A Phase 2 Open-Label Trial to Assess the Efficacy and Safety of KRN23, an Antibody to FGF23, in Subjects With Tumor-Induced Osteomalacia (TIO) or Epidermal Nevus Syndrome (ENS)-Associated Osteomalacia
Phase: PHASE2
Conditions: Tumor Induced Osteomalacia (TIO), Epidermal Nevus Syndrome (ENS)
Sponsor: Kyowa Kirin, Inc.

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PPD

Protocol Number: UX023T-CL201 
Amendment 1 
21 January 2015 
 
 
 
Proprietary and Confidential 
Page 2 of 67 
CLINICAL STUDY PROTOCOL AMENDMENT 
SUMMARY OF CHANGES AND RATIONALE 
UX023T-CL201 Amendment 1 
21 January 2015 
 
Protocol UX023T-CL201 (dated 29 August 2014) has been modified by Amendment 1 to incorporate 
feedback provided by the US Food and Drug Administration (FDA) and investigational study sites, 
and to clarify details/schedule of procedures to be conducted in the study. The protocol changes are 
summarized below: 
1. Study Sites: The number of study sites has been increased from a single site to multiple 
sites. 
Rationale: Due to the rare nature of TIO/ENS, additional sites may be necessary in order to 
identify enough subjects to fully enroll the study.  
2. Schedule of Events: Updates have been made to the frequency or timing of certain 
assessments as detailed in Table 2.1 and Table 2.2 (Schedule of Events). In addition, the first 
telephone call was changed to a home health visit at Study Week 1 and a new home health 
visit (HHV10.1) was added at Study Week 21.  
Rationale: Changes have been made to reduce the number of measurements for reasons of 
subject convenience or to clarify differences in specific assessments taken at clinic visits 
versus home health visits. The sponsor believes the changes in assessment frequency and 
timing will not influence the ability to evaluate the safety and efficacy of study drug. Home 
health visits 1 and 10.1 will ensure that phosphorus, 1,25(OH)2D, and calcium will be 
adequately collected and measured throughout the study.   
3. Inclusion Criteria: Inclusion Criterion #6 (Section 7.3.1) has been modified to show that 
subjects with an estimated glomerular filtration rate (eGFR) of ≥30 but <60 mL/min will be 
considered eligible so long as, in the opinion of the investigator, the decline in renal function 
is not related to nephrocalcinosis. 
Rationale: Older adult subjects may routinely have eGFR <60 mL/min without there being 
any indication of nephrocalcinosis. 
4. Exclusion Criteria (Section 7.3.2):  
a. Exclusion Criterion #11 has been modified to show that a history of allergic reaction 
to or have shown adverse reactions to declomycin is no longer exclusionary. 

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Rationale: Labeling with declomycin is no longer required. Labelling subjects with 2 
rounds of tetracycline HCL prior to each bone biopsy is sufficient to allow the biopsy 
to be read appropriately.  
b. Exclusion Criterion #12 has been modified to clarify that the decision to exclude 
subjects who have conditions which could present a concern for either subject 
safety or difficulty with data interpretation can be made by the investigator and the 
sponsor. 
Rationale: Many patients with ENS have a number of potentially confounding 
comorbidities. To help ensure subject safety and the integrity of the data collected 
in the study, both the investigator and the sponsor may decide to exclude subjects 
based on these potentially confounding comorbidities.  
5. Bone Biopsy Labeling: Section 7.5 has been modified to show that subjects will be labelled 
with 2 rounds of tetracycline HCL prior to each bone biopsy rather than 1 round of 
declomycine (or equivalent) followed by 1 round of tetracycline.  
Rationale: Labeling with declomycin is no longer required. Labelling subjects with 2 rounds 
of tetracycline HCL prior to each bone biopsy is sufficient to allow the biopsy to be read 
appropriately. 
6. Bone Biopsy: Table 2.1 (Schedule of events) has been revised to note that a bone biopsy is 
not required at the Baseline visit if a previous bone biopsy confirmed the diagnosis of 
osteomalacia, the subjects’ clinical manifestations have not changed significantly since the 
time of the previous biopsy/diagnosis, and the tissue collected at that biopsy is made 
available for testing for this protocol.  A similar change has been made to Section 7.5. 
Rationale: It is expected that there would be no significant change in untreated TIO/ENS 
subjects from the time that their original bone biopsy confirmed the diagnosis of 
osteomalacia; therefore a historical sample can be used as the baseline comparator within 
this study.  
7. Clinical Outcome Measures: Section 7.5.3.2 has been revised to replace the 6MWT with the 
Sit to Stand (STS) test and the Weighted Arm Lift (WAL) test. 
Rationale: The 6MWT has been removed because some subjects may not be ambulatory 
and thus not able to complete the test.  
8. Tumor Imaging: Imaging of the tumor (Section 7.5.5.9) has been incorporated at the request 
of the FDA. Imaging will be completed at the screening visit, and every 6 months thereafter 
for tumors that are visible at screening.  
Rationale: As part of the overall safety assessment of TIO/ENS patients, evaluation of overall 
change in tumor size and volume is being incorporated into this study. 

