 
Safety Follow 
Up Visit89 
PD MEASURES 
 
 
 
 
 
 
 
Serum Phosphorus74 
 
X 
 
X 
X 
 
X 
1,25(OH)2D74 
 
X 
 
X 
X 
 
X 
2-hour urine74, 75 
 
 
X 
X 
X 
 
 
24-hour urine76 
 
 
X 
X 
X 
 
 
Bone biomarkers: 
ALP74 
 
 
X 
X 
X 
 
 
EFFICACY MEASURES 
 
 
 
 
 
 
 
Growth (standing 
height, sitting height, 
arm length and leg 
length) 
 
 
X 
X 
X 
 
 
Bilateral PA hand/wrist 
X-ray 
 
 
 
X 
X 
 
 
Bilateral AP knee X-ray 
 
 
 
X 
X 
 
 
Standing long leg X-ray 
 
 
 
X 
X 
 
 
XtremeCT of forearm, 
tibia 
 
 
 
 
X 
 
 
6MWT 
 
 
 
X 
X 
 
 
POSNA-PODCI, SF-10 
 
 
X 
X 
X 
 
 
BOT-2 
 
 
 
 
X 
 
 
HHD 
 
 
 
 
X 
 
 
PHARMACOKINETICS 
 
 
 
 
 
 
 
Serum Pre-Dose 
KRN2377 
 
 
 
X 
X 
 
 
SAFETY 
 
 
 
 
 
 
 
Vital signs78 
 
X 
 
X 
X 
 
X 
Weight 
 
X 
 
X 
X 
 
 
Physical examination 
 
X 
 
X 
X 
 
X 
Tanner staging 
 
 
 
X 
X 
 
 
Concomitant 
medications79 
X 
 
 
X 
X 
X 
X 

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Q2W 
Q12W 
Q24W 
EOS II  Visit86 
ET Visit87 
Safety Follow 
Up TC 88 
Safety Follow 
Up Visit89 
Adverse Events79 
X 
 
 
X 
X 
X 
X 
Renal Ultrasound 
 
 
 
X 
X 
 
 
ECHO 
 
 
 
X 
X 
 
 
ECG 
 
 
 
X 
X 
 
 
Chemistry, 
Hematology, 
Urinalysis80 
 
X 
 
X 
X 
 
X 
Serum Amylase81 
 
X 
 
X 
X 
 
X 
Serum Lipase82 
 
X 
 
X 
X 
 
X 
Serum 25(OH)D 
 
X 
 
X 
X 
 
 
Serum Calcium74 
 
X 
 
X 
X 
 
X 
Serum Creatinine74 
 
X 
 
X 
X 
 
 
Serum iPTH 
 
 
X 
X 
X 
 
 
Serum FGF2377 
 
 
 
X 
X 
 
X 
Anti-KRN23 antibody 
(ADA)77, 83 
 
 
 
X 
X 
 
 
Pregnancy Test84 
 
X 
 
X 
X 
 
 
DOSE TITRATION85 
 
X 
 
 
 
 
 
DRUG 
ADMINISTRATION79 
X 
 
 
 
 
 
 
73 
During Treatment Extension Period II (Weeks 162-EOS), clinic visits will occur at 12-week intervals (± 5 days) starting at Week 172. Telephone calls 
from the site will occur every 2 weeks (± 5 days) to confirm administration of study drug by the subject’s caregiver (Q2), and reporting of concomitant 
medications and adverse events. The visit window is ± 5 days. Telephone visits may also be conducted at the clinic depending on proximity of the 
subject to the investigational site. 
74 
Blood and urine to be collected after a minimum overnight fasting time of 4 hours and prior to drug administration (if applicable). Peak serum 
phosphorus may be collected as an unscheduled lab if necessary. 
75 
2-hour urine collections for urinary calcium, phosphorous, and creatinine and calculation of TmP/GFR and TRP 
76 
24-hour urine collections for urinary phosphorus, calcium, and creatinine 
77 
If there is a technical or operational issue obtaining results for PK, FGF23, or ADA, an additional blood sample may be obtained at the next suitable 
clinic visit.  
78 
Vital sign measurements consist of seated systolic/diastolic BP measured in millimeters of mercury (mm Hg), HR (beats per minute), respiration rate 
(breaths per minute), and temperature in degrees Celsius (°C).  Obtain at the beginning of each visit before any additional assessments are completed 
and after the subject has rested for 5 minutes.  A second BP measurement should be obtained at the end of the study visit after all procedures have been 
performed. 

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79 
During Treatment Extension Period II, study drug will be administered by the subject’s parent or caregiver at Q2 week intervals (± 5 days and no fewer 
than 8 days apart). Study drug administration will be confirmed by the study site during biweekly telephone calls to the subject. Adverse event and 
concomitant medicine information will also be collected during these biweekly telephone calls.  
80 
Serum chemistry panels may include PD parameters (i.e. serum phosphorus and ALP), and safety parameters of interest (i.e. calcium) to avoid 
duplication of testing. See Table 7.5.5.8.1 for complete listing of Clinical Laboratory Assessments for Safety. 
81 
Reflexive assessment of amylase isoenzymes will be performed if the serum amylase level is elevated to ≥1.5 times the upper limit of the reference 
range (ULRR) beginning at Week 40 or the first scheduled time point after appropriate approvals are obtained. 
82 
Serum lipase will be assessed as part of the serum chemistry panel beginning at Week 40 or the first scheduled time point after appropriate approvals are 
obtained.  
83 
If the development of anti-KRN23 antibodies is suspected in a given subject, samples may be obtained at additional time points, and may include 
additional blood volume required to perform a neutralization assay on a case-by-case basis, if warranted. 
84 
Pregnancy testing will be performed for any female subject of childbearing potential who has experienced menarche. Pregnancy testing will be 
performed at site visits every 12 weeks as indicated. 
85 
Dose titration during Treatment Extension Period II will apply only to subjects meeting the following criteria: 1) two consecutive serum phosphorus 
measurements are below the normal range (3.2-6.1 mg/dL [1.03-1.97 mmol/L]); 2) serum phosphorus has increased by < 0.5 mg/dL from baseline; and 
3) the subject has not missed a dose of study drug that would account for the decrease in serum phosphorus. If the subject has a single serum phosphorus 
measurement below the normal range and criteria 2 and 3 are met, the serum phosphorus measurement should be repeated through an unscheduled blood 
draw at the study site within 4 weeks and a dose adjustment made if the serum phosphorus remains below the normal range. 
86 
The EOS II visit will be the End of Study efficacy visit for subjects in the US and should occur before September 30, 2018. The EOS II visit may be up 
to 2 days in duration due to the volume of testing; required blood draws may be split across the 2 days. Radiography (x-rays) of wrists and knees, 
6MWT, and ECHO will not be performed at the EOS II Visit if the assessment was conducted within 3 months of termination.  Radiography (x-rays) of 
standing long legs will not be performed at the EOS II visit if a postbaseline assessment was conducted within 12 months of termination.  
87 
The ET visit may be up to 2 days in duration due to the volume of testing; required blood draws may be split across the 2 days. Radiography (x-rays) of 
wrists and knees, XtremeCT, 6MWT, BOT-2, HHD and ECHO will not be performed at the ET Visit if the assessment was conducted within 3 months 
of termination.  Radiography (x-rays) of standing long legs will not be performed at the ET visit if a postbaseline assessment was conducted within 
12 months of termination. BOT-2 and HHD will not be performed if the ET Visit occurs after Week 64. XtremeCT will be performed for ET visits 
occurring between Week 40 and Week 64 at select sites based on scheduling and availability of equipment. 
88 
To be completed for those subjects who complete EOS II and do not continue on KRN23 treatment immediately on commercial use or through another 
mechanism. Site personnel will initiate a safety follow-up telephone call 5 weeks (+ 5 days) after the EOS II visit to collect information on whether 
KRN23 has been started through another mechanism and, if not, any ongoing or new AEs, serious AEs, or concomitant medications.  
89 
A safety visit will take place 10 weeks ±1 week after the ET or EOS II visit for those subjects who discontinue treatment after Week 160 and before the 
EOS II visit or for those subjects within the US who complete EOS II and do not continue on KRN23 through commercial use or another mechanism. 
This safety visit will not occur for subjects in the US who complete EOS II and are documented to be continuing on KRN23 on commercial use or 
through another mechanism.  Every reasonable effort should be made to have subjects return to the clinic for the final safety visit; however, subjects 
who are unable to return to the clinic for the final safety visit will be given the option of having a final safety telephone call for the collection of any 
ongoing or new AEs, serious AEs, or concomitant medications.  

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3 TABLE OF CONTENTS 
1 TITLE PAGE .......................................................................................................................1 
2 SYNOPSIS ...........................................................................................................................5 
3 TABLE OF CONTENTS ...................................................................................................32 
4 LIST OF ABBREVIATIONS AND DEFINITION OF TERMS ......................................37 
5 INTRODUCTION .............................................................................................................40 
5.1 Overview of XLH .....................................................................................................41 
5.2 Brief Overview of KRN23 Development .................................................................42 
5.2.1 
Brief Description of KRN23 .......................................................................42 
5.2.1.1 
Mechanism of Action in XLH .....................................................42 
5.2.2 
Nonclinical Studies ......................................................................................43 
5.2.3 
Previous Clinical Studies .............................................................................44 
5.3 Summary of Overall Risks and Potential Benefits ....................................................44 
5.4 Study Rationale .........................................................................................................46 
6 STUDY OBJECTIVES ......................................................................................................48 
7 INVESTIGATIONAL PLAN ............................................................................................49 
7.1 Overall Study Design and Plan .................................................................................49 
7.2 Discussion of Study Design, Including Choice of Control Group ............................52 
7.3 Selection of Study Population ...................................................................................53 
7.3.1 
Inclusion Criteria .........................................................................................54 
7.3.2 
Exclusion Criteria ........................................................................................55 
7.3.3 
Removal of Subjects from Therapy or Assessment ....................................56 
7.3.3.1 
Stopping Rules .............................................................................57 
7.4 Treatments .................................................................................................................58 
7.4.1 
Investigational Product ................................................................................58 
7.4.2 
Reference Therapy ......................................................................................59 
7.4.3 
Method of Assigning Subjects to Treatment Groups ..................................59 

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7.4.4 
Selection of Doses and Study Duration .......................................................59 
7.4.5 
Prior and Concomitant Therapy ..................................................................63 
7.4.5.1 
Prohibited Medications ................................................................64 
7.4.5.2 
Permitted Medications .................................................................64 
7.4.6 
Treatment Compliance ................................................................................64 
7.5 Study Procedures and Assessments ..........................................................................65 
7.5.1 
Schedule of Events ......................................................................................65 
7.5.2 
Pharmacodynamic Measures .......................................................................67 
7.5.3 
Clinical Efficacy Measures .........................................................................68 
7.5.3.1 
Efficacy – Bone Health ................................................................68 
7.5.3.2 
Efficacy – Clinical Outcomes: .....................................................70 
7.5.4 
Drug Concentration Measurements .............................................................72 
7.5.5 
Safety Measures & General Assessments ...................................................72 
7.5.5.1 
Medical History ...........................................................................72 
7.5.5.2 
Interval History ............................................................................73 
7.5.5.3 
Vital Signs and Weight ................................................................73 
7.5.5.4 
Physical Examination...................................................................74 
7.5.5.5 
Renal Ultrasound and Glomerular Filtration Rate .......................74 
7.5.5.6 
Echocardiogram ...........................................................................74 
7.5.5.7 
Electrocardiogram ........................................................................74 
7.5.5.8 
Clinical Laboratory Tests for Safety ............................................75 
7.5.5.9 
Anti-KRN23 Antibody Screening................................................76 
7.5.5.10 
Pregnancy Testing ........................................................................77 
7.5.5.11 
Pregnancy in Subject or Partner ...................................................77 
7.5.5.12 
Concomitant Medications/Therapies ...........................................78 
7.5.5.13 
Dose Limiting Toxicity ................................................................78 
7.5.5.14 
Adverse Events ............................................................................78 

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7.5.6 
Appropriateness of Measures ......................................................................79 
7.6 Statistical Methods and Determination of Sample Size ............................................80 
7.6.1 
Determination of Sample Size .....................................................................80 
7.6.2 
Analysis Populations ...................................................................................80 
7.6.2.1 
Efficacy Analysis Set ...................................................................80 
7.6.2.2 
Safety Analysis Set ......................................................................80 
7.6.2.3 
Pharmacokinetic and Pharmacodynamic Analysis Set ................81 
7.6.3 
Principles .....................................................................................................81 
7.6.3.1 
Subject Accountability .................................................................81 
7.6.3.2 
Demographic and Baseline Characteristics .................................81 
7.6.3.3 
Baseline ........................................................................................81 
7.6.3.4 
Dose and Dose Regimen Evaluation............................................81 
7.6.3.5 
Pharmacodynamic Parameters .....................................................82 
7.6.3.6 
Clinical Efficacy Endpoints .........................................................82 
7.6.4 
Pharmacodynamic and Efficacy Analyses ..................................................83 
7.6.4.1 
Week 16 Analysis ........................................................................83 
7.6.4.2 
Week 24 Analysis ........................................................................83 
7.6.4.3 
Week 40 Analysis ........................................................................83 
7.6.4.4 
Week 64 Analysis ........................................................................84 
7.6.4.5 
Treatment Extension Period Analyses .........................................84 
7.6.5 
Pharmacokinetic Analyses ..........................................................................84 
7.6.6 
Safety Analyses ...........................................................................................84 
7.6.7 
Data Monitoring Committee .......................................................................85 
8 STUDY CONDUCT ..........................................................................................................86 
8.1 Ethics .........................................................................................................................86 
8.1.1 
Institutional Review Board or Ethics Committee ........................................86 
8.1.2 
Ethical Conduct of Study ............................................................................86 

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8.1.3 
Subject Information and Consent ................................................................86 
8.2 Investigators and Study Administrative Structure ....................................................87 
8.3 Investigational Product Accountability .....................................................................87 
8.4 Data Handling and Record Keeping .........................................................................88 
8.4.1 
Case Report Forms and Source Documents ................................................88 
8.4.2 
Data Quality Assurance ...............................................................................88 
8.4.3 
Record Retention .........................................................................................89 
8.5 Reporting and Follow-up of Adverse Events ............................................................89 
8.5.1 
Definition of Adverse Events ......................................................................89 
8.5.2 
Severity of Adverse Events .........................................................................90 
8.5.3 
Relationship of Adverse Events to Study Drug ...........................................91 
8.5.4 
Adverse Event Reporting to Ultragenyx .....................................................92 
8.5.4.1 
General .........................................................................................92 
8.5.4.2 
Serious Adverse Events, Serious Adverse Drug Reactions, 
and Requirements for Immediate Reporting ................................92 
8.5.4.3 
Pregnancy Reports .......................................................................92 
8.5.5 
Communication Plan ...................................................................................93 
8.5.5.1 
Review of Safety Data .................................................................93 
8.5.5.2 
Adverse Drug Reaction Reporting ...............................................93 
8.5.6 
Urgent Safety Measures ..............................................................................94 
8.5.7 
Safety Contact Information .........................................................................95 
8.6 Financing and Insurance ...........................................................................................95 
8.7 Publication Policy .....................................................................................................95 
9 REFERENCES ..................................................................................................................96 
10 SIGNATURE PAGE .......................................................................................................100 
 

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List of Tables 
Table 2.1: 
KRN23 Dose Titration Scheme .............................................................8 
Table 2.2: 
Schedule of Events – Titration Period Visits .......................................16 
Table 2.3: 
Schedule of Events –Treatment Period Visits (Weeks 18 – 40) ..........19 
Table 2.4: 
Schedule of Events –Treatment Period Visits (Weeks 42 – 64) ..........22 
Table 2.5: 
Schedule of Events –Treatment Extension Period I Visits 
(Weeks 66 – 160) .................................................................................25 
Table 2.6: 
Schedule of Events–Treatment Extension Period II Visits 
(Week 162 – End of Study)74 ...............................................................29 
Table 7.4.4.1: 
KRN23 Initial Dose Titration Scheme .................................................63 
Table 7.5.2.1: 
Pharmacodynamic Measures ...............................................................67 
Table 7.5.5.8.1: 
Clinical Laboratory Assessments for Safety ........................................76 
 
List of Figures 
Figure 2.1: 
UX023-CL201 Study Schema .............................................................10 
Figure 7.1.1: 
UX023-CL201 Study Schema .............................................................52 
 

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4 LIST OF ABBREVIATIONS AND DEFINITION OF TERMS 
Abbreviations 
25(OH)D 
1,25(OH)2D 
6MWT 
25-hydroxyvitamin D 
1,25-dihydroxyvitamin D 
Six Minute Walk Test 
ADA 
Anti-drug antibody 
AE 
adverse event 
ALP 
ANCOVA 
AP 
BALP 
BOT-2 
BUN 
alkaline phosphatase 
analysis of covariance 
anteroposterior 
bone-specific alkaline phosphatase 
Bruininks-Oseretsky Test of Motor Proficiency – 2nd Edition 
blood urea nitrogen 
°C 
CFR 
degrees Celsius 
Code of Federal Regulations 
CRF 
case report form 
CT 
computed tomography 
CTx 
carboxy-terminal cross-linked telopeptide of type I collagen 
Dl 
DLT 
DMC 
deciliter 
dose limiting toxicity 
Data Monitoring Committee 
EC 
Ethics Committee 
ECG 
electrocardiogram 
ECHO 
ECLA 
EDC 
echocardiogram 
electrochemiluminescent assay 
electronic data capture 
EEI 
energy expenditure index 
EOS 
EU 
EudraCT 
end of study 
European Union 
European Union Drug Regulating Authorities Clinical Trials 
FDA 
Food and Drug Administration 
FGF23 
GCP 
fibroblast growth factor 23 
Good Clinical Practice 
GFR 
glomerular filtration rate 
GLP 
Good Laboratory Practice 

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GMP 
Good Manufacturing Practice 
HH 
HHD 
HIPAA 
Home Health 
hand-held dynamometry 
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 
Registration of Pharmaceuticals for Human Use 
IND 
Investigational New Drug (application) 
iPTH 
ITT 
intact parathyroid hormone 
intent-to-treat 
IV 
IWRS 
intravenous 
Interactive Web Randomization System 
kg 
KHK 
L 
LS 
LVH 
m 
mAb 
kilogram 
Kyowa Hakko Kirin Pharma, Inc. 
liter 
least squares 
left ventricular hypertrophy 
meter 
monoclonal antibody 
MedDRA 
Medical Dictionary for Regulatory Activities 
mg 
mm Hg 
mmol 
MVIC 
NCI CTCAE 
milligram 
millimeters of mercury 
millimole 
maximum voluntary isometric contraction 
National Cancer Institute Common Terminology Criteria for Adverse 
Events 
NOAEL 
no adverse effect level 
P1NP 
procollagen type 1 N-propeptide 
PA 
posteroanterior 
PD 
pharmacodynamic (s) 
PHEX 
Phosphate regulating gene with homology to endopeptidases located on 
the X chromosome 
PHS-10 
Physical Summary Score 
PK 
PODCI 
pharmacokinetic(s) 
Pediatric Outcomes Data Collection Instrument 

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POSNA 
Pediatric Orthopedic Society of North America 
PSS-10 
Psychosocial Summary Score 
PT 
Preferred Term 
PTH 
Q2 
Q4 
RBC 
parathyroid hormone 
biweekly, once every two weeks 
monthly 
red blood cell 
RGI-C 
RSS 
Radiographic Global Impression of Change 
Rickets Severity Score 
SAE 
serious adverse event 
SAP 
statistical analysis plan 
SC 
subcutaneous 
SF-10 
SF-10 for Children Health Survey 
SOC 
standard of care 
SSRT 
Study Safety Review Team 
SUSAR 
suspected unexpected serious adverse reaction 
TEAE 
TmP/GFR 
 
TRP 
ULN 
treatment emergent adverse event 
ratio of renal tubular maximum reabsorption rate of phosphate to 
glomerular filtration rate 
tubular reabsorption of phosphate 
upper limit of normal 
ULRR 
Upper limit of the reference range 
US 
United States 
WBC 
XLH 
white blood cell 
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 Registration of 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 renal phosphate wasting, and the most 
common heritable form of rickets. In XLH patients, a defect in the phosphate sensing 
mechanism in osteocytes leads to the production of aberrantly high circulating levels of 
fibroblast growth factor 23 (FGF23) that causes an inappropriate loss of phosphate 
reabsorption in the kidney. The impact of FGF23 on the kidney causes hypophosphatemia 
and low-normal circulating 1,25-dihydroxyvitamin D (1,25(OH)2D) levels. The low serum 
phosphorus levels result in hypomineralization of bone and associated abnormalities 
including rickets, bowing of the legs and short stature. 
The current standard of care consists of oral phosphate and 1,25(OH)2D (calcitriol) 
replacement. Treatment can improve rickets disease but provides limited benefit in 
some patients or in other aspects of the disease and does not treat the underlying cause 
(Carpenter et al. 2011). The treatment regimen requires balancing the benefits of treatment 
with complicated monitoring and potential risks such as nephrocalcinosis, hypercalciuria, and 
hyperparathyroidism (Carpenter et al. 2011). By blocking the action of the aberrantly 
elevated FGF23, the reabsorption of phosphate 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 
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 Pharma, Inc. (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 conducted 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 
associated treatment extension study. The current Phase 2 study will evaluate the 
pharmacodynamics (PD) of KRN23 to determine the appropriate dose range and dose 
regimen, and establish the safety profile of KRN23 in children with XLH. Effects on 
phosphate homeostasis and the clinical impact of KRN23 on skeletal disease, growth and 
physical function will also be examined. 

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5.1 
Overview of XLH 
XLH, also described as vitamin D-resistant rickets, is a rare genetic metabolic disorder.  
The incidence of XLH is 3.9-5 per 100,000 live births (Davies et al. 1981); (Beck-Nielsen et 
al. 2009). XLH is the most common inherited form of rickets and the most common inherited 
defect in renal tubular phosphate transport. There is a great deal of variability in the 
manifestations of XLH. In the mildest cases, only hypophosphatemia is evident (Holm et al. 
2012). In more severe disease, hypophosphatemia leads to decreased mineralization of newly 
formed bone and the clinical findings of rickets. Surgical correction of limb deformities is 
often required. 
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 the decreasing phosphate needs 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).  
XLH is transmitted as an X-linked dominant disorder, although autosomal recessive and 
dominant forms of hypophosphatemia have also been observed (Dixon et al. 1998).  
Mutations resulting in the loss of function of PHEX (Phosphate regulating gene with 
Homology to Endopeptidases located on the X chromosome) form the genetic basis for XLH 
(Carpenter et al. 2011). Approximately 20% of PHEX mutations are de novo (i.e. not 
inherited from a parent) based on genetic testing and clinical observations in non-familial 
XLH patients (Dixon et al. 1998); (Whyte et al. 1996). 
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 (Carpenter et al. 
2011); (Rowe 2012).  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 dihydroxyvitamin D [1,25(OH)2D] levels by inhibiting 
1-alpha-hydroxylase activity in the kidney, thereby decreasing intestinal absorption of 
phosphate and calcium. Both actions by FGF23 on the tubular reabsorption and intestinal 
absorption via vitamin D metabolism lead to a decrease in serum phosphorus levels. 
Current treatment options for patients with XLH are directed at correcting osteomalacia and 
replacing lost serum phosphorus by administering oral phosphate supplements and an active 
vitamin D metabolite (e.g. calcitriol) several times per day. However, the resulting transient 
yet pronounced increases in serum phosphorus lower serum ionized calcium causing 
compensatory increases in parathyroid hormone (PTH). The combination of increased 
urinary phosphate excretion and increased PTH can increase the risk for extra-osseus 
calcifications and precipitation of calcium-phosphate in the kidney. The administration of 
oral phosphate also increases serum FGF23 concentrations (Imel et al. 2010); (Carpenter et 

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al. 2010), which is the underlying cause of hypophosphatemia in patients with XLH and 
could further suppress phosphate reabsorption and drive further complications. 
Treatment with oral phosphate supplements and calcitriol therefore requires frequent and 
continued monitoring of patients. Serum and urine mineral metabolites levels and imaging 
studies are required to assess toxicity and secondary complications, including 
nephrocalcinosis, hypercalciuria, and hyperparathyroidism (Carpenter et al. 2011). 
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 monoclonal antibody 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 
metabolism in XLH patients. KRN23 binds the amino-terminal domain of FGF23 that 
interacts with the FGFR1-binding portion of the combination FGFR1/Klotho receptor, 
preventing FGF23 from binding and signaling 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. The dual action on kidney reabsorption and intestinal absorption, 
improves 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. 

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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 
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). In adult Hyp mice, anti-FGF-23 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 the characteristic abnormalities associated with XLH. 
KRN23 binds to human, rabbit, and monkey FGF23 with comparable affinities. In a GLP 
study, 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 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 IV infusion sites or 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. 

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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 
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 
Previous Clinical Studies 
Four clinical studies have been conducted 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-001), and an associated treatment extension study 
(KRN23-INT-002). An additional open-label long-term extension study (UX023-CL203), a 
double-blind, placebo-controlled, Phase 3 study (UX023-CL303), and an open-label, paired 
bone biopsy Phase 3 study to evaluate changes in osteomalacia at the tissue level with 
KRN23 treatment are ongoing. Details of study parameters and PK, PD, clinical efficacy and 
safety results are provided in the IB. 
Data from clinical studies to date are consistent with the model 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 
long-term 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 every 4 weeks 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 AEs have been reported. In the extension 
study, 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 long-term 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 treatment. 
5.3 
Summary of Overall Risks and Potential Benefits 
KRN23 is a recombinant human IgG1 mAb. Although KRN23 is a fully human antibody, 
there is still a potential risk of anti-drug antibody (ADA) production against KRN23. It is 

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important to monitor for the presence of ADA, especially when repeat-doses of KRN23 are 
given. No positive anti-KRN23 antibodies have been detected following IV or SC 
administration of KRN23 at the dose levels tested. Following SC administration of KRN23, 
injection site pain and urticaria have been reported. 
Based on the anticipated actions of KRN23, subjects could experience hyperphosphatemia 
for a certain period of time due to excessive pharmacologic effects of KRN23. While no 
clinically relevant changes in laboratory values suggestive of a treatment-related adverse 
effect have been observed for KRN23, careful attention should be paid to serum levels of 
phosphorus and other related factors, such as calcium, 1,25(OH)2D, and iPTH. 
Nephrocalcinosis was observed in some toxicology studies; it may occur due to an excessive 
increase in serum phosphorus and/or a potential increase in serum calcium. Many XLH 
patients develop nephrocalcinosis as a result of SOC therapy. Potential subjects with 
nephrocalcinosis severe enough to impair renal function will not be enrolled in the study.  
The presence of nephrocalcinosis will be examined prior to KRN23 treatment and will be 
monitored closely throughout the study. 
An analysis of the risk of ectopic calcification from the non-clinical and clinical program 
suggests that the serum phosphorus and calcium levels achieved in KRN23 clinical studies 
would not likely be associated with a clinical risk of ectopic mineralization, and that a safety 
margin exists relative to the mineral levels achieved during nonclinical toxicology 
experiments. Clinical data using renal ultrasound and ultra-fast CT scans of the heart have 
not identified a clinically significant increase or the appearance of novel calcifications in the 
most susceptible organs. Risks to subjects are mitigated by careful, detailed, and controlled 
monitoring of serum phosphorus levels and other biochemically-related factors in serum, 
such as calcium, 1,25(OH)2D, and iPTH. Surveillance via imaging modalities (i.e. renal 
ultrasound and echocardiogram [ECHO]) further monitor risks for the subjects. 
KRN23 treatment results in elevation and accumulation of bound FGF23, but this does not 
appear to have any effect on phosphate metabolism despite an apparent associated 
increase in free FGF23. Although elevated free FGF23 has been associated with left 
ventricular hypertrophy (LVH) in patients with advanced chronic kidney disease (Faul et al. 
2011); (Faul 2012); (Gutierrez 2013); (Wolf 2012), these findings have not been observed 
following anti-FGF23 treatment in the Hyp mouse model or as assessed by ECG in XLH 
patients in the KRN23 clinical program. Some reports have suggested that XLH patients on 
oral phosphate therapy have signs of LVH which likely increases FGF23 without any 
mitigation (Nehgme et al. 1997); (Carpenter et al. 2010). Cardiac monitoring has been 
incorporated into the study design to assess the potential risk. 
The nonclinical and clinical experience with KRN23 indicates treatment induces expected 
PD effects, including increased serum phosphorus, TmP/GFR, and serum 1,25(OH)2D levels, 
without negatively impacting urine calcium levels. Data from the long-term 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.  