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9. Fasting Serum Phosphate Range: The synopsis and Sections 7.1, 7.4, and 7.5 were updated 
to change the target fasting serum phosphate range from 2.5 – 3.5 mg/dL to 2.5 – 
4.0 mg/dL.  
Rationale: The fasting serum phosphate range is being expanded to allow for additional 
flexibility. 
10. Bone Scan Assessment of Bone Turnover: Criteria for evaluation were updated; the bone 
scan will not be utilized to assess bone turnover and the number of central readers will be 
reduced from three readers to a single reader.  
Rationale: Due to high sensitivity but low specificity and the undefined temporal appearance 
of pseudofracture healing by bone scan, bone scan will be used to identify potential 
pseudofractures at BL, wk 24 and wk 48.  For this purpose, a single central reader is deemed 
appropriate. Exploratory analyses of change from BL will be defined in the SAP.  
 
 

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CLINICAL STUDY PROTOCOL AMENDMENT 
SUMMARY OF CHANGES AND RATIONALE 
UX023T-CL201 Amendment 2 
14 October 2015 
 
Protocol UX023T-CL201 Amendment 1 (dated 21 January 2015) has been modified by 
Amendment 2 to increase the sample size, modify the description of ENS, clarify 
details/schedule of procedures to be conducted in the study, and to make other minor 
modifications. Important protocol changes are summarized below: 
1. Sample Size: In Section 7.1, the sample size has been increased from approximately 6 to 
approximately 15 adult subjects. 
Rationale: The Sponsor has become aware of additional subjects meeting eligibility 
criteria. 
2. Description of ENS: The description of ENS has been updated throughout the protocol 
to indicate that ENS is not merely a variant of TIO but a distinct congenital disorder of 
which one syndrome includes FGF23-induced hypophosphatemia and associated 
osteomalacia and shares a similar biochemical and clinical profile to TIO. 
Rationale: Based on a recent literature review on ENS, it is apparent that unlike the 
mesenchymal tumors that typically characterize TIO, epidermal nevi are non-neoplastic 
hematoma. Further, FGF23 protein or FGF23 mRNA is not detectable in samples of 
ENS-associated osteomalacia. Both TIO and ENS share the underlying pathophysiology 
of elevated serum FGF23 which leads to hypophosphatemia and the associated metabolic 
bone disease. Unlike TIO, complete resection and surgical cure leading to removal of the 
source of excess FGF23 is less likely. Nonetheless, in older literature case reports, there 
has been documentation of improved phosphorus levels following skin 
debridement/excision surgery in some but not all cases. ENS lesions may be extensive, 
often covering 10-60% of the skin. Thus the protocol was updated with this new 
information. 
3. Primary Efficacy Evaluation:  Section 7.5 and Section 7.6 have been updated to specify 
co-primary efficacy evaluations. Specifically, efficacy will be evaluated based on change 
from baseline in serum phosphorus levels over time and change from baseline in 
osteomalacia at 48 weeks as determined by histomorphometric evaluation of trans-iliac 
crest bone biopsies. 

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Rationale: TIO and ENS-associated osteomalacia are clinically heterogeneous; some 
patients experience substantial bone pain, and muscle weakness is common, but the 
frequency and intensity of these symptoms vary significant from patient to patient. 
However, all subjects with these disorders have elevated FGF23 levels and consequent 
hypophosphatemia and osteomalacia. Moreover, when surgical treatment of TIO and 
ENS-associated osteomalacia is successful, serum phosphorus levels normalize and 
osteomalacia resolves. Thus, improvement in serum phosphorus levels and improvement 
in osteomalacia as determined by bone biopsy assessment have been selected as the 
primary endpoints for this study and are meaningful endpoints to evaluate the efficacy of 
KRN23 treatment in this population of subjects whose tumor or skin lesions are 
considered inoperable. 
4. Inclusion Criteria: Inclusion criterion number 4 has been updated to indicate an iFGF23 
level ≥100 pg/mL as measured by Kainos assay is required for inclusion in the study. 
Previously the required FGF23 level was ≥2 times the upper limit of normal. 
Rationale: A review of the FGF23 assay literature suggested that a normal level was not 
well established for TIO and ENS-associated osteomalacia. A study of FGF23 levels in 
patients with TIO or ENS found that 12 of 13 patients studied had FGF23 levels at or 
above 100 pg/mL (Ito et al. 2005), thus the Sponsor has selected this level as a reasonable 
cutoff to ensure eligible patients do have elevated FGF23 consistent with TIO or 
ENS-associated osteomalacia. 
5. Previous Bone Biopsy: Section 7.5.2 has been updated with additional details about the 
acceptability of using results from a previous trans-iliac crest bone biopsy as the Baseline 
bone biopsy assessment. A previous bone biopsy will be acceptable if it was obtained 
within 12 months of Screening, confirmed the diagnosis of osteomalacia, the subjects’ 
clinical manifestations have not changed significantly since the time of the previous 
biopsy/diagnosis, and the tissue collected at that biopsy is made available for testing for 
this protocol.  Evaluability of previous bone biopsy specimens must be confirmed by a 
central reader before Baseline. Dosing may begin once evaluability is confirmed. 
Rationale: Given that determining the effects of KRN23 on improvement in osteomalacia 
in trans-iliac crest bone biopsies is now a co-primary objective in the study, it is essential 
that a previously obtained bone biopsy is reflective of a subject’s baseline disease and is 
evaluable for determination of the endpoint. Thus, it will now be required that the biopsy 
be taken within 12 months of Screening and that its evaluability is confirmed prior to 
baseline and dosing. 
6. Study Procedures and Assessments: Section 7.5 has been amended to add or remove 
certain assessments.  
Functional Outcomes and PROs: The Six Minute Walk Test (6MWT) has been added 
and will be administered at Screening (for practice), Baseline (Day -2), and Weeks 12, 