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KRN23 treatment has been well tolerated, with no deaths, study drug related SAEs, or 
immunogenicity reported to date. Overall, based on the scientific rationale, unmet medical 
need, and results from nonclinical studies and clinical studies to date, continued clinical 
investigation of KRN23 in patients with XLH is warranted.  
5.4 
Study Rationale 
The current standard of care (SOC) therapy consists of multiple daily doses of oral phosphate 
combined with appropriate doses of active vitamin D metabolites. SOC therapy, when taken 
with a high degree of compliance and monitoring, can improve the skeletal disease but often 
does not fully address the bone and growth abnormalities nor does it target the 
pathophysiological cause of the disease: renal phosphate wasting induced by high FGF23 
levels. SOC therapy also requires careful monitoring to avoid potential risks such as 
nephrocalcinosis, hypercalciuria, and hyperparathyroidism. More efficacious, safer, and 
convenient therapies clearly are needed. 
KRN23 is a recombinant fully human monoclonal IgG1 antibody being developed to treat 
XLH by binding and inhibiting FGF23 activity, thereby restoring normal phosphate 
homeostasis. Four clinical studies have been conducted 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-001), and an associated treatment extension 
study (KRN23 INT-002). An additional open-label long-term extension study 
(UX023-CL203), a double-blind, placebo-controlled, Phase 3 study (UX023-CL303), and an 
open-label, paired bone biopsy Phase 3 study to evaluate changes in osteomalacia at the 
tissue level with KRN23 treatment are ongoing. The safety data from these studies has shown 
that KRN23 in single and repeated monthly doses up to 1.0 mg/kg 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. These data 
support the initiation of further studies to evaluate the therapeutic benefit of KRN23 in 
children who experience the most severe physical and health manifestations associated with 
XLH. Currently, there are no approved treatments and a high unmet medical need in pediatric 
XLH patients. 
Adults and children with XLH have the same underlying defect but are at a different stage of 
the disease. In childhood, normal phosphorus levels are higher to promote bone formation, 
whereas in adults, the normal range is lower, coincident with reduced demand for bone 
formation. Therefore, smaller, more frequent dosing may be preferred for pediatric 
hypophosphatemic patients to maximize treatment effect without a plateau, drive serum 
phosphorus levels closer to the normal range and minimize the troughs. This Phase 2 study 
will examine the PD, efficacy, and safety of KRN23 administered at multiple doses and dose 
regimens in pediatric XLH patients. 
The dose response of KRN23 will be evaluated at 3 starting dose levels. Monthly (Q4) and 
biweekly (i.e. every other week; Q2) dosing regimens will also be compared. KRN23 dosing 

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will be individually adjusted every 4 weeks as needed, according to serum phosphorus levels. 
The goal is to achieve stable serum phosphorus levels in the target range, while minimizing 
changes in the calcium control system. During Treatment Extension Periods I (and II, if 
applicable), all subjects will receive KRN23 at the Q2 dosing regimen. Data collected in this 
study will establish a KRN23 dose and dose regimen for pediatric patients, and provide 
information about the PD, PK, clinical efficacy and safety of KRN23 in children with XLH.  

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6 STUDY OBJECTIVES 
The objectives of the study are to:  
• Identify a dose and dosing regimen of KRN23, based on safety and PD effect in pediatric 
XLH patients     
• Establish the safety profile of KRN23 for the treatment of children with XLH including 
ectopic mineralization risk, cardiovascular effects, and immunogenicity profile  
• Characterize the PK/PD of the KRN23 doses tested in the monthly (Q4) and biweekly 
(Q2) dose regimens in pediatric XLH patients 
• Determine the PD effects of KRN23 treatment on markers of bone health in pediatric 
XLH patients 
• Obtain a preliminary assessment of the clinical effects of KRN23 on bone health and 
deformity, muscle strength, and motor function 
• Obtain a preliminary assessment of the effects of KRN23 on patient-reported outcomes, 
including pain, disability, and quality of life in pediatric XLH patients 
• Evaluate the long-term safety and efficacy of KRN23 

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7 INVESTIGATIONAL PLAN 
7.1 
Overall Study Design and Plan 
UX023-CL201 is a randomized, multicenter, open-label, dose finding Phase 2 study.  
The study will be conducted in prepubescent children aged 5-12 years with XLH to assess 
the PD and safety of KRN23 administered via subcutaneous (SC) injections monthly 
(Q4, 28 days, and no fewer than 12 days apart) or biweekly (Q2, 14 days, and no fewer than 
8 days apart) for up to 160 weeks for subjects at study sites outside the US and up to 
216 weeks (until September 2018) for subjects at study sites in the US. The study will consist 
of an individual dose Titration Period (16 weeks), a Treatment Period (48 weeks), and a 
Treatment Extension Period I (up to 96 weeks). For subjects at study sites outside the US the 
Week 160 visit will be their end of study efficacy visit (EOS I). In the US, the study will also 
include a Treatment Extension Period II (up to 56 weeks) at the end of which the US subjects 
will have their EOS efficacy visit (referred to as EOS II). A safety follow-up telephone call 
will occur at 5 weeks (+ 5 days) after the EOS (I or II) efficacy visit, and a final safety visit 
will occur at 10 weeks (± 1 week) after the EOS (I or II) efficacy visit for subjects that are 
not continuing on KRN23 treatment through commercial use or another mechanism. The end 
of study is defined as the date of the last protocol-specified procedures (including telephone 
contact) for the last subject in the study. During Treatment Extension Period I (and II, if 
applicable), all subjects will receive KRN23 with Q2 administration.  
The study initially enrolled 36 pediatric subjects with XLH and radiographic evidence of 
bone disease (pre-expansion subjects). The study was expanded to include additional subjects 
who were required to have a level of rickets severity of at least 1.5 points at the knee as 
defined by the Rickets Severity Score (RSS) method for a total of approximately 50 subjects 
overall (Thacher et al. 2000). 
Potential subjects will come in to the site for an initial screening visit and sign informed 
consent. Once the diagnosis of XLH and radiographic evidence of active bone disease 
(pre-expansion subjects) or a RSS of at least 1.5 points at the knee (expansion subjects) have 
been confirmed, subjects will discontinue oral phosphate and vitamin D metabolite therapy 
prior to randomization and throughout the duration of the study (Section 7.4.5.1). 
Subjects who successfully pass the initial screening requirements will return to the site for a 
second screening visit a minimum of 14 days after vitamin D metabolite treatment has been 
stopped and a minimum of 7 days after oral phosphate treatment has been stopped (as 
applicable); the remaining screening assessments to confirm eligibility will be performed. 
The Baseline visit may occur up to 7 days after the second screening visit. 
All Screening/Baseline assessments and inclusion/exclusion criteria based on local lab results 
must be satisfied prior to randomization and dosing. 
There will be 3 cohorts in this study (n = 10 in cohorts 1 and 2 [pre-expansion subjects] and 
n = 30 in cohort 3 [comprising both pre-expansion and expansion subjects]); each with a Q4 
and Q2 dosing group. Subjects will be randomized 1:1 to the Q4 or Q2 dosing regimens 
within each cohort; randomization will be stratified on subject gender. In order to maintain a 

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level of gender balance, no more than 20 patients of either sex can be enrolled in the 
pre-expansion group. No requirement for gender balance will be applied in the expansion 
group. The cohorts will be enrolled sequentially. The first cohort will examine the lowest 
doses (0.2 mg/kg Q4 and 0.1 mg/kg Q2) and will be enrolled first. As an added precautionary 
measure in this pediatric population, the second cohort (0.4 mg/kg Q4 and 0.2 mg/kg Q2) 
cannot begin dosing until the fourth subject in the first cohort completes the Week 4 visit.  
The third cohort will be administered the highest starting doses (0.6 mg/kg Q4 and 
0.3 mg/kg Q2). 
Dosing During the Titration Period (Weeks 0-16) 
The initial 16-week Titration Period is intended to identify the KRN23 dose required to 
achieve the target peak PD effect. The goal is to identify an individualized KRN23 dose that 
maintains serum phosphorus levels in the target range for a given subject. 
The target fasting serum phosphorus range for this study is 3.5- 5.0 mg/dL 
(1.131.62 mmol-/L), based on the peak PD effect of KRN23. The dose will be adjusted every 
4 weeks, as needed, based on 2-week post-dose fasting serum phosphorus levels. The KRN23 
dose titration scheme will be used as a guideline should the peak fasting serum phosphorus 
level fall outside of the target range (Table 7.4.4.1). 
Dosing During the Treatment Period (Weeks 18-64) 
If the serum phosphorus level is rising but has not yet reached the pre-specified target range 
by the end of the Titration Period, the titration may continue into the Treatment Period until 
the target range is reached, provided there are no safety concerns. For those subjects whose 
dose titration continues into the Treatment Period, 2-week post-dose peak serum phosphorus 
levels may be measured through unscheduled blood draws at corresponding study visits 
(e.g., at Week 18, 26, or 34) and the titration scheme (Table 7.4.4.1) followed until the target 
range is reached. 
The visit window for HH visits is ± 3 days during the Titration Period and Treatment Period. 
If at any time during dose titration the subject is dosed earlier than the allowable ±3-day 
window, the previous dose should be repeated (i.e. no titration).  If a subject is dosed later 
than the allowable ±3-day window, dosing should be determined as if the dosing occurred 
within the allowable window (i.e. by using the most recent post-dose peak serum phosphorus 
level and the dose titration scheme). 
Dosing During Treatment Extension Period I (Week 66 up to Week 160) and II 
(Week 162 up to Week 216) 
During Treatment Extension Period I (and II, if applicable), all subjects will receive biweekly 
(Q2) administration of KRN23. Subjects in the Q2 dosing regimen during the Treatment 
Period will continue to receive KRN23 at the KRN23 dose they were receiving at Week 64. 
At the Week 64 study visit, subjects in the Q4 dosing regimen will receive KRN23 at 60% of 
their established total Q4 dose level (rounded to the nearest 10 mg) and continue on that dose 
biweekly (Q2) through the Extension Period.  

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The visit window for HH visits is ± 5 days during Treatment Extension Period I. The window 
for dosing and telephone calls from the site during Treatment Extension Period II is ± 5 days.  
General Dosing Guidelines 
The rounding of doses to the nearest 10 mg will not be applied during the Titration Period 
(Weeks 0-16). During the Treatment Period and Treatment Extension Periods I and II, dose 
rounding will be applied once study sites have obtained appropriate approvals. Calculated 
doses below 15 mg will be adjusted to 15 mg. Calculated doses ≥15 mg will be rounded to 
the nearest 10 mg up to a maximum dose of 90 mg. The dose level should not exceed 
2.0 mg/kg for either the Q4 regimen or the Q2 regimen. The total administered dose may 
differ slightly from the total calculated or rounded dose due to rounding of the volume drawn 
for administration (to the nearest 0.1 mL). After the initial dose titration is complete, the dose 
may be increased at any time during the Treatment Period or Treatment Extension Periods I 
or II if a subject meets the following dose adjustment criteria: 1) two consecutive serum 
phosphorus measurements are below the normal range (3.2-6.1 mg/dL [1.03-1.97 mmol/L]); 
2) the serum phosphorus level is < 0.5 mg/dL above baseline; and 3) the subject has not 
missed a dose of study drug that would account for the decrease in serum phosphorus. If the 
subject has a single serum phosphorus measurement below the normal range and criteria 2 
and 3 are met, the serum phosphorus measurement should be repeated through an 
unscheduled blood draw within 4 weeks and a dose adjustment made if the serum phosphorus 
measurement remains below the normal range. When post-titration dose adjustment is needed 
during the Treatment Period or Treatment Extension Periods I or II, doses may be adjusted in 
10 mg total dose increments (e.g., a 20 mg rounded total dose would be increased to a 30 mg 
total dose). The dose level should not exceed 2.0 mg/kg (Q2). 
If serum phosphorus increases above 5.0 mg/dL (1.62 mmol/L) at any time, the dose will be 
titrated down. During the Titration Period the dose should be titrated down according to the 
dose titration scheme (Table 7.4.4.1). During the Treatment Period or Treatment Extension 
Periods I or II, the total dose should be decreased by 10 mg. Following a dose reduction in a 
subject, the investigator and medical monitor will determine when and how that subject’s 
dose will be titrated up. 
If a subject does not receive a dose within 10 days of a scheduled dose for the Q2 regimen, 
that dose should be skipped and next dose will be administered at the next scheduled Q2 
dosing visit. If a subject does not receive a dose within 21 days of a scheduled dose for the 
Q4 regimen, that dose should be skipped and the next dose will be administered at the next 
scheduled Q4 dosing visit. 
At the end of the Titration Period, the population of 50 subjects will consist of essentially 
two groups of 25 subjects, each with individually optimized dosing of KRN23 at either a Q4 
week or Q2 week frequency. Analyses of safety and available PD and efficacy data are 
planned at the end of the Titration Period (Week 16) and at Week 24 for pre-expansion 
subjects. Further analyses in the pre-expansion group alone and for the overall population are 
planned at Week 40 and at Week 64 at the end of the Treatment Period to compare treatment 
outcomes to baseline (pre-dose). Analyses of long-term safety and efficacy will be conducted 

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Protocol Number:  UX023-CL201  
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After 16 weeks of individual dose titration, subjects will enter a 48-week Treatment Period at 
an optimized KRN23 dose level. Dose titration may continue into the Treatment Period if 
necessary. The goal of the Treatment Period is to assess ongoing safety and sustained PD, 
PK, and clinical efficacy. The duration of treatment is intended to define whether KRN23 is 
safe for long-term use and provide sufficient insight on sustained clinical effects and 
improvements in rickets and active bone disease in pediatric XLH patients. 
The main efficacy comparison will focus on dose finding and determining whether Q4 or Q2 
dosing provides the optimal profile of phosphate control with acceptable levels of other bone 
mineral metabolites. In addition, the effect of the two regimens on bone health will be 
compared. While the lack of a placebo control group may introduce difficulties in 
discerning natural disease progression from treatment effectiveness, a placebo-controlled 
study of 64-weeks duration is difficult to conduct and possibly not ethical given the need for 
ongoing disease management in developing children. Use of SOC as a parallel active-control 
group would be reasonable, but might require a substantially larger trial size and a longer 
time frame to conduct. Given that the severity of rickets on x-rays of the wrists and knees 
will be scored in a blinded fashion using the RSS method, it is not necessary to subject 
pediatric patients to placebo in this Phase 2 study. 
The goal of Treatment Extension Period I (up to 96 weeks) is to evaluate the long-term safety 
and efficacy of KRN23. All subjects will receive KRN23 at a Q2 dosing regimen. Beginning 
at Week 64, subjects previously assigned to Q4 dosing will receive KRN23 at 60% of their 
established Q4 dose level (rounded to the nearest 10 mg) and continue on that dose biweekly 
(Q2).  It is expected that the maintenance of phosphate control during the Treatment 
Extension Period will allow for continued healing of rickets and bowing and maximize 
growth outcomes. Changes in growth and correction of lower extremity bowing may take 
longer to observe than the healing of rickets; thus, these outcomes will continue to be 
followed in Treatment Extension Period I. 
The goal of Treatment Extension Period II is to continue to provide KRN23 treatment to 
subjects in the US through September 2018 while also continuing to collect long-term safety 
and efficacy data. 
7.3 
Selection of Study Population 
The study will be conducted in approximately 50 prepubescent pediatric XLH subjects 
(aged 5 – 12 years) whom are likely to benefit from KRN23 treatment. The inclusion criteria 
are structured to enroll subjects with XLH, typically presenting with similar biochemical and 
clinical characteristics, including reduced serum phosphorus levels and radiographic 
evidence of rickets and/or bowing. The enrollment of patients with active rachitic disease 
should be prioritized due to the potential for a positive treatment effect in this population; 
expansion subjects will be required to have a level of rickets severity of at least 1.5 points at 
the knee as defined by the RSS. 