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24, and 48 (or Early Termination). The Timed Up and Go (TUG) and WOMAC 
assessments have been removed. 
Rationale: Testing of initial study subjects has provided insights into the functional 
abilities and limitations of subjects with TIO and ENS-associated osteomalacia leading to 
these changes. Screening data from the initial TUG administrations suggest that the test 
does not appear to be sensitive to the functional limitations experienced by patients with 
TIO or ENS-associated osteomalacia as all of the subjects were able to complete the test 
without difficulty.  The TUG has been replaced with the 6MWT, which is longer in 
duration and requires more energy expenditure for completion.  These features increase 
the likelihood that the 6MWT will capture the impact of the mobility deficits, bone/joint 
pain, and muscle weakness experienced by patients with TIO or ENS-associated 
osteomalacia. In addition to the TUG, the WOMAC has been removed due to issues 
identified during the initial administrations of the PRO measure. A standardized 
administration of the WOMAC, which was originally developed for use in osteoarthritis, 
requires the subject to complete all items based on the impact to the hips and/or knees or 
a single joint. Subjects have reported difficulty with the identification of a target area 
given the impact of TIO on various bones and joints throughout the body, including the 
neck, back and upper and lower extremities. Subjects have reported difficulty with the 
identification of a single joint for assessment given the impact of TIO on various bones 
and joints throughout the body. The remaining PROs will continue to be administered in 
the protocol.   
Tumor Imaging: In Section 7.5.6.9, changes have been made to clarify the methodology 
related to tumor imaging. Tumor imaging will be done for TIO subjects only and not 
subjects with ENS-associated osteomalacia. (Assessment of skin lesions in ENS subjects 
is addressed below.) CT and MRI imaging will be performed with the capability of 
assessing tumor size if the tumor is localized. The radiologist will indicate whether tumor 
size and volume have changed over time. If applicable, RECIST measurements will be 
done. 
Rationale: Many TIO tumors are difficult to localize because they are very small, slow 
growing, and often are in areas of bone or soft tissue which make them difficult to find 
using recommended imaging tools.  Common localization techniques involve the use of 
high resolution whole body CT or MRI often in combination with FDG PET scans and/or 
octreotide scans, which are both highly sensitive but not specific. A proportion of the 
patients who will be enrolled in the UX023T-CL201 may not have had their tumor 
localized. In instances where these tumors were previously localized, these patients may 
not have responded to surgical excision. Images from CT/MRI assessments will be 
analyzed for assessment by independent radiologist readers using software that is 
compatible with RECIST. If a lesion is present it is measured and marked with an arrow. 
The radiologist will review and indicate whether tumor size and volume have changed 
over 6 monthly intervals. Given the knowledge of the slow growing natural history of 
these mesenchymal tumors, it is expected that little change in tumor size will be detected. 
RECIST scores will be assessed if applicable. 

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Dermatologic Assessment for Subjects with ENS-associated Osteomalacia: 
Section 7.5.6.10 has been updated to add that serial photographs of skin lesions will be 
taken at Baseline and post treatment at Weeks 12, 24, 36, and 48 to assess progress in the 
skin lesions over time with KRN23 treatment (ENS subjects only). 
Rationale: Serial photographs for dermatologic assessment has been added to formally 
capture progress in skin lesions over time as a safety assessment. 
7. Safety Contact Information: The safety contact information in Section 8.5.5 has been 
updated to reflect the most current information. 
Rationale: Administrative change. 
  
 
 

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CLINICAL STUDY PROTOCOL AMENDMENT 
SUMMARY OF CHANGES AND RATIONALE 
UX023T-CL201 Amendment 3 
17 February 2016 
 