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Children with XLH undergo a normal pubertal growth spurt. Post-pubertal height is predicted 
by pre-pubertal height, indicating that loss of height potential generally occurs prior to 
puberty. Thus, initiation of therapy at early ages is recommended to achieve improved height 
outcomes (Carpenter et al. 2011). Specific inclusion criteria were designed to enroll patients 
with open growth plates who have not yet entered puberty (Tanner Stage ≤ 2), to maximize 
detection of treatment effects on bone growth. However, children younger than 5 were not 
included due to requirements for frequent blood draws and routine monitoring of 24-hour 
urine to accurately assess dose-finding and treatment effectiveness. 
The Sponsor has taken reasonable measures to ensure the protection and safety of this 
population. Patients with evidence of tertiary hyperparathyroidism or nephrocalcinosis will 
be excluded. Appropriate pediatric expertise will be available at all trial sites, and site 
personnel will be focused on minimizing risk, fear, pain and distress during conduct of the 
study. However, a series of frequent blood draws are required during the Titration Period to 
ensure subject safety and to assist in the determination of the appropriate dose and dose 
regimen since KRN23 has not been previously administered to the pediatric XLH population. 
7.3.1 
Inclusion Criteria 
Individuals eligible to participate in this study must meet all of the following criteria: 
1) Male or female, aged 5 – 12 years, inclusive, with open growth plates 
2) Tanner stage of 2 or less based on breast and testicular development  
3) Diagnosis of XLH supported by ONE of the following: 
- Confirmed PHEX mutation in the patient or a directly related family member 
with appropriate X-linked inheritance  
- Serum FGF23 level > 30 pg/mL by Kainos assay 
4) Biochemical findings associated with XLH including: 
- 
Serum phosphorus ≤ 2.8 mg/dL (0.904 mmol/L)* 
- 
Serum creatinine within age-adjusted normal range*  
5) Standing height < 50th percentile for age and gender using local normative data 
6) Radiographic evidence of active bone disease including rickets in the wrists and/or 
knees, AND/OR femoral/tibial bowing,  
OR, for expansion subjects, a RSS score in the knee of at least 1.5 points as 
determined by central read 
7) Willing to provide access to prior medical records for the collection of historical 
growth, biochemical and radiographic data, and disease history 

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8) Provide written or verbal assent (if possible) and written informed consent by a 
legally authorized representative after the nature of the study has been explained, and 
prior to any research-related procedures 
9) 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 
10) Females who have reached menarche must have a negative pregnancy test at 
Screening and undergo additional pregnancy testing during the study. If sexually 
active, male and female subjects must be willing to use two highly effective  methods 
of contraception for the duration of the study  
*Criteria to be determined based on overnight fasting (min. 4 hours) values collected at 
Screening Visit 2 
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 a pharmacologic vitamin D metabolite or analog (e.g. calcitriol, 
doxercalciferol, alfacalcidiol, and paricalcitol) within 14 days prior to Screening 
Visit 2; washout will take place during the Screening Period 
2) Use of oral phosphate within 7 days prior to Screening Visit 2; washout will take 
place during the Screening Period 
3) Use of calcimimetics, aluminum hydroxide antacids (e.g. Maalox® and Mylanta®), 
systemic corticosteroids, and thiazides within 7 days prior to Screening Visit 1 
4) Use of growth hormone therapy within 3 months before Screening Visit 1 
5) Use of bisphosphonates for 6 months or more in the 2 years prior to Screening Visit 1 
6) Presence of nephrocalcinosis on renal ultrasound graded ≥ 3 based on the following 
scale: 
0 = Normal 
1 = Faint hyperechogenic rim around the medullary pyramids 
2 = More intense echogenic rim with echoes faintly filling the entire pyramid 
3 = Uniformly intense echoes throughout the pyramid  
4 = Stone formation: solitary focus of echoes at the tip of the pyramid 
7) 
Planned or recommended orthopedic surgery, including staples, 8-plates or 
osteotomy, within the clinical trial period 
8) 
Hypocalcemia or hypercalcemia, defined as serum calcium levels outside the 
age-adjusted normal limits * 

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9) 
Evidence of tertiary hyperparathyroidism as determined by the investigator 
10) Use of medication to suppress PTH (e.g. Sensipar®, cinacalcet, calcimimetics) 
within 2 months prior to Screening Visit 1 
11) 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   
12) Presence of a concurrent disease or condition that would interfere with study 
participation or affect safety  
13) Previously diagnosed  with human immunodeficiency virus antibody, hepatitis B 
surface antigen, and/or hepatitis C antibody  
14) History of recurrent infection or predisposition to infection, or of known 
immunodeficiency 
15) Use of a therapeutic monoclonal antibody within 90 days prior to Screening Visit 1 
or history of allergic or anaphylactic reactions to any monoclonal antibody 
16) Presence or history of any hypersensitivity to KRN23 excipients that, in the 
judgment of the investigator, places the subject at increased risk for adverse effects 
17) Use of any 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 
* Criteria to be determined based on overnight fasting (min. 4 hours) values collected at 
Screening Visit 2 
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 may withdraw a subject at any time at their 
discretion. 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  
• At the request of the subject, investigator, or Ultragenyx, for administrative or other 
reasons 
• Protocol deviation or noncompliance 

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During Treatment Extension Period I (Weeks 66-160) and II (Weeks 160 up to Week 216), 
orthopedic surgery will be permitted if recommended by the investigator or consulting 
physician. Subjects who develop secondary or tertiary hyperparathyroidism may also remain 
on study; however, use of medication to suppress PTH (e.g., Sensipar®, cinacalcet, 
calcimimetics) is not permitted at any time during the study (Section 7.4.5.1). 
Subjects should be removed from study if treatment for hyperparathyroidism becomes 
medically necessary. 
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. 
An additional follow-up safety telephone call will take place 5 weeks (+ 5 days) after the 
subject’s EOS (I or II) efficacy visit to collect information on any ongoing or new AEs, 
SAEs, or concomitant medications. An additional safety visit will occur 10 weeks ±1 week 
(approximately 5 times the elimination half-life) after the date of the subject’s EOS  (I or II) 
visit for a subject who has not continued KRN23 therapy under commercial use or another 
mechanism. Subjects who are unable to return to the clinic for the final safety visit will be 
given the option of providing blood and urine samples as part of a HH visit. 
Subjects who withdraw or are removed from the study after receiving study drug may be 
replaced on a case-by-case basis, at the discretion of Ultragenyx. 
7.3.3.1 
Stopping Rules 
A DMC will be constituted for Study UX023-CL201 and will act in an advisory capacity to 
monitor the safety of KRN23 on a routine basis until the end of the Treatment Period 
(Week 64) (Section 7.6.7). The DMC may provide advice to Ultragenyx in any determination 
of whether study enrollment should be paused or if the study should be halted. During 
Treatment Extension Periods I and II, safety data will be reviewed by the Ultragenyx Study 
Safety Review Team (SSRT) as described in Section 8.5.5.1. 
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 by renal ultrasound and 
echocardiogram. If new or clinically significant worsening in mineralization is considered 

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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 IRB/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 
There will be 3 cohorts in this study (n = 10 in cohorts 1 and 2 [pre-expansion subjects] and 
n = 30 in cohort 3 [comprising both pre-expansion and expansion subjects]); each with a Q4 
and Q2 dosing group. Subjects will be randomized 1:1 to the Q4 or Q2 dosing regimens 
within each cohort; randomization will be stratified on subject gender. Starting doses for all 
3 cohorts are below the highest doses studied in adult XLH subjects (i.e., 1 mg/kg 
administered monthly). The cohorts will be enrolled sequentially. The first cohort will 
examine the lowest doses (0.2 mg/kg Q4 and 0.1 mg/kg Q2) and will be enrolled first. As an 
added precautionary measure in this pediatric population, the second cohort (0.4 mg/kg Q4 
and 0.2 mg/kg Q2) cannot begin dosing until the fourth subject in the first cohort completes 
the Week 4 visit. The third cohort will be administered the highest starting doses (0.6 mg/kg 
Q4 and 0.3 mg/kg Q2). The goal is to identify an individualized KRN23 dose which 
maintains serum phosphorus levels in the target range.  
The amount of KRN23 administered will be calculated based on the subject’s weight. 
The rounding of doses to the nearest 10 mg will not be applied during the Titration Period 
(Week 0-16). During the Treatment Period and Treatment Extension Period, dose rounding 
will be applied once study sites have obtained appropriate approvals. Calculated doses below 
15 mg will be adjusted to 15 mg. Calculated doses ≥15 mg will be rounded to the nearest 
10 mg up to a maximum dose of 90 mg. The dose level should not exceed 2.0 mg/kg for 
either the Q4 regimen or the Q2 regimen.  
During Treatment Extension Periods I and II, all subjects will receive KRN23 at a Q2 dosing 
regimen. Selection of doses, dose titration, and dose adjustments are described in 
Section 7.4.4.  
7.4.1 
Investigational Product 
KRN23 is supplied as a sterile, clear, colorless and preservative-free solution in single-use 
5 mL vials containing 1 mL of KRN23 at a concentration of 10 mg/mL or 30 mg/mL.  At the 
study site, KRN23 should be securely stored at 2- 8°C and protected from light. It should not 
be frozen.  In the home setting, study drug should be handled as directed by the study 
personnel.  
Trained personnel will administer study drug by SC injection to the abdomen, upper arms or 
thighs; the injection site should be rotated with each injection including to a different 

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quadrant of the abdomen. If the dose level exceeds 1 mL in volume, the dose may be 
administered at two injection sites. However, the maximum volume administered at a single 
injection site should not exceed 1.5 mL. After proper training by study personnel in SC 
injection technique, a subject’s parent or non-healthcare provider caregiver may administer 
KRN23 to the subject. Parents or caregivers will be instructed to follow the directions 
provided in the Instructions for Use. The dosing schedule will remain the same. 
The study drug is manufactured, packaged, and labeled according to Good Manufacturing 
Practice (GMP) regulations.   
7.4.2 
Reference Therapy 
The study design is open-label; all subjects will receive investigational product. No placebo 
or reference therapy will be administered in this study. 
7.4.3 
Method of Assigning Subjects to Treatment Groups 
Eligible subjects will be enrolled in the study and sequentially assigned an identification 
number. Three treatment cohorts (n = 10 in cohorts 1 and 2 [pre-expansion subjects] and 
n = 30 in cohort 3 [comprising both pre-expansion and expansion subjects]) will be 
sequentially enrolled, each with a Q4 and Q2 dosing group. Once the full allotment of 
subjects has been enrolled into a cohort (defined as completion of informed consent), the 
next cohort may begin enrolling. Subjects will be randomized 1:1 to the Q4 or Q2 dosing 
regimens within each cohort via an Interactive Web Response System (IWRS) based on a 
randomization schedule developed by an independent third-party vendor. Randomization 
will be stratified on gender; no more than 20 subjects of either gender will be enrolled in the 
pre-expansion group. No requirement for gender balance will be applied in the expansion 
group. 
The IWRS will be programmed such that a subject in the 2nd cohort cannot be randomized 
until the fourth subject in the 1st cohort has completed the Week 4 study visit and a safety 
review has been completed. Sites and investigators will be notified if dosing of new or 
existing subjects will be paused between cohort 1 and 2, and if so, when they can resume 
dosing.  
7.4.4 
Selection of Doses and Study Duration  
A multiple-dose, dose escalation Phase 1/2 study (KRN23-INT-001) was conducted in adult 
XLH subjects. KRN23 was well tolerated following SC administration of 4 intra-subject 
escalating doses (0.05 mg/kg → 0.1 mg/kg → 0.3 mg/kg →0.6 mg/kg) administered once per 
28 days. The proportion of KRN23-treated subjects with serum phosphorus levels in the 
target range (> 2.5 to ≤ 3.5 mg/dL) increased with KRN23 dose level but did not exceed the 
upper limit of normal (4.5 mg/dL) in any subject at any time point. A direct PK-PD 
relationship between serum KRN23 concentrations and serum phosphorus levels was noted 
in the study. In an associated extension study (KRN-INT-002), doses up to 1.0 mg/kg 

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KRN23 administered monthly were well tolerated by adult XLH subjects over a period of 
48 weeks.  
Adults and children with XLH have the same underlying defect but are at a different stage of 
the disease. In childhood, normal phosphorus levels are higher to promote bone formation, 
whereas in adults, the normal range is lower, coincident with reduced demand for bone 
formation. Successful treatment of XLH requires sustained increases in serum phosphorus 
levels (Carpenter et al. 2011). Smaller, more frequent dosing may be preferred for pediatric 
hypophosphatemic patients to maximize treatment effect by maintaining serum phosphorus 
levels closer to the normal range and minimize the troughs. Therefore, the key objectives of 
this study are to determine both the optimal KRN23 dosing regimen for pediatric XLH 
patients and identify an acceptable dose that will allow for the improvement in rickets and 
associated clinical consequences, while avoiding hypercalciuria, hypercalcemia and 
hyperparathyroidism. 
The dose-finding goal of this study is to identify an individualized KRN23 dose that 
maintains serum phosphorus levels in the target range. Dose finding will be conducted 
progressively in three distinct dosing cohorts, each evaluating a different starting dose level 
and dose regimen (Q4 or Q2). Starting doses for all three cohorts are below the highest 
doses studied in adult XLH (1 mg/kg administered monthly). Dose escalation will be 
individually titrated based on PD effects on serum phosphorus, safety and tolerability.  
During the Titration and Treatment Periods, dosing will be initiated and titrated in a stepwise, 
controlled fashion over a 16-week period to achieve serum phosphorus levels in a target 
range below the age-adjusted upper limit of normal.  
The amount of KRN23 administered will be calculated based on the subject’s weight. 
The rounding of doses to the nearest 10 mg will not be applied during the Titration Period 
(Week 0-16). During the Treatment Period and Treatment Extension Periods I and II, dose 
rounding will be applied once study sites have obtained appropriate approvals. Calculated 
doses below 15 mg will be adjusted to 15 mg. Calculated doses ≥15 mg will be rounded to 
the nearest 10 mg up to a maximum dose of 90 mg. The dose level should not exceed 
2.0 mg/kg for either the Q4 regimen or the Q2 regimen.  
Since phosphorus requirements in growing children are greater than in adults, the design 
provides the provision to increase the dose level as high as 2.0 mg/kg for the Q4 regimen and 
2.0 mg/kg for the Q2 regimen to a maximum dose of 90 mg. Previous studies with KRN23 in 
adult XLH patients did not show any “off target” effects; therefore, the safety profile is 
expected to be related solely to the PD effect, essentially increased serum phosphorus. 
Since the serum phosphorus target range is defined well below the upper limit of normal, the 
likelihood of a dose-related safety issue is low. The efficacy data on phosphate control from 
these previous studies also suggest there is a plateau in effect between 0.6 -1.0 mg/kg, which 
may or may not be the case in pediatric patients in whom phosphate metabolism is clearly 
different. Therefore, the protocol allows limited flexibility to adapt to incrementally higher 
doses, if the expected doses based on adult data are inadequate to achieve an acceptable 
increase in serum phosphorus within the accepted safe range. 