Protocol UX023T-CL201 Amendment 2 (dated 14 October 2015) has been modified by 
Amendment 3 to extend the study duration by 96 weeks, to clarify assessments in the 
screening skeletal survey; to add routine lipase testing and reflexive testing for serum 
amylase isoenzymes if serum amylase levels are elevated; to update a follow-up period for 
adverse events and duration of effective contraception after stopping study drug; to update an 
inclusion and exclusion criteria; to specify language for tetracycline labeling; to update that 
echocardiogram will be read centrally; and to update disease information for TIO/ENS and 
summary of overall risks and potential benefits of KRN23 to be consistent with the 
Investigator’s Brochure. Important protocol changes are summarized below: 
1. Overall Study Design and Plan: Section 7.1 has been updated to extend the study 
duration. After completing the initial treatment period of the study (48 weeks), subjects 
may continue into a planned Treatment Extension Period in which subjects will receive 
KRN23 treatment for up to an additional 96 weeks or until one of the following occurs:  
the study drug is commercially available in the subject’s local territory, the subject 
withdraws consent and discontinues from the study, the subject is discontinued from the 
study at the discretion of the Investigator or Ultragenyx, or the study is terminated. 
Rationale: The goal of the 96-week Treatment Extension Period is to evaluate the long-
term safety and efficacy of KRN23 in patients with TIO/ENS. In eligible patients where 
tumors are considered inoperable due to the location of the tumor or extent of disease or 
an inability to localize the tumor, hypophosphatemia is a chronic disease. It is expected 
that the maintenance of phosphate control will allow for continued healing of 
osteomalacia in patients with TIO/ENS. The 96-week Treatment Extension Period will 
provide long-term data on safety and efficacy to further characterize the benefit:risk 
profile of KRN23 treatment in this patient population. 
2. Clinical Assessments: Section 7.5.4.3 has been updated to clarify assessments in the 
screening skeletal survey. 
Rationale: The protocol has been amended to provide clarification and alignment with 
central imaging requirements with regards to the skeletal survey of the lateral spine, AP 
chest, right and left hand/wrist, right and left humerus, right and left radius/ulna, right and 

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left femur/pelvis, right and left tibia/fibula, and right and left foot to be obtained at 
screening. 
3. Safety Measurements: Section 7.5.6.4 has been updated to add assessments of serum 
lipase in all subjects and to specify additional laboratory analyses that will be performed 
reflexively on prospectively drawn specimens if serum amylase levels are elevated to ≥2x 
the upper limit of the reference range (ULRR). 
Rationale: Mild asymptomatic elevations in serum amylase have been observed in some 
subjects at baseline and during the study. Amylase is produced by several organs 
including the pancreas and salivary gland and so elevated amylase levels are not 
diagnostic in the absence of other information. In ongoing and completed KRN23 studies 
at baseline, mild elevations of amylase (<2x ULRR) have been noted. Post treatment mild 
shifts in amylase elevation (< 2xULRR) has been noted without association with GI 
symptoms. No adverse events of pancreatitis have been observed. The reflexive testing 
for serum amylase isoenzymes when serum amylase levels are elevated will allow a 
determination of whether the elevations are from pancreatic or salivary gland sources. 
4. Pregnancy Testing and Reporting and Follow-up of Adverse Events: In Section 
7.5.6.13 and Section 8.5, the follow-up period for adverse events (AEs) and duration of 
contraception after the end of the study have been extended from 30 days to 12 weeks. 
Rationale: Subjects will need to be followed for approximately 5 times the elimination 
half-life. The half-life is 16.4 days making the duration of follow up approximately 3 
months. Thus, participants of child-bearing potential or with partners of child-bearing 
potential who have not undergone a bilateral salpingo-oophorectomy and are sexually 
active must consent to use two forms of effective method of contraception as determined 
by the principal investigator from the period following the signing of informed consent 
through 12 weeks (approximately 5 times the elimination half-life) after stopping the 
study drug. Language in the inclusion criteria has also been amended to reflect this 
change (see below).  
Additionally, all AEs will be collected from the time the subject signs informed consent 
through 12 weeks (approximately 5 times the elimination half-life) following the last 
dose of study drug.  
4. Inclusion and Exclusion Criteria: An inclusion criterion in Section 7.3.1 and an 
exclusion criterion in Section 7.3.2 have been updated.  
Rationale: Inclusion criterion #9 was updated to clarify that “subjects must be willing to 
use two forms of effective methods of contraception while participating in the study 
(sexually active subjects) and for 12 weeks after the last dose of study drug.” This change 
is intended to align with the revised Pregnancy Testing and Reporting language in 
Section 7.5.6.13 as described above. In addition, exclusion criterion #9 was updated to 
“Have a history of malignancy within 5 years of study entry with the exception of 
PMT-MCT (Phosphaturic mesenchymal tumors of the mixed connective tissue type) 

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tumors or non-melanoma skin cancers such as basal cell skin cancer.” This criterion was 
amended to ensure that the safety profile of KRN23 can be properly characterized in 
patients with classic TIO (PMT-MCT) before being studied in subjects with TIO-like 
syndrome, such as prostate cancer, lung cancer, etc. 
5. Study Procedures and Assessments: In Section 7.5 and throughout the document, the 
language for use of a tetracycline has been updated to provide clarity. 
Rationale: The current language in the protocol was narrowly worded to allow use of 
tetracycline hydrochloride (HCl) to facilitate histomorphometric analysis. To provide 
greater clarity and flexibility, this language has been revised to allow for use of “a 
tetracycline (e.g., tetracycline hydrochloride ([HCl] and demeclocycline).” 
6. Echocardiogram: In Section 7.5.6.7, the procedure for assessments of echocardiograms 
(ECHO) has been revised to central reading.    
Rationale: ECHO results will be read centrally rather than at local sites to ensure 
consistent criteria across the study are used to assess ECHO parameters by trained 
personnel. Clinically significant abnormalities detected following central ECHO reading 
will be promptly reported to the principal investigator for attention as indicated. 
7. Overview of the Disease and Summary of Overall Risks and Potential Benefits: In 
Section 5.2 and Section 5.4, the disease information for TIO/ENS and the summary of 
overall risks and potential benefits of KRN23 have been updated. 
Rationale: The disease description of TIO/ENS and the overall risks and potential 
benefits of KRN23 were revised to reflect the recently updated KRN23 Investigator’s 
Brochure (IB) (19 November 2015). 
 