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The target fasting serum phosphorus range for this study is 3.5 – 5.0 mg/dL 
(1.13 -1.62 mmol/L), based on the peak PD effect of KRN23, which is approximately 
14 days post-dose. The target range represents the low- to mid-range of normal values in 
children.  Consultations with physicians who are expert in the field indicate this level is 
sufficient to improve rickets and other bone defects (T. Carpenter, personal communication), 
while minimizing the risk of ectopic mineralization. With additional treatment experience 
gained during the study, it was determined that achieving serum phosphorus levels within the 
target range (3.5-5.0 mg/dL) may not be required to achieve positive outcomes. Therefore, 
once a stable dose is reached, the need for dose escalation during the Treatment Period and 
the Extension Period will be based on achieving a serum phosphorus level above the lower 
limit of the normal range (3.2 mg/dL) or at least 0.5 mg/dL above baseline.  
During the Titration Period the dose will be adjusted every 4 weeks, as needed, based on 
2-week post-dose fasting serum phosphorus levels. During the Titration Period doses will be 
adjusted according to the titration scheme detailed below. The titration scheme 
(Table 7.4.4.1) will be used as a guideline for dose adjustments should the peak fasting serum 
phosphorus level fall outside of the target range. If the serum phosphorus level is rising but 
has not yet reached the pre-specified target range by the end of the Titration Period, the 
titration can continue into the Treatment Period until the target range is reached, provided 
there are no safety concerns. For those subjects whose dose titration continues into the 
Treatment Period, 2-week post-dose peak serum phosphorus levels may be measured through 
unscheduled blood draws at corresponding study visits (e.g., at Week 18, 26, or 34) and the 
titration scheme followed (Table 7.4.4.1) until the target level is achieved. During the 
Treatment Extension Period, all subjects will receive biweekly (Q2) administration of 
KRN23. Subjects in the Q2 dosing regimen during the Treatment Period will continue to 
receive KRN23 at the KRN23 dose they were receiving at Week 62. At the Week 64 study 
visit, subjects in the Q4 dosing regimen will receive KRN23 at 60% of their established total 
Q4 dose level (rounded to the nearest 10 mg) and continue on that dose biweekly (Q2).  
During the Treatment Period and Treatment Extension Period I (and II, if applicable), dose 
rounding will be applied once study sites have obtained appropriate approvals. Calculated 
doses below 15 mg will be adjusted to 15 mg. Calculated doses ≥15 mg will be rounded to 
the nearest 10 mg up to a maximum dose of 90 mg. The dose level should not exceed 
2.0 mg/kg for either the Q4 regimen or the Q2 regimen. The total administered dose may 
differ slightly from the total calculated or rounded dose due to rounding of the volume drawn 
for administration (to the nearest 0.1 mL).  
After the initial dose titration is complete, the dose may be increased at any time during the 
Treatment Period or the Treatment Extension Periods if a subject meets the following dose 
adjustment criteria: 1) two consecutive serum phosphorus measurements are below the 
normal range (3.2-6.1 mg/dL [1.03-1.97 mmol/L]); 2) the serum phosphorus level is 
< 0.5 mg/dL above baseline; and 3) the subject has not missed a dose of study drug that 
would account for the decrease in serum phosphorus. If the subject has a single serum 
phosphorus measurement below the normal range and criteria 2 and 3 are met, the serum 
phosphorus measurement should be repeated through an unscheduled blood draw within 

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4 weeks and a dose adjustment made if the serum phosphorus remains below the normal 
range. When post-titration dose adjustments are needed during the Treatment Period or 
Treatment Extension Periods, doses may be adjusted in 10 mg total dose increments (e.g., a 
20 mg rounded total dose would be increased to a 30 mg total dose). The dose level should 
not exceed 2.0 mg/kg for either the Q4 regimen or the Q2 regimen.  If serum phosphorus 
increases above 5.0 mg/dL (1.62 mmol/L) at any time, the dose will be titrated down. During 
the Titration Period the dose should be titrated down according to the dose titration scheme 
(Table 7.4.4.1). During the Treatment Period or Treatment Extension Periods I or II, the total 
dose should be decreased by half. Following a dose reduction in a subject, the investigator 
and medical monitor will determine when and how that subject’s dose will be titrated up. 
When dose titration is applied due to safety concerns, the investigator judgment prevails. 
During the Titration Period, the Treatment Period, and Treatment Extension Period I, if a 
subject does not receive a dose within 10 days of a scheduled dose for the Q2 regimen, that 
dose should be skipped and next dose will be administered at the next scheduled Q2 dosing 
visit. During the Titration Period or the Treatment Period, if a subject does not receive a dose 
within 21 days of a scheduled dose for the Q4 regimen, that dose should be skipped and next 
dose will be administered at the next scheduled Q4 dosing visit. 
During Treatment Extension Period II, if a subject does not receive a dose within 10 days of 
a scheduled dose for the Q2 regimen, that dose should be skipped and next dose will be 
administered on the next scheduled Q2 dosing day.  

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Table 7.4.4.1: KRN23 Initial Dose Titration Scheme 
Serum Phosphorus  
(2 weeks Post-Dose) 
Dose Adjustment 1,5 
< 3.5 mg/dL 2 
< 1.13 mmol/L 
In 2 weeks, increase dose by 0.3 mg/kg for Q2 OR 0.4 mg/kg 
for Q43 
3.5 – 4.5 mg/dL 
1.13 – 1.45 mmol/L 
Repeat previous dose 
>4.5 – 5.0 mg/dL 
>1.45 – 1.62 mmol/L 
Repeat previous dose and then repeat serum phosphorus in at 
2 weeks after that dose; determine next dose based on the repeat 
serum phosphorus level. 
> 5.0 mg/dL (1.45 mmol/L) and 
 ≤ age adjusted ULN 
In 2 weeks, decrease dose by 0.3 mg/kg for Q2 OR 0.4 mg/kg 
for Q4 and then repeat serum phosphorus at 2 weeks after that 
dose3 
> age adjusted ULN 
Skip next 2 doses for Q2 OR skip next dose for Q4, then re-
initiate dosing at last dose level at which the subject’s peak serum 
phosphorus was in range4 
1 
Dose adjustments for subjects assigned to the Q2 regimen will only be made after 2 consecutive peak 
measurements. 
2 
During the Treatment Period, if a subject’s serum phosphorus level has not increased, as defined by a 
change no greater than 0.1 mg/dL, after 2 consecutive dose escalations, even if the target range has not 
been achieved, then the previous dose will be considered that subject’s optimized dose and not escalated 
further. 
3 
If needed, the final dose adjustment increment may be less than 0.3 mg/kg for Q2 or 0.4 mg/kg for Q4 to 
reach the 2.0 mg/kg maximum dose 
4 
The investigator should consult with the medical monitor to determine when and how to titrate up 
5 
Calculated doses below 15 mg will be adjusted to 15 mg. Calculated doses ≥15 mg will be rounded to the 
nearest 10 mg up to a maximum dose of 90 mg.  
 
The planned duration of treatment in this study will vary by region. The study consists of an 
individual dose Titration Period (16 weeks) a Treatment Period (48 weeks), and a Treatment 
Extension Period I (up to 96 weeks) for a total treatment duration of up to 160 weeks for 
subjects at study sites outside the US. For subjects at study sites outside the US the Week 160 
visit will be their EOS I visit. In the US, the study will also include Treatment Extension 
Period II (up to 56 weeks) until September 2018 for a maximum total treatment duration of 
up to 216 weeks. The duration of Treatment Extension Period II will vary for individual 
subjects and will be determined by the time from Week 160 through their EOS II visit. 
For each US subject, the study site will schedule an End of Study visit to take place before 
30 September 2018 with assessments performed as indicated on the Schedule of Events 
(Table 2.6). The end of study is defined as the date of the last protocol-specified procedures 
(including telephone contact) for the last subject in the study.     
7.4.5 
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 listed in Section 7.4.5.1. All concomitant medications taken during the study will be 

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recorded in the CRF with indication, dose information, and dates of administration.  
Any changes to concomitant medication will also be documented. 
7.4.5.1 
Prohibited Medications 
To be eligible for the study, subjects must agree to discontinue use of certain medications for 
the indicated timeframe prior to randomization. These medications will remain prohibited 
throughout the conduct of the study. Any subject who resumes or requires the use of any of 
these medications before the EOSI/II efficacy visit will be discontinued from the study. 
• Pharmacologic vitamin D metabolites or analogs (e.g. calcitriol, doxercalciferol, 
alfacalcidiol, and paricalcitol) (14 day washout required) 
• Oral phosphate (7 day washout required) 
• Adjunctive growth hormone (3 month washout required) 
• Aluminum hydroxide antacids (e.g. Maalox® and Mylanta®) or thiazide (7 day washout 
period), thiazide (7 day washout required)  
• Bisphosphonate therapy 
• Chronic use of systemic corticosteroids (short courses acceptable if indicated) 
• PTH suppressors (e.g. Sensipar®, cinacalcet, calcimimetics) 
• Any mAb therapy (other than study drug) 
NOTE: Oral phosphate treatment must be down-titrated slowly to avoid hypercalciuria. 
Vitamin D metabolites or analogs may be discontinued without titration.  
7.4.5.2 
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 during the 
30 days prior to Screening visit will be reviewed and recorded. 
7.4.6 
Treatment Compliance 
Trained personnel will administer study drug by SC injection at the investigational site or 
during HH visits as indicated in the Schedule of Events (Table 2.2, Table 2.3, Table 2.4, 
Table 2.5, and Table 2.6). During the Treatment Period and the Treatment Extension Period 
I, at the discretion of the investigator and after proper training by study personnel in SC 
injection technique, a subject’s parent or non-healthcare provider caregiver may administer 
KRN23 to the subject under the supervision of a HH nurse where local regulations permit 
and where logistically feasible. Parents or caregivers will be instructed to follow the 
directions provided in the Instructions for Use. Confirmation of dosing will be communicated 

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to the study site during scheduled biweekly telephone calls. Site personnel will record the 
related information about each administration of study drug on the CRF. 
During Treatment Extension Period II, study drug will be administered Q2 at home by a 
parent or other non-healthcare provider caregiver between site visits. The parents or 
caregivers of subjects in the US who have not been previously trained on study drug 
administration will be trained beginning at the Week 156 site visit. The parent/caregiver will 
administer the study drug to the subject under the supervision of a healthcare provider at that 
visit. The parent/caregiver will subsequently administer study drug to the subject under the 
supervision of a healthcare provider at the Week 158 HH visit and at the Week 160 site visit. 
Thereafter, study drug will be administered by a parent or caregiver at home, except for study 
weeks that correspond to a site visit when parent/caregiver administration is optional. 
The parent or caregiver must have demonstrated competency in administration of SC 
injections before unsupervised home administration will be permitted. For subjects whose 
parent/caregiver prefers not to administer study drug, study drug may be administered at the 
study site. Parents or caregivers will be instructed to follow the directions provided in the 
Instructions for Use. The study site will schedule a telephone call with the subject’s 
parent/caregiver every two weeks on the designated day to confirm drug administration has 
occurred and the confirmation will be recorded on the CRF.  If a subject does not receive a 
dose within 10 days of a scheduled dose for the Q2 regimen, that dose should be skipped and 
the next dose will be administered at the next scheduled Q2 dosing day. Empty vials will be 
returned to the study site as directed by study personnel for drug accountability records. 
7.5 
Study Procedures and Assessments 
7.5.1 
Schedule of Events 
The schedule of visits and assessments are provided in Table 2.2, Table 2.3, Table 2.4, 
Table 2.5, and Table 2.6.  HH visits may also be conducted at the investigational site 
depending on the preference of the subject and proximity of the subject to the clinic. Refer to 
the Study Reference Manual for additional details and a recommended schedule of specific 
assessments.  
Potential subjects will come in to the site for an initial screening visit and provide informed 
consent. All pre-expansion subjects will have x-rays obtained and read locally at Screening 
Visit 1 to determine if the subject meets the eligibility criteria. If radiographic evidence of 
active bone disease is not present, the subject will be considered a screen failure.  
For expansion subjects, knee x-rays collected at Screening Visit 1 will be read centrally for 
the determination of eligibility. Patients with radiographic evidence of active bone disease 
and expansion subjects with confirmed rickets severity eligibility by central read who also 
have a confirmed PHEX mutation (or a confirmed PHEX mutation in an appropriate directly 
related family member) can start the process of weaning from SOC therapy (Section 7.4.5.1) 
and return to the site within 2-4 weeks for Screening Visit 2 and the Baseline visit. 
Total FGF23 levels in serum will be determined for those subjects who do not have PHEX 
mutation confirmation (self or appropriate family member) available at study entry. 

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Patients who have radiographic evidence of bone disease, but do NOT have a confirmed 
PHEX mutation or an appropriate family member with a confirmed PHEX mutation (referred 
to as “sporadic” XLH cases) will wait until the FGF23 results are available to confirm the 
diagnosis of XLH before starting the process of weaning from SOC therapy. “Sporadic” 
patients with FGF23 levels < 30 pg/mL will also be considered a screen failure. 
Subjects who successfully pass the initial screening requirements will return to the site for 
Screening Visit 2 following discontinuation of SOC therapy: a minimum of 14 days after 
vitamin D metabolite treatment has been stopped and a minimum of 7 days after oral 
phosphate treatment has been stopped. Screening Visit 2 should be conducted 14 – 35 days 
following Screening Visit 1. The remaining screening assessments to confirm eligibility 
will be performed; Screening Visit 2 and Baseline visits can be conducted on consecutive 
days pending the availability of biochemical laboratory results, but may be conducted no 
more than 7 days apart. Motor function tests (6MWT, BOT-2, HHD) and questionnaires 
(POSNA-PODCI, SF-10) may be completed at either Screening Visit 2 or the Baseline visit, 
but must be assessed on the same day.  At Screening/Baseline, renal ultrasound, ECHO, 
ECG, and x-rays and may be performed ± 3 days of the clinic visit to accommodate 
scheduling availability. XtremeCT may be performed any time between Screening Visit 1 
and the Baseline visit and performed ± 10 days of the Week 64 or Early Termination visit if 
it occurs between Week 40 and Week 64; however, all Screening/Baseline assessments and 
inclusion/exclusion criteria based on local lab results must be satisfied prior to randomization 
and dosing. 
Through Week 158, subjects may be monitored between site visits through a series of HH 
visits depending on the preference of the subject and the proximity of the subject to the site.  
The visit window for HH visits is ± 3 days during the Titration Period and Treatment Period 
and ± 5 days during the Treatment Extension Period. During the Titration Period of the study 
(Weeks 0 – 16), subjects will return to the clinic for visits at 2 week intervals (± 3 days and 
no fewer than 8 days apart for the Q2 dose group and no fewer than 12 days apart for the Q4 
dose group).  During Weeks 16 – 40 of the Treatment Period, clinic visits will occur at 
4-week intervals (± 3 days). During Weeks 40-64, clinic visits will occur at approximately 
8-week intervals (± 3 days). During the Treatment Extension Period I (Weeks 64 up to 
Week160), clinic visits will occur at approximately 24-week intervals (±5 days).  
During Treatment Extension Period II, clinic visits will occur at approximately 12-week 
intervals (±5 days). Study sites will schedule biweekly telephone calls with the subject’s 
parent/caregiver to confirm administration of study drug, and for collection of adverse events 
and concomitant medication information. 
For subjects who discontinue prior to completing the study, every reasonable effort should be 
made to perform the Early Termination visit procedures within 4 weeks of discontinuation. 
X-rays and ECHO will not be performed at the Early Termination visit if post-treatment 
test(s) have been performed within 3 months of Early Termination. Similarly, the 6MWT, 
BOT-2, and HHD will not be performed at the Early Termination visit if post-treatment 
test(s) have been performed within 3 months of Early Termination or if Early Termination 

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occurs after Week 64. XtremeCT will only be performed at ET visits occurring between 
Week 40 and Week 64 (inclusive). The Week 40, Week 64, Week 88, Week 112, Week 136, 
Week 160/EOS I and, if applicable, EOS II, and Early Termination visits (if applicable) may 
be conducted over a period of 2 days due to the volume of testing; required blood draws may 
be split across the 2 days.  
A safety follow-up telephone call will occur at 5 weeks (+ 5 days) after the EOS (I or II) 
efficacy visit for a subject who has not continued KRN23 therapy under commercial use or 
another mechanism to collect information on any ongoing or new AEs, SAEs, or concomitant 
medications. An additional safety visit will occur 10 weeks ±1 week (approximately 5 times 
the elimination half-life) after the after the EOS (I or II) efficacy visit for a subject who has 
not continued KRN23 therapy under commercial use or another mechanism. Subjects who 
are unable to return to the clinic for the final safety visit will be given the option of having a 
final safety telephone call for the collection of any new or ongoing AEs, SAEs or 
concomitant medications. 
7.5.2 
Pharmacodynamic Measures 
KRN23 binds to and inhibits FGF23. As a phosphaturic hormone, FGF23 plays an important 
role as a specific regulator of serum phosphorus levels. Serum phosphorus is designated as 
the primary biomarker of KRN23 efficacy in this study. 
To assess the spectrum of KRN23 biological activity on phosphate homeostasis and markers 
of bone health, and optimize dose level and regimen, a panel of PD markers (Table 7.5.2.1) 
will be assessed as indicated in the Schedule of Events (Table 2.2, Table 2.3, Table 2.4, and 
Table 2.5 and Table 2.6). 
Table 7.5.2.1: Pharmacodynamic Measures 
Serum PD Markers* 
Urine PD Markers* 
Phosphate Reabsorption 
Bone 
Biomarkers† 
Phosphorus 
Phosphorus (24 hr) 
TmP/GFR 
P1NP 
1,25(OH)2D 
 
TRP 
CTx 
 
 
 
BALP 
 
 
 
ALP 
* Blood and urine to be collected after a minimum overnight fasting time of 4 hours and prior to drug 
administration (if applicable) per dosing regimen 
†Only ALP will be measured during the Treatment Extension Period. 
 
The local lab at the investigational site will be used to assess PD parameters required for 
study eligibility (except FGF23). Where possible, PD parameters (serum phosphorus 
and ALP) will be assessed as part of the standard clinical laboratory tests for safety 
(Section 7.5.5.8). 

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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, 
and is applicable in both fasting and non-fasting children (Alon et al. 1994). The duration of 
fasting time for all PD parameters will be recorded on the CRF. 
Refer to the Study Reference Manual for additional details on PD parameters. 
7.5.3 
Clinical Efficacy Measures 
Clinical efficacy measures will evaluate the effect of KRN23 on bone health and functional 
outcome in children with XLH. Measures of growth, healing of rickets in the wrists and 
knees, and correction of skeletal deformity in the legs (including tibial/femoral bowing) will 
provide an overall assessment of KRN23 treatment on bone health. Assessments of walking 
ability, muscle strength, gross motor function, and self-reported pain and disability will 
provide insight into the effect of KRN23 on clinical outcomes. XtremeCT of the forearm and 
tibia will be performed as an exploratory efficacy measure of bone mineral density/content at 
select sites. 
Refer to the Study Reference Manual for additional details on clinical efficacy measures. 
7.5.3.1 
Efficacy – Bone Health 
The primary goals of treatment in children with XLH are to correct or improve 
rickets/osteomalacia, radiographic abnormalities, and skeletal deformities (Carpenter et al. 
2011). Important endpoints to establish therapeutic efficacy of KRN23 include the evaluation 
of growth as measured by changes in height and limb length, and radiographic evaluation of 
the severity of rickets and lower limb deformities. Beginning at Week 64 and during 
Treatment Extension Periods I and II, radiographs will be evaluated for epiphyseal closure. 
Growth:  Short stature is one of the predominant features in growing children with XLH.  
Growth of the legs and trunk has been shown to be uncoupled in XLH and related to serum 
phosphate levels (Zivicnjak et al. 2011). Growth will be measured by changes in standing 
height (and percentiles) prior to and following treatment. Standing height measurements prior 
to treatment will be abstracted from medical records where available. At Screening Visit 1, 
standing height will be measured to confirm study eligibility. To assess growth during 
KRN23 treatment, standing height, sitting height, arm length, and leg length will be 
measured by a physical therapist at Baseline and Week 16, 24, 40, 56, 64 88, 112, 136, and 
160/EOS I; and, if applicable, every 12 weeks during Treatment Extension Period II, and at 
the EOS II (or Early Termination) visit.  
Severity of Rickets and Epiphyseal Abnormalities:  XLH causes rickets in the wrists 
and/or knees and other bone abnormalities. Bilateral anteroposterior (AP) knee radiographs 
will be taken at Screening Visit 1, and the Weeks 40, 64, 88, 160/EOS I, and, if applicable, at 
the EOS II study visits (or Early Termination if post-baseline radiographs have not been 
obtained within 3 months of termination). Bilateral posteroanterior (PA) hand/wrist 
radiographs will be taken at Screening Visit 1, and the Weeks 40, 64, 88, 160/EOS I, and, if 

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applicable, at the EOS II (or Early Termination) visits if post-baseline radiographs have not 
been obtained within 3 months of termination. For pre-expansion subjects, radiographs will 
be interpreted at the investigational site to determine eligibility; for expansion subjects, knee 
radiographs will read centrally for eligibility determination. The Screening Visit 1 
radiographs will also be treated as baseline data. Changes in the severity of rickets and 
epiphyseal (growth plate) abnormalities will be assessed by central readings using two 
methods.  
The RSS system is a 10-point radiographic scoring method that was developed to assess the 
severity of nutritional rickets in the wrists and knees based on the degree of metaphyseal 
fraying and cupping and the proportion of the growth plate affected (Thacher et al. 2000). 
With the RSS method, each radiograph is scored individually by a central rater who is 
blinded to subject number and radiograph sequence. As an additional blinding measure, and 
to provide context to the treatment data, at the Week 40 and Week 64 evaluation, the central 
rater will also score wrist and knee radiographs from a historical reference group consisting 
of children with a confirmed diagnosis of XLH with similar clinical characteristics to the 
cohort enrolled in this study.  
As a complementary analysis to the RSS rating, a disease-specific qualitative Radiograph 
Global Impression of Change (RGI-C) scoring system will be used. Pairs of wrist, knee and 
standing long leg images from treated subjects will be presented to a rater with the Screening 
image on the left and the later image (Week 40, 64, 88, 160/EOS I, and, if applicable, EOS II 
(or Early Termination)) on the right. Raters will be asked to assess change in rickets severity 
in the wrists and knees and extent of bowing in the legs using a 7-point ordinal RGI-C scale 
score ranging from -3 (very much worse, or severe worsening of rickets) to +3 (very much 
better, or complete or near complete healing of rickets). Ratings will be performed by 
3 independent pediatric radiologists who are blinded to subject number. Radiographs from 
KRN23-treated subjects may also be compared with radiographs from a historical reference 
group in a blinded fashion at the Week 40 and Week 64 analyses depending on the 
availability of data from a comparable group of subjects. The historical reference group 
would consist of radiographs of the wrists, knees and legs of children between the ages of 5 
and 12 years with a confirmed diagnosis of XLH and similar clinical characteristics to the 
subject population enrolled in this study. To keep the radiologists blinded to group 
(i.e., KRN23 treatment or historical reference group), X-ray pairs will be presented for 
review in random order and the radiologists will not be provided access to the protocol, 
patient identifiers, or information related to KRN23 or SOC treatment. 
Lower Extremity Deformity:  Clinical manifestations of XLH vary in severity, but 
patients most commonly present in childhood with genu varum or genu valgus deformities 
of the legs from prolonged weight bearing on softened bones. Progressive bowing, knock 
knees, and antero-medial rotational torsion of tibiae are the predominant skeletal features of 
XLH in growing children (Carpenter et al. 2011). To assess lower extremity deformity and/or 
trabeculation, as well as other disease-specific lower extremity abnormalities, standing long 
leg x-rays will be taken at Screening Visit 1, Week 64, 88, 160/EOS I, and, if applicable EOS 
II (or Early Termination) if post-baseline x-rays have not been obtained within 12 months. 

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Radiographs will be interpreted at the investigational site to determine eligibility; the 
Screening Visit 1 radiographs will also be treated as baseline data. Central readings of the 
standing long leg X-rays will be performed and ratings assigned using a disease-specific 
qualitative RGI-C scoring system. To further assess the severity of genu varum (bowing of 
the legs) and genu valgum (knock knees), the intercondylar distance (distance between the 
knees) and intermalleolar distance (distance between the ankles) will be obtained at 
Screening Visit 1, and Weeks 40, 64, 88, 160/EOS I, and, if applicable, EOS II, (or Early 
Termination) study visits. Beginning at Week 88 the measurement of intercondylar and 
intermalleolar distance will be performed using the standing long leg radiographs. 
The measurement will be made at EOS II (or early termination) only if standing long-leg 
x-rays have not been obtained within 12 months.  
Bone Mineral Density or Content:  XtremeCT (SCANCO Medical AG) is designed to 
perform high-resolution peripheral quantitative computed tomography studies for direct 
comparisons of density and structure characteristics over time. As an exploratory efficacy 
measure, XtremeCT of the forearm and tibia will be performed to assess bone mineral 
density or content at the cortical and trabecular compartment. XtremeCT will be performed at 
Baseline (Week 0) and Week 64 (or Early Termination if the ET visit is performed between 
Week 40 and Week 64). XtremeCT will be performed at select sites depending on scheduling 
and the availability of equipment. XtremeCT administration procedures will be standardized 
and results will be read locally by trained site personnel.  
7.5.3.2 
Efficacy – Clinical Outcomes: 
Gross motor impairment, including diminished walking ability, pain and muscle weakness 
are potential complications associated with XLH-related skeletal deformities. Endpoints to 
establish clinical outcomes associated with KRN23 treatment include walking ability, gross 
motor function and muscle strength. Functional disability, pain, and health-related quality of 
life will also be assessed using validated questionnaires. 
Walking Ability:  The Six Minute Walk Test (6MWT) will be administered at Screening 
Visit 1 (for practice), Baseline (Week 0), Weeks 16, 24, 40, 64, 88, 160/EOS I, and EOS II 
visit (if applicable) (or Early Termination). The 6MWT will not be performed at the EOS (or 
Early Termination) visit if post-baseline 6MWT has been obtained within 3 months of the 
visit. The 6MWT will be administered by a trained clinician in accordance with general 
principles set forth in the American Thoracic Society guidelines (ATS 2002). Subjects will 
be instructed to walk the length of a pre-measured course for six consecutive minutes. 
The total distance walked at the end of six minutes will be recorded in meters. The percent of 
predicted normal values will be calculated using published normative data based on age, 
gender, and height (Geiger et al. 2007).  

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Gross Motor Function:  The Bruininks-Oseretsky Test of Motor Proficiency – 2nd Edition 
(BOT-2) is a standardized, norm-referenced test of fine and gross motor skills in individuals 
4-21 years of age (Bruininks et al. 2005). Only the subtests for running speed/agility and 
strength will be administered. The BOT-2 will be assessed at Screening Visit 1 (for practice), 
Baseline (Week 0), Weeks 16, 24, 40, and 64 (or Early Termination if post-baseline BOT-2 
has not been obtained within 3 months of termination and Early Termination occurs at or 
before Week 64). The BOT-2 will not be performed during Treatment Extension Periods I or 
II. 
Muscle Strength:  Hand-held dynamometry (HHD) will be used to assess muscle strength.   
HHD testing will be administered at Screening Visit 1 (for practice), Baseline (Week 0), 
Weeks 16, 24, 40, and 64 (or Early Termination if post-baseline HHD has not been obtained 
within 3 months of termination and Early Termination occurs at or before Week 64). HHD 
testing will not be performed during Treatment Extension Periods I or II. Formal training will 
be conducted with the trained clinicians administering the HHD testing to standardize 
technique and minimize variability.  The maximum voluntary isometric contraction (MVIC) 
against a dynamometer will be used to measure bilateral strength in the following muscle 
groups:  knee flexors, knee extensors, hip flexors, hip extensors and hip abductors, as well as 
gross grip strength.   
Functional Disability and Pain:  The Pediatric Outcomes Data Collection Instrument 
(PODCI) was developed by the Pediatric Orthopedic Society of North America (POSNA) 
(Daltroy et al. 1998) will be used to assess functional disability. The POSNA-PODCI was 
developed to measure the functional health of pediatric and adolescent patients with a variety 
of musculoskeletal disorders. The instrument is designed to assess overall health, pain, and 
ability to participate in normal daily activities, as well as in more vigorous activities 
associated with young people. The questionnaire will be completed by the subject’s 
caregiver. If possible, the same individual caregiver should complete the assessment 
throughout the study for consistency. The POSNA-PODCI will be administered at Baseline 
(Week 0), Weeks 24, 40, 64, 88, and 160/EOS I; and, if applicable, every 12 weeks during 
Treatment Extension Period II, and at the EOS II (or Early Termination) visit.   
Health-Related Quality of Life:  Individuals with XLH are affected by skeletal 
abnormalities which may impact their physical and mental health status. The SF-10 for 
Children Health Survey (SF-10) is a caregiver-completed questionnaire designed to 
assess physical and psychosocial health-related quality of life in healthy and ill children 
(Saris-Baglama et al. 2006). The 10 items were adapted from the Child Health Questionnaire 
and utilize a 4-week recall period.  Responses are used to generate 2 component summary 
scores: physical summary score (PHS-10) and psychosocial summary score (PSS-10). 
Higher global scores are associated with better quality of life. The SF-10 will be 
administered during the Baseline visit (Week 0), Weeks 24, 40, 64, 88, and 160/EOS I; and, 
if applicable, every 12 weeks during Treatment Extension Period II and at the EOS II 
(or Early Termination) visit. Every attempt should be made to ensure that the responder 
completing the first administration completes subsequent administrations to minimize 
variability.  