 
 

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CLINICAL STUDY PROTOCOL AMENDMENT 
SUMMARY OF CHANGES AND RATIONALE 
UX023T-CL201 Amendment 4 
10 November 2017 
Protocol UX023T-CL201 Amendment 3 (dated 17 February 2016) has been modified by 
Amendment 4 to increase the duration of the Treatment Extension period and add safety 
follow-up telephone calls; update and clarify the Schedule of Events; update the clinical 
study background information; update the contraception requirements; update the maximum 
injection volume of KRN23; update the safety reporting language; and make administrative 
updates regarding the medical monitor and record retention language. Minor edits and 
typographical corrections have also been made. Important protocol changes are summarized 
below: 
1. Study Duration: Section 7.1 and related sections have been updated to extend the 
treatment duration from 140 weeks to up to 216 weeks or until June 30, 2019, plus an 
additional safety follow-up period. 
Rationale: The study is being extended until the approximate expected date of 
commercial drug availability to allow continuation of treatment in these subjects. 
2. Investigational Product Administration: Section 7.4.2.1 has been updated to increase 
the maximum volume of KRN23 that may be administered in a single injection from 
1.0 to 1.5 mL and to indicate that rotation of injections may include rotation to a different 
quadrant of the abdomen. 
Rationale: This modification in dosing volume will allow more flexibility in 
subcutaneous administration of investigational product and more specific information 
about the dosing procedures. 
3. Introduction: In Section 5, Information on Previous and Ongoing Clinical Studies 
(Section 5.3.3) and Summary of Overall Risks and Potential Benefits (Section 5.4) have 
been updated to incorporate the most recent clinical trial data from the X-linked 
hypophosphatemia (XLH) program. 
Rationale: Updated to reflect the currently available clinical data on KRN23 use in XLH 
and TIO. 
4. Removal of Subjects from Therapy or Assessment: Section 7.3.3 has been updated to 
indicate that a subject may be removed if she becomes pregnant during the study or if a 
previously unidentified causal tumor is identified and determined to be amenable to 
surgical removal. 
Rationale: Experience with KRN23 in pregnant women is limited and the study drug may 
involve risks to a pregnant female or unborn baby that are currently unknown. Therefore, 
use of a highly effective method of contraception is required during the study, and 

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subjects who become pregnant during the study will be discontinued as a safety 
precaution. Removing a subject from study who is determined to have a tumor that is 
amenable to complete resection is consistent with the inclusion criterion requiring a 
tumor that is not amenable to cure by surgical excision. 
5. Study Procedures and Assessments: Several changes have been made to Section 7.5 
and the Schedules of Events, and a new Schedule of Events Table 2.4 has been added to 
describe assessments during Weeks 145 through the End of Study (EOS) visit and the 
Safety Follow-up period. 
a. In Section 7.5 and the Schedules of Events for Screening and Baseline and the 
Treatment Period (Table 2.1 and Table 2.2), the Day −21, −20, and −19 time points 
before the Baseline and Week 48 Day 2 Visits at which subjects should take the first 
course of tetracycline have been revised to Days −20, −19, and −18 before those 
visits.  
Rationale: The time points for administration of the first course of tetracycline before 
biopsy have been made consistent with the Transiliac Bone Biopsy Manual.  
b. A Home Health visit has been added at Week 142 for collection of peak serum 
phosphorous levels. Adverse events (AEs), vital signs, and concomitant medications 
will also be recorded. In addition, peak serum phosphorus levels will be collected 
during the new portion of the extension period (Weeks 145 – End of Study) at Weeks 
166, 190, and 214. 
Rationale: To obtain peak serum phosphorus levels at time points later in the study.  
c. Physical Examinations at Home Health visits have been removed during the treatment 
extension period. Physical Examinations will continue to be performed at all site 
visits. 
Rationale: Removing physical examinations will streamline Home Health visits as the 
physical exam is not needed at such frequency. 
d. Anti-KRN23 antibody assessments have been added at site visits (ie, every 24 weeks) 
during the treatment extension period. 
Rationale: The addition of anti-KRN23 antibody assessments will allow ongoing 
monitoring of potential anti-KRN23 antibody formation in subjects during the 
treatment extension period of the study. 
e. Serum KRN23 concentration assessments have been added at site visits (ie, every 24 
weeks) during the treatment extension period. 
Rationale: The addition of serum KRN23 assessments will allow ongoing monitoring 
of KRN23 concentrations during the treatment extension period of the study. 