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7.5.4 
Drug Concentration Measurements 
To assess KRN23 concentration and possible accumulation, serum pre-dose levels will be 
evaluated as a PK parameter in this study. A pre-dose blood sample will be obtained at 
Baseline (Week 0), during the Titration Phase (Weeks 1, 2, 4, 12, 14, and 16), during the 
stable dose Treatment Period (Weeks 24, 36, 38, 40, 56, and 64), during the Treatment 
Extension Period at Weeks 88, 112, 136, and 160/EOS I, and, if applicable, at the EOS II 
visit. At Week 1, the serum KRN23 sample will only be taken for subjects enrolled in 
Cohorts 2 and 3. Week 24 pre-dose serum KRN23 concentration will be retrospectively 
tested on subjects’ previously collected samples, if available. For each sample collection, the 
time elapsed since last study drug administration will be recorded on the CRF. 
7.5.5 
Safety Measures & General Assessments 
General assessments include Tanner staging for breast and testicular development, medical 
history and demographics, and PHEX mutation analysis. 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, 
additional genetic testing will be performed to assess mutations in other genes associated 
with phenotypes overlapping with XLH. 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). The investigator will be provided the genetic testing results and 
will determine when and whether the information should be shared with 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, interval history and physical examination, GFR, clinical laboratory evaluations 
(including additional KRN23/XLH biochemical parameters of interest), concomitant 
medications, and ECG.  Ectopic mineralization safety assessments include renal ultrasound 
and ECHO; serum calcium, phosphorus and iPTH, and urinary calcium and creatinine. 
The development of anti-KRN23 antibodies and dose limiting toxicities (DLTs) will also be 
assessed. Refer to the Study Reference Manual for additional details on safety assessments. 
7.5.5.1 
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 an assessment of symptoms and conditions associated with XLH and SOC treatment. 
Subjects must be willing to provide access to prior medical records for the collection of 
historical growth, 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.  

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XLH treatment history and relevant concomitant medications will be recorded (start date, 
stop date, dose, dose regimen). Treatments may include calcitriol and oral phosphate, and 
growth hormone 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. 
7.5.5.2 
Interval History 
Each interval history is intended to record any signs, symptoms, or events experienced by the 
subject that are not related to study procedure(s) performed at prior study visits or study drug.  
Interval history may include exacerbation or improvement in existing medical conditions 
(including clinical manifestations of XLH) that might interfere with study participation, 
safety, and/or positively or negatively impact performance of functional assessments.  
Interval history may identify under-reported AEs, and will be collected at the study visits 
indicated in the Schedule of Events (Table 2.2, Table 2.3, Table 2.4, Table 2.5, and 
Table 2.6). 
7.5.5.3 
Vital Signs and Weight 
Vital signs will include seated systolic blood pressure and diastolic blood pressure measured 
in millimeters of mercury (mm Hg), heart rate in beats per minute, respiration rate in breaths 
per minute, and temperature in degrees Celsius (°C). Vital signs measurements will be 
performed before any additional assessments are completed and after the subject has rested 
for 5 minutes. A second BP measurement should be obtained at the end of the study visit 
after all procedures have been performed. All vital sign measurements will be performed at 
every site visit (except Screening Visit 2, and including Early Termination or the Safety 
Follow Up visit, if applicable) and at HH visits through Week 62. At HH visits between 
Weeks 66-160, vital signs will be measured every 4 weeks, beginning at Week 68. 
During Treatment Extension Period II (if applicable), vital signs will be measured at site 
visits only. 
A cohort of subjects who had elevated post-baseline BP measurement (≥ 95th percentile for 
height, age, and sex) on 3 or more site visits were asked to do home monitoring of blood 
pressure for a period of time. The measurements will be conducted by a subject’s parents or 
guardians in between study visits. An automated blood pressure recording device was issued 
to parents or guardians with instructions to measure their child’s blood pressure twice per 
day, three days per week for one month; record the date, time, and value of the 
measurements, and return the record to the site at the next study visit.  
At each site visit (except Screening Visit 2 and the Safety Follow Up visit, if applicable), 
weight (in kilograms) will be obtained using a scale. Weight measurements will be used to 
calculate the appropriate KRN23 dose to be administered on a mg/kg basis. Weight will not 
be collected at HH visits. 

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7.5.5.4 
Physical Examination 
Complete physical examinations will be performed at both Screening visits and the Week 4, 
8, 14, 20, 32, 40, 46, 56, 64, 88, 112, 136, and 160/EOS I visits; and, if applicable, every 
12 weeks during Treatment Extension Period II, at the EOS II (or Early Termination) visit, 
and at the Safety Follow Up visit. 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. 
7.5.5.5 
Renal Ultrasound and Glomerular Filtration Rate 
Renal ultrasounds will be conducted at Screening Visit 1 and Weeks 16, 40, 64, 88, 112, 136, 
160/EOS I, and, if applicable, at the EOS II (or Early Termination) visit.  Ultrasonographic 
findings of nephrocalcinosis will be graded on a 5-point scale (Verge et al. 1991). 
The ultrasound will be interpreted by qualified personnel at the investigational site for 
purposes of inclusion criteria. Results obtained at Screening Visit 1 will serve as baseline 
data.  However, central readings will be performed for all post-treatment renal ultrasounds to 
evaluate changes in calcifications and all other renal abnormalities from baseline 
(i.e. screening assessment).  
The glomerular filtration rate (GFR) will be calculated at Baseline, Weeks 16, 40, 64, 88, 
112, 136, and 160/EOS I; and, if applicable, every 24 weeks during Treatment Extension 
Period II; and at the EOS II (or Early Termination) visit. GFR will be calculated by using the 
Bedside Schwartz equation (Schwartz et al. 2009). 
7.5.5.6 
Echocardiogram 
ECHO will be performed at Baseline and Weeks 16, 40, 64, 88, 112, 136, 160/EOS I, and, if 
applicable, at the EOS II (or Early Termination) visit if not performed within 3 months of 
termination. 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 read centrally by trained personnel who 
are blinded to the dose and dose regimen of the subjects.  
7.5.5.7 
Electrocardiogram 
A standardized 12-lead ECG will measure PR, QRS, QT, and QTc at Baseline, Weeks 16, 
40, 64, 88, 112, 136, 160/EOS I, and, if applicable, at the EOS II (or Early Termination) visit. 
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 at an imaging facility. The ECG results will be assessed for 
any clinically significant abnormality or relevant changes from baseline. 

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7.5.5.8 
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. Certain analytes (i.e. ALP and serum 
phosphorus) in the routine Chem-20 panel are also designated as PD/efficacy parameters in 
this study (Section 7.5.2). KRN23/XLH biochemical parameters of interest include serum 
25(OH)D, amylase, lipase, total calcium, creatinine, FGF23 (total and unbound), iPTH; and 
urinary calcium and creatinine. Reflexive testing for amylase isoenzymes will be performed 
if serum amylase levels are elevated by ≥1.5 times the upper limit of the reference range 
(ULRR). 
FGF23 concentrations will be measured using a validated electrochemiluminescent assay 
(ECLA) developed by the Sponsor’s development partner, KHK, and transferred to a contract 
laboratory.  
Blood and urine samples will be collected at screening, baseline, and regular intervals 
throughout the study as indicated in the Schedule of Events (Table 2.2, Table 2.3, Table 2.4 
and Table 2.5, and Table 2.6). The local lab at the investigational site will be used to assess 
safety parameters required for study eligibility (except FGF23). Fasting for a minimum of 
4 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, 
Section 7.5.2) will also be obtained from 24-hour urine samples.   
Clinical laboratory parameters to be assessed for safety are provided in Table 7.5.5.8.1. 
See Study Reference Manual for details on sample collection and processing. 

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Table 7.5.5.8.1: 
Clinical Laboratory Assessments for Safety 
Chemistry 
Hematology 
Urinalysis 
25(OH) D 
Hematocrit 
Appearance 
Alanine aminotransferase (ALT) 
Hemoglobin 
Color 
Alkaline phosphatase (ALP)* 
Platelet count 
pH 
Amylase 
Red blood cell (RBC) count 
Specific gravity 
Amylase isoenzymes† 
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) 
 
24-hour Urine 
Chloride 
 
Calcium 
Carbon dioxide (CO2) 
 
Calcium/creatinine ratio 
Cholesterol (total) 
 
Creatinine 
Creatinine 
 
Phosphorus/creatinine 
ratio 
Gamma-glutamyl transpeptidase 
(GGT) 
 
Phosphorus 
Glucose 
 
 
FGF23 (total and unbound) 
 
 
Intact parathyroid hormone (iPTH) 
 
2-hour Urine 
Lactate deyhydrogenase (LDH) 
 
Calcium 
Lipase 
 
Phosphorus  
Phosphorus* 
 
Creatinine 
Potassium 
 
Pregnancy Test (if 
applicable) 
Protein (albumin and total) 
 
 
Sodium 
 
 
Uric acid 
 
 
* Also designated as PD/efficacy parameter 
† Will be assessed reflexively if amylase levels are ≥1.5 ULRR 
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. 
7.5.5.9 
Anti-KRN23 Antibody Screening 
To determine the immunogenicity profile of KRN23 in children with XLH, blood samples 
will be obtained for analysis of anti-KRN23 antibodies (ADA) at the Baseline (Week 0), 
Week 16, 24, 36, 56, 64, 88, 112, 136, 160/EOS I, and, if applicable, EOS II (or Early 
Termination) visits. The concentration of anti-KRN23 antibodies in human serum will be 
determined using a validated sandwich ELISA and a 2-tiered strategy: screening assay and 
specificity confirmation assay. 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. 

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7.5.5.10 Pregnancy Testing 
Female subjects who have reached menarche prior to or during the study will have urine 
pregnancy tests at screening, baseline, and approximately every 4 to 6 weeks thereafter.  
A serum pregnancy test will be performed in the event of a positive or equivocal urine 
pregnancy test result. Female subjects with a positive serum pregnancy test at Screening will 
not be enrolled in the study. Female subjects with a positive serum pregnancy test at Baseline 
or any subsequent visit will be discontinued from the study. Females who have not 
experienced menarche will not undergo pregnancy testing. During Treatment Extension 
Period II, female subjects who have reached menarche will perform a urine pregnancy test at 
clinic visits every 12 weeks. 
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 12 weeks 
after stopping the study drug. 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 12 weeks after stopping the study drug. 
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)  
7.5.5.11 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. Female subjects who, at any time during the study, have 
a positive serum pregnancy test will be discontinued from the study. The investigator must 
make every effort to follow the pregnancy of either subject or partner through resolution of 
the pregnancy (delivery or termination) and report the resolution to Ultragenyx or its 
designee. 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.  

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Refer to the Study Reference Manual for details on the reporting procedures to follow in the 
event of pregnancy. 
7.5.5.12 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, beginning at the initial Screening visit and 
continuing through the final safety follow up visit.  Concomitant medications and therapies 
will also be assessed during HH visits during Weeks 18-158. Between study site visits during 
Treatment Extension Period II (Week 162 to End of Study), concomitant medications and 
therapies will be reviewed by telephone call from the study site every 2 weeks and recorded 
in the subject’s CRF. Concomitant medications and therapies will also be collected during 
the safety follow-up telephone call (as defined in Section 7.5.1) and recorded on the subject’s 
CRF. 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 AFOs, braces, cane, crutches, walker, wheelchair etc.) utilized during the 30 days 
prior to Screening will also be reviewed and recorded. At each subsequent visit or biweekly 
telephone call, change in medications and therapies since the previous visit will be recorded.  
A discussion of concomitant medications and therapies is provided in Section 7.4.5.  
7.5.5.13 Dose Limiting Toxicity 
A DLT is defined as the occurrence of any of the following: 
• Unexpected SAEs occurring during treatment considered to be either definitely, probably, 
or possibly related to the investigational product 
• A confirmed serum phosphorus level of ≥ 6.5 mg/dL (defined as hyperphosphatemia) at 
any time after dosing 
If a subject experiences a DLT, the planned dosing for that subject will be evaluated by the 
Investigator and Medical Monitor. The outcome of this investigation will determine the 
subjects’ continuation or withdrawal from the study. 
7.5.5.14 Adverse Events 
All AEs will be recorded from the time the subject signs the informed consent through the 
final safety follow-up telephone call or safety visit (as defined in Section 7.5.1). 
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, at HH visits during Weeks 18-158, and during biweekly telephone calls during 
Treatment Extension Period II. 

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Clinically significant changes from baseline in physical examination findings, vital signs, 
clinical laboratory parameters, renal ultrasounds, GFR, ECHO and ECGs will be recorded as 
AEs or SAEs, if appropriate.   
7.5.6 
Appropriateness of Measures 
The assessments and timing of assessments used in this study, and the variables analyzed, 
are typical of those used to evaluate hypophosphatemia, renal reabsorption, vitamin D 
metabolism, and skeletal defects in subjects with XLH. The primary goals of treatment in 
pediatric XLH patients are to improve growth and correct or minimize rickets/osteomalacia, 
radiographic abnormalities, and skeletal deformities (Carpenter et al. 2011). KRN23 binds to 
and inhibits FGF23; total and unbound FGF23 levels will be monitored throughout the study. 
FGF23 plays an important role in phosphate homeostasis, as such, serum phosphorus levels 
will be the primary PD marker of KRN23 efficacy in this study. 
Additional assessments are included both as PD and safety indicators of potential secondary 
complications associated with treatment, including serum calcium, 1,25(OH)2D and urinary 
calcium and creatinine, as hypercalciuria may occur in the absence of hypercalcemia.  
Intact PTH (iPTH) levels and TmP/GFR are routinely measured as a part of SOC in XLH, 
as secondary hyperparathyroidism is common. Biomarkers of bone formation (P1NP, ALP, 
BALP) and resorption (CTx) may provide an indication of treatment effect. The relatively 
extensive panel of biomarkers has been included in this Phase 2 study to provide the most 
information on relevant clinical laboratory parameters for endpoint confirmation and 
analysis. Where possible, timing of assessments has been coordinated with standard safety 
laboratory tests to minimize risk and discomfort and avoid unnecessary duplication of 
testing. 
Radiographs are routinely recommended during the initial evaluation of XLH, and to 
evaluate healing of rickets and skeletal deformities. Performance measures such as the 
6MWT and BOT-2 have been successfully used in other clinical development programs.  
Additional age-appropriate, patient-reported outcomes were included to assess functional 
disability, pain, and health-related quality of life (i.e. POSNA-PODCI and SF-10).  
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, concomitant medications, and other routine clinical and laboratory procedures.  
Routine, non-invasive procedures will provide relevant indicators of possible renal and 
cardiac risk; renal ultrasounds and ECHO will be used to detect any calcinosis in susceptible 
organs. Since elevated free FGF23 has been associated with LVH in patients with chronic 
kidney disease, ECHO and ECGs will examine the potential risk in XLH subjects.  
The study will be conducted in a pediatric population, as such additional safety measures 
including HH visits and a DMC have been incorporated into the study design.  Where 
possible, measures to minimize pain and distress to the subject have been considered for this 
study protocol. However, a series of frequent blood draws are required during the Titration 

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Period to ensure subject safety and determine appropriate KRN23 dosing. These assessments 
are imperative for safety since KRN23 has not previously been tested in children, and the PK 
of the Q2 regimen has not been established. Should a subject complete all assessments at all 
study visits, the maximum blood volume obtained throughout the 226-week maximum total 
study duration is estimated to be approximately 350 mL. Any unscheduled blood draws 
would be in addition to this volume. 
7.6 
Statistical Methods and Determination of Sample Size 
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. The procedures for handling missing, spurious, or unused data, 
and the detailed method for analyses will be presented in the Statistical Analysis Plan (SAP); 
the information below is intended as a guide to planned analyses.   
7.6.1 
Determination of Sample Size 
A sample size of at least 10 per cohort will provide at least 90% power to detect a serum 
phosphorus increase from baseline of at least 0.8 mg/dL, assuming a standard deviation of 
0.7 mg/dL or smaller, at the 2-sided level of significance of 0.05. In addition, a total sample 
size of 50 subjects (25 subjects per monthly [Q4] or Q2 week regimen) will provide at least 
90% power to detect a 0.5 mg/dL difference between the two dosing regimens assuming a 
standard deviation of 0.4 and 2-sided level of significance of 0.05. 
Phosphate and mineral control are adequately powered based on the clinical experience to 
date with KRN23. The degree of powering for bone health will depend on the degree of 
effect expected which is not known. However, powering for adequate phosphate control 
should provide the potential for improved bone health based on prior experience with oral 
phosphate replacement therapy (Carpenter et al. 2011). 
In addition, for the RSS endpoint, the expected sample size of 50 subjects will provide at 
least 90% power of rejecting the hypothesis of no change from baseline in knee total score 
when the true mean change is 0.5 with a standard deviation of 0.5, at the two-sided 0.05 level 
of significance. 
7.6.2 
Analysis Populations 
7.6.2.1 
Efficacy Analysis Set 
The Intent to Treat (ITT) population will consist of all subjects who receive at least one dose 
of study therapy and have at least one pre- and post- study drug measurement. 
7.6.2.2 
Safety Analysis Set 
The safety analysis set will consist of all subjects who receive at least one dose of study 
therapy. 

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7.6.2.3 
Pharmacokinetic and Pharmacodynamic Analysis Set 
The analyses sets will consist of all subjects who receive at least one dose of therapy and 
have evaluable plasma data. 
7.6.3 
Principles 
Descriptive statistics will be used to summarize the data. For continuous variables, the mean, 
the standard error, median, minimum, and maximum will be provided. For discrete data, the 
frequency and percent distributions will be provided. Statistical tests will use 2-sided 
alpha =0.05 significance level. Two-sided 95% confidence intervals will also be presented. 
7.6.3.1 
Subject Accountability 
The number of subjects who received study treatment will be summarized. The reason for 
study treatment discontinuation and study discontinuation will be summarized as well.  
7.6.3.2 
Demographic and Baseline Characteristics 
Demographics (age, gender, and race) and other baseline disease characteristics will be 
summarized using descriptive statistics for the Safety Analysis Set. 
7.6.3.3 
Baseline 
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.  
7.6.3.4 
Dose and Dose Regimen Evaluation  
At the end of the Titration Period, the population of 50 subjects will consist of essentially 
two groups of 25 subjects, each with individually optimized dosing of KRN23 at either a Q4 
week or Q2 week frequency. Analyses of safety and available PD and efficacy data are 
planned at the end of the Titration Period (Week 16) and at Week 24 for pre-expansion 
subjects. Further analyses in the pre-expansion group alone and for the overall population are 
planned at Week 40 and at Week 64 at the end of the Treatment Period to compare treatment 
outcomes to baseline (pre-dose). Analyses of long-term efficacy and safety will be conducted 
during and at the completion of the Treatment Extension Period (Weeks 64-160).  
Details on planned analysis of dose and dose regimen will be provided in the SAP. 

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7.6.3.5 
Pharmacodynamic Parameters 
PD parameters will be summarized at baseline and at each time point. Additionally, the 
maximum and minimum observed post-baseline values will be summarized along with the 
change from baseline to the maximum observed value, minimum observed value, and last 
observed value. 
7.6.3.6 
Clinical Efficacy Endpoints 
Efficacy parameters will be summarized at baseline and at each observed time that are 
collected. The following endpoints will be examined: 
• Healing of rickets as measured by bilateral PA hand/wrist and AP knee radiographs 
scored with the 10-point RSS. RSS total score (max = 10 points) as well as scores for the 
knees (max = 6 points) and wrists (max = 4 points) will be determined. Subgroup 
analyses will be conducted based on baseline rickets severity, including a subgroup 
analysis of subjects with an RSS score of ≥1.5 points at the knee.  
• Healing of rickets in the wrists and knees as measured by an XLH-specific RGI-C scale. 
• Correction of lower limb bowing and deformities as measured by standing long leg 
radiographs scored with an XLH-specific RGI-C scale and measures of intercondylar and 
intermalleolar distance 
• Increased growth as measured by the change in standing height, sitting height, arm 
length, and leg length and changes in standing height growth percentiles post-treatment 
as compared to the pre-treatment period (using historical growth data for standing height 
where available) 
• Improved mineralization and increased cortical thickness in the forearm and lower leg as 
measured by XtremeCT evaluation of the forearm and tibia (where evaluable) 
• Improved walking ability as measured by change in the distance walked on the 6MWT in 
meters and percent predicted normal values and change in EEI 
• Improved gross motor function as measured by change in BOT-2 running speed/agility 
and strength subtest scores (raw, scaled, and normative scores) 
• Increased muscle strength as measured by changes in raw and % predicted normal scores 
for bilateral gross grip, knee flexors/extensors, hip flexors/extensors and hip abductors 
assessed by HHD 
• Reduction in functional disability and pain as measure by changes in POSNA global and 
subscale scores 
• Improved health-related quality of life as measured by changes in the SF-10 PHS-10 
score 

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7.6.4 
Pharmacodynamic and Efficacy Analyses 
7.6.4.1 
Week 16 Analysis 
PD and safety data will be summarized for each cohort and each dose regimen within a 
cohort after pre-expansion subjects have completed the Titration Period (Week 16).  
7.6.4.2 
Week 24 Analysis 
An analysis will be conducted to review the PK/PD, dose response, differences in the PD 
response between the two dose regimens (Q2 and Q4)) and to evaluate initial efficacy and 
overall safety. Data will be summarized for each cohort and each dose regimen within a 
cohort after pre-expansion subjects have completed the Week 24. 
7.6.4.3 
Week 40 Analysis 
An analysis will be performed when all pre-expansion subjects have completed the Week 40 
visit. The analysis will be repeated for the entire study population when expansion subjects 
have completed the Week 40 visit. All efficacy analyses will be performed on the Efficacy 
Analysis Set. All PD analyses will be performed on the PD Analysis Set.  
For each cohort and each dosing regimen, all the PD and efficacy parameters will be 
analyzed using the data collected during the Treatment Period. These will be the primary 
analyses. Any changes from baseline will utilize the values at Week 0, the values prior to 
treatment with study drug. The treatment comparison will be performed using the Wilcoxon 
rank-sum on appropriate endpoints. 
ANCOVA models of change from baseline (Week 0) to Week 40 endpoints will be used to 
estimate the treatment effect and will include dosing regimen and baseline measurement as 
covariate. The ANCOVA will present least squares (LS) mean estimates, 2-sided 95% 
confidence intervals for mean changes and p-values between dosing regimen comparisons. 
The effect of other covariates such as age and gender will also be examined. 
Generalized Estimation Equations (GEE) Model will be used to fit observed measurements at 
all scheduled visits. The model will include the dosing regimen and baseline as covariates. 
To model the covariance structure within subjects, the exchangeable covariance matrix will 
be selected initially. If the exchangeable covariance structure leads to non-convergence, 
Quasi-Likelihood Information Criterion (QIC) will be used to select the best covariance 
structure. 
The association between efficacy and PD endpoints will be performed using the change from 
baseline of the PD parameters at Week 40 as covariate in the ANCOVA or repeated measure 
models. In addition, the Pearson correlation will be calculated. 

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7.6.4.4 
Week 64 Analysis 
Similar analyses will be performed for the Week 64 data as described in Section 7.6.4.3. 
7.6.4.5 
Treatment Extension Period Analyses 
Additional analyses to evaluate long-term efficacy will be performed at the completion of 
Treatment Extension Period I for the overall population as described in Section 7.6.4.2. 
Some assessments will not be continued beyond the Treatment Period of the study and 
therefore will not be analyzed in the either of the Treatment Extension Periods.  
A final analysis will be performed at the end of the study. Some assessments will not be 
continued beyond the Treatment Period or Treatment Extension Period I of the study and 
therefore will not be analyzed in Treatment Extension Period II. 
7.6.5 
Pharmacokinetic Analyses 
Summary statistics will be generated for pre-dose PK parameters for each cohort and dose 
regimen. 
7.6.6 
Safety Analyses 
Analysis of safety data will be conducted at Weeks 16, 24, 40, 64, at the completion of the 
Treatment Extension Period I, and at the end of the study. Additional safety analyses may be 
conducted as needed. Safety of each cohort and each dose regimen within a cohort will be 
assessed. 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, interval history and physical examinations, renal ultrasound, GFR, ECHO, and 
ECG findings; chemistry, hematology, and urinalysis; and anti-KRN23 antibody testing. 
Safety data will be periodically reviewed by the DMC through the end of the Treatment 
Period (Week 64). During Treatment Extension Periods I and II, safety data will be reviewed 
by the SSRT on an ongoing basis (Section 8.5.5.1). 
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 (PT), 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 by treatment group. The numbers (frequency) and incidence rates of AEs and 
SAEs will be summarized during exposure to KRN23 throughout the study including the 
continuation period. 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 

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laboratory data. Descriptive statistics will be calculated for each laboratory analyte at 
baseline and at each scheduled time point. Changes from baseline results will be presented in 
pre- versus post-treatment cross tabulations (with classes for below, within, and above 
normal ranges). A listing of subjects with any markedly abnormal laboratory results will be 
provided. 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. 
The SAP will provide additional details on the planned safety analyses. 
7.6.7 
Data Monitoring Committee 
An independent DMC that includes members with expertise in metabolic bone disease and 
the conduct of clinical trials in children will act in an advisory capacity to monitor subject 
safety on a routine basis through the end of the Treatment Period (Week 64). The DMC will 
also meet for approximately quarterly data reviews. During Treatment Extension Periods I 
and II, safety data will be reviewed by the SSRT on an ongoing basis (Section 8.5.5.1). 

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8 STUDY CONDUCT 
8.1 
Ethics 
8.1.1 
Institutional Review Board or Ethics Committee 
The IRB/Ethics Committee (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 
to each subject that the subject is completely free to refuse to enter the study or to withdraw 

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from it at any time. Subjects under the age of 18 years (or 16 years, depending on the region) 
will provide written assent (if possible), and his/her legally authorized representative (parent 
or legal guardian) will provide written informed consent for such subjects. 
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. 
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. In the home setting, study drug should be handled as directed by study personnel.  

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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. During Treatment Extension Period II, subject caregivers 
will retain empty vials and return them to the study site as directed by study personnel for 
drug accountability. 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 

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e-mail, telephone, facsimile, and/or mail. The investigator and all other site personnel agree 
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 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.  
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. 

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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 
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 “Not Related” events: 
• Definitely Not Related:  This category applies to an AE that is clearly not related to the 
investigational agent/procedure, beyond a reasonable doubt. That is, another cause of the 
event is most plausible; and/or a clinically plausible temporal sequence is inconsistent 
with the onset of the event and the exposure to study drug and/or a causal relationship is 
considered biologically implausible. 
• Probably Not Related:  This category applied to an AE that is doubtfully related to the 
investigational agent/procedure. That is, an alternative explanation is more likely, 
e.g., concomitant drug(s), concomitant disease(s), known consequences of the disease 
under investigation or the relationship in time suggest that a causal relationship is 
unlikely. 
Categories of attributions for “Related” events: 
• Possibly Related: This category applies to an AE that may be related to the 
investigational agent/procedure. That is the AE follows a reasonable temporal sequence 
from administration of the study drug and that follows a known or expected response 
pattern to the suspected study drug, but that could readily have been produced by a 
number of other factors. 
• Probably Related: This category applies to an AE that is likely related to the 
investigational agent/procedure. That is, the AE has a temporal relationship to the 
administration of the investigational agent(s) or research intervention, follows a known 
or suspected pattern of response, and is strongly associated with study drug exposure. 
An alternative explanation is less likely, e.g., concomitant drugs(s), concomitant 
medication(s).  
• Definitely Related: This category applies to an AE that is clearly related to the 
investigational agent/procedure. That is, the AE is listed as a possible adverse reaction 
and cannot be reasonably explained by an alternative explanation, e.g., concomitant 
drug(s), concomitant disease(s), known consequences of the disease under investigation 

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or the relationship in time is very suggestive (e.g., it is confirmed by dechallenge and 
rechallenge). 
For the purposes of reporting to regulatory agencies, AEs deemed as Definitely, Probably or 
Possibly Related will be considered Related and those deemed Definitely Not or Probably 
Not 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.  
All AEs will be collected from the time the subject signs informed consent through the final 
safety follow-up telephone call or safety visit (as defined in Section 7.5.1). 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 telephone call or safety visit (as defined in 
Section 7.5.1) should have a comment in the source document by the Investigator that 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 
Ultragenyx or its designee must be notified of the occurrence of any SAE that occurs during 
the reporting period within 24 hours of the Investigator, designee, or site personnel’s 
knowledge of the event. SAEs will be reported by completing and submitting SAE report 
forms to Ultragenyx or designee.   
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.  
All deaths, regardless of causality, occurring from signing of the informed consent until the 
final safety follow-up telephone call or safety visit (as defined in Section 7.5.1) are to be 
reported as SAEs to Ultragenyx or its designee within 24 hours of knowledge.   
8.5.4.3 
Pregnancy Reports 
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 

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known. Pregnancy associated SAEs will be processed and submitted, as necessary, as per the 
suspected unexpected serious adverse reaction (SUSAR) reporting process indicated in 
Section 8.5.5.2. 
8.5.5 
Communication Plan 
8.5.5.1 
Review of Safety Data 
The Ultragenyx SSRT, Medical Monitor and investigator(s) will actively review safety data 
during the course of the study. The SSRT and Medical Monitor will review safety data and a 
meeting will be convened after the first four (4) subjects in the first cohort have been treated 
for four (4) weeks. This safety data review will be completed prior to a decision to initiate 
enrollment of the second cohort. As an added precautionary measure, the IWRS will be 
placed on hold to ensure that subjects cannot be enrolled into cohort 2. The Ultragenyx 
Medical Monitor will authorize in writing when enrollment to the second cohort may start. 
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 safety analysis of cohort 
and/or 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 on a routine 
basis through the end of the Treatment Period (Week 64). The DMC may meet on an 
approximately quarterly 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. 
8.5.5.2 
Adverse Drug Reaction Reporting 
Ultragenyx or its designee will submit SUSARs to appropriate Regulatory Authorities 
(including Competent Authorities in all Member States concerned), Ethics Committees, and 

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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 telephone call or safety visit (as defined in Section 7.5.1). 
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. 
8.5.6 
Urgent Safety Measures 
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 
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 
measures is the period from the signing of the ICF through the final safety follow-up 
telephone call or safety visit (as defined in Section 7.5.1).  Investigators are required to report 
any urgent safety measures to Ultragenyx within 24 hours. 

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