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f. In Section 7.5.6.9 and the Schedules of Events the frequency of tumor imaging during 
the treatment extension period has been changed from once every 6 months to once 
every 12 months. In addition, language has been added to indicate that a historical 
tumor image obtained within 12 months of Screening may be used as the Screening 
image. The section has also been updated to indicate that when applicable, mint 
Lesion™ software, rather than RECIST, will be used to assess changes in tumor size 
and volume over time. 
 
Rationale: Reducing the frequency of tumor imaging decreases subject burden and 
remains in line with standard medical practice of imaging every 6-12 months. 
Similarly, use of a historical tumor image within 12 months is consistent with medical 
practice. Use of the mint Lesion software™ reflects a software update and is most 
applicable to the timing and location of tumor imaging in the study. 
g. Section 7.5.6.9 and the Schedules of Events have been updated to indicate that for 
subjects with tumor-induced osteomalacia (TIO) in whom the tumor had not been 
located at baseline, yearly evaluation will be performed beginning at Week 120 in an 
attempt to locate the tumor. The preferred imaging technique is 68Ga-DOTATATE 
positron emission tomography (PET)/computed tomography (CT). Octreotide-SPECT 
(SPECT/CT) or FDG-PT/CT may be used if DOTATATE PET/CT is not available. 
(If none of these methods is available, another imaging technique may be used at 
investigator discretion.)  
Rationale: The protocol previously did not specify ongoing attempts at tumor 
identification during the study in those subjects for whom tumors were not identified 
at baseline. This change clarifies that imaging for potential tumor identification will 
be ongoing during the study.  
h. Dual-energy X-ray absorptiometry (DXA) assessment of the wrist has been removed. 
Rationale: Wrist DXA was added in Amendment 2 but not implemented so it is being 
removed. DXA of the lumbar spine and hip will continue to be performed through 
Week 144. 
i. Ambulatory status has been added to the Schedule of Events and to Section 7.5.4.4. 
Ambulatory status at baseline will be retrospectively collected; prospective collection 
of ambulatory status will begin at the first scheduled site visit following 
implementation of and consent to this amendment and will continue at all subsequent 
site visits.  
Rationale: This addition will allow evaluation of functional disability in these 
subjects with TIO and any changes with KRN23 treatment. 
j. Serial photographs of skin lesions in subjects with epidermal nevus syndrome 
(ENS)-associated osteomalacia have been removed as an assessment. Dermatologic 
assessment will continue to be performed as part of the physical examination. 

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Rationale: Administrative decision given only one subject with ENS-associated 
osteomalacia is enrolled in the study. 
 
6. Study Endpoints: In Section 7.6.1 the wording of the co-primary endpoint regarding 
histomorphometry assessments has been updated to be: The change from baseline in 
excess osteoid based on analysis of iliac crest bone biopsies after 48 weeks of KRN23 
treatment using the following  histomorphometric indices: O.Th, OS/BS, OV/BV, and 
MLt. Previously the endpoint had specified percent change from baseline. In addition, 
Secondary endpoints of additional measures to assess serum phosphorus levels over time 
have been updated to indicate that these reflect a Week 24 time point. In addition, in the 
synopsis, the description of exploratory endpoints was updated to align with the 
description of these endpoints in Section 7.6.1 and with the Statistical Analysis Plan.  
Rationale: Wording was updated to align with the Statistical Analysis Plan v 1.0 (dated 
04 May 2016). 
7. Treatments: Sections 7.1, 7.4.1, and 7.4.5 have been updated to indicate that if a subject 
undergoes treatment of the underlying tumor (ie, radiation therapy or excision) at any 
point during the study, KRN23 treatment should be interrupted. If the investigator 
determines, based on serum phosphorus levels below the lower level of normal in the 
subject, that KRN23 treatment should be resumed, the dose should be restarted at 
0.3 mg/kg Q4W and titrated to a new maintenance dose based on peak and trough serum 
phosphorus levels, up to a maximum dose of 2.0 mg/kg.  
Rationale: Radiation therapy or tumor excision has the potential to reduce tumor activity 
or tumor ability to produce FGF23, thereby altering previous FGF23 levels. Therefore, 
resuming KRN23 treatment at a low dose and re-titrating to a new maintenance dose is 
being implemented as a safety measure. 
8. Prohibited Medications: In Section 7.4.7.1, an exception has been added to allow use of 
oral phosphate and/or pharmacologic vitamin D metabolites in the case of a subject who 
needs to discontinue treatment with KRN23 for more than 4 weeks to undergo treatment 
of the underlying tumor. 
Rationale: This change has been added in conjunction with the requirement that a subject 
discontinues KRN23 treatment if they will undergo treatment for the underlying tumor 
(see Summary of Changes #7) as management of hypophosphatemia may still be needed 
in this circumstance.  
9. Anti-KRN23 Antibodies: In Section 7.5.6.5, the term HAHA (human anti-human 
antibody) in reference to anti-KRN23 antibody testing has been replaced with the term 
ADA (anti-drug antibody). The assay methodology has also been updated. 
Rationale: This change is a clarification. The immunogenicity of KRN23 is evaluated by 
quantifying total ADA, independent of isotype, in human serum. While the study 
protocol previously used the term “HAHA” for this assessment, it has been replaced with 
the more correct and specific term, ADA. The updated assay methodology language 
reflects the current assay. 

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10. Contraception Methods: In Section 7.5.6.12, the list of examples of highly effective 
contraception methods was updated. In addition, Section 7.3.3 was updated to indicate 
that subjects who become pregnant will be discontinued from study. 
Rationale: These change was made to align the acceptable methods of contraception in 
compliance with the Clinical Trial Facilitation Group (CTFG) guideline, 
“Recommendations related to contraception and pregnancy testing in clinical trials” and 
to be consistent with clinical trials in adults with XLH. 
11. Data Quality Assurance and Record Retention: Sections 8.4.2 and 8.4.3 have been 
updated to state that all study records must be retained for at least 25 years after the end 
of the trial or in accordance with national law and the right of regulatory authorities, the 
IRB, and/or Ultragenyx or its designees to access these records will also be retained for at 
least 25 years or in accordance with national law. 
Rationale: This administrative change has been made to reflect regulations by health 
authorities. 
12. Safety Assessments: In the Synopsis, electrocardiogram (ECG) is now listed as a general 
safety assessment. Previously it was listed within the safety assessments for ectopic 
mineralization. 
Rationale: ECG is performed to evaluate for changes associated with left ventricular 
hypertrophy. Ectopic mineralization is not expected to affect ECG parameters and ECG 
was inadvertently listed in that section in the original protocol.  Ectopic mineralization in 
the heart will be assessed by centrally read ECHOs. 
13. Reporting and Follow-up of Adverse Events. Section 8.5 and subsections have been 
updated to indicate that wherever possible, the severity of all AEs will be graded using 
the NCI CTCAE version 4.0. In addition, language regarding procedures for AE 
reporting to Ultragenyx have been updated as well as the name and contact information 
for the medical monitor.  
Rationale: These updates to AE reporting and follow up were made to align with current 
guidelines and clarify current practices. The update to the medical monitor contact 
information was an administrative change. 
 
 
 

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CLINICAL STUDY PROTOCOL AMENDMENT 
SUMMARY OF CHANGES AND RATIONALE 
UX023T-CL201 Amendment 5 
27 April 2018 
Protocol UX023T-CL201 Amendment 4 (dated 10 November 2017) has been modified by 
Amendment 5 to extend the study duration until December 2019, to clarify procedures for 
dose optimization in later stages of the study, to allow Q2W dosing in certain cases, to add 
and clarify study procedures, and to note US and EU approval of KRN23 for the treatment of 
X-linked hypophosphatemia (XLH), a separate indication. Minor edits and typographical 
corrections have also been made. Important protocol changes are summarized below: 
1. Study Duration: Section 7.1 and related sections have been updated to extend the 
treatment duration from up to 216 weeks or June 30, 2019 to up to 244 weeks or until 
December 31, 2019, plus an additional safety follow-up period. These additional study 
visits are reflected in the Schedule of Events Table 2.5. 
Rationale: The study is being extended until the approximate expected date of 
commercial drug availability to allow continuation of treatment in these subjects. 
2. Selection and Timing of Doses: Dose adjustment beyond the 16-week titration period is 
permitted during the study. Section 7.4.5 and related sections have been updated to 
clarify the procedures related to these later dose adjustments. Specifically, if fasting 
serum phosphorus levels at trough (i.e., 4 weeks after a dose and before the subsequent 
dose) remain below the lower limit of normal (< 2.5 mg/dL), the dose may be increased 
in 0.5 mg/kg increments up to a dose of 2.0 mg/kg Q4W. In addition, if trough levels of 
serum phosphorus remain < 2.5 mg/dL after the dose is increased to 2.0 mg/kg Q4W, the 
dose frequency may be increased to every 2 weeks (Q2W). In these subjects, Q2W 
dosing will be initiated at 60% of the Q4W total dose. Serum phosphorus levels will be 
measured every 4 weeks (prior to subsequent doses) for 12 weeks and if levels remain 
< 2.5 mg/dL, the dose may be increased to 2.0 mg/kg Q2W, the maximum dose. 
Rationale: Clarifying the procedures for dose adjustment later in the study will provide 
additional guidance for investigators to manage dosing in subjects. Allowing an increased 
dose frequency to Q2W in subjects who do not maintain a trough serum phosphorus 
within the normal range at a dose of 2.0 mg/kg Q4W will allow evaluation of whether 
more frequent dosing can maintain serum phosphorus levels within the normal range.  
3. Study Assessments: (a) A supplemental Schedule of Events has been added (Table 2.6) 
to identify additional assessments to be performed for subjects who have a dose 
optimization at or after Week 96. (b) The Sit to Stand (STS) test has been added to 
Table 2.4 and Table 2.5 only for those subjects who have a dose optimization at or after 
Week 96. (c) Home health visits at Weeks 166, 190, and 214 have been changed to site 
visits to allow assessment of PROs and the STS. (d) Assessment of serum concentrations 
of KRN23 in stable samples has been added at Weeks 8, 32, 36, and 40 in Table 2.2. 

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(e) Section 7.5.6.9 has been clarified to indicate that in subjects for whom a tumor was 
not identified at baseline but who have the tumor located by 68Ga-DOTATATE PET/CT 
imaging or another method while on study, MRI or CT should be performed within 
21 (±7 days) days of tumor identification to assess tumor size. Thereafter, tumor imaging 
should be performed using the same method (MRI or CT) according to the Schedules of 
Events. If the MRI/CT imaging following tumor identification has occurred within 
3 months of the next scheduled MRI/CT assessment, that assessment will be skipped and 
the Schedules of Events will be followed thereafter. (f) A radiographic skeletal survey 
has been added to the Schedule of Events at Week 144 in Table 2.4. (g) Genetic testing to 
evaluate for mutations in PHEX, the gene responsible for XLH, in subjects with TIO 
symptoms from childhood and for whom the tumor has not been identified has been 
added to the Schedule of Events in Table 2.3. 
Rationale: (a), (b), and (c) The additional assessments at the start of and following dose 
optimization include serum phosphorus measurements, PRO assessments (Brief Pain 
Inventory, Brief Fatigue Inventory, and SF-36), and functional assessments (STS test). 
These assessments will allow evaluation of the new dose on how the subject feels and 
functions both at the mid-point (with Q4W dosing) and at the end of the dose cycle. 
(d) The assessment of serum KRN23 concentrations at Weeks 8, 32, 36, and 40 were 
included in a previous version of the protocol and removed in Amendment 3. The 
assessments are being reinstated to enable retrospective evaluation of stable stored study 
samples collected at these time points to allow a more complete assessment of the 
relationship between serum phosphorus, KRN23 dose, and KRN23 concentration. 
(e) This is a clarification that the MRI or CT to assess tumor size should be performed 
within 21 (±7) days of identification by 68Ga-DOTATATE PET/CT imaging and then 
according to the Schedule of Events. Previously it stated imaging should be performed 
according to the Schedule of Events. 
(f) Addition of the skeletal survey at Week 144 will enable a full evaluation of fractures 
and pseudofractures at a time point when bone scans are also performed. This may allow 
a better assessment of the effects of KRN23 on fracture burden in these subjects with TIO 
or ENS.  
(g) Mutational analysis of the PHEX gene has been added to rule out a possible XLH 
diagnosis due to the similar clinical features of the diseases in specific subjects who have 
had clinical symptoms and hypophosphatemia since childhood and in whom the tumor 
has not been identified.  
4. Contraception Requirement: In Section 7.3.1, language regarding contraception in 
Inclusion Criteria #8 and #9 has been updated for consistency with changes made 
previously to other parts of the protocol.  
Rationale: The definition of women not of childbearing potential was updated to align 
with the Clinical Trial Facilitation Group (CTFG) guideline. The change to a single 
highly effective form of contraception had previously been made to Section 7.5.6.12 
(Pregnancy Testing and Contraception) but not to the Inclusion criteria because the study 

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was fully enrolled. The current update was made for the purpose of consistency 
throughout the protocol. 
5. Coordinating Investigator: In Section 8.2, language has been added to detail selection 
and roles of a Coordinating Investigator for the study. Dr Suzanne Jan De Beur has been 
named as the Coordinating Investigator on the title page. 
Rationale: This change was made to indicate that a Coordinating Investigator has been 
identified for the study. 
6. Timing of Safety Follow-up Telephone Calls: In Section 7.1 and related sections, the 
wording regarding Safety Follow-up Telephone Calls has been modified. The timing of 
the telephone calls is now based on the timing of the last dose of study drug; previously it 
had been based on the timing of the EOS/ET visit. The Safety Follow-up Telephone Calls 
will now be performed at 6 weeks (+5 days) and 12 weeks (+ 5 days) after the subject’s 
last dose of study drug. In addition, the first safety follow up call will now be performed 
for all subjects, not only in those not continuing KRN23 treatment through commercial 
use or another mechanism upon completion of study. 
Rationale: Changing the timing of the Safety Follow-up Telephone Calls to be based on 
the last dose of study drug was done to allow consistency of timing from last dose, given 
that some subjects may be receiving Q2W dosing. All subjects will be called as a 
conservative approach to ensure no safety data are missed.  
7. Regulatory Approvals of KRN23 (burosumab) for XLH: In Section 5.1, the FDA 
approval of burosumab for the treatment of XLH in adults and pediatric patients 1 year of 
age and older and conditional marketing authorization in the EU for the treatment of 
XLH with radiographic evidence of bone disease in children 1 year of age and older and 
adolescents with growing skeletons have been noted. 
Rationale: This change was made to update the Background section with the most current 
regulatory status of KRN23. 
 

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CLINICAL STUDY PROTOCOL AMENDMENT 
SUMMARY OF CHANGES AND RATIONALE 
UX023T-CL201 Amendment 6 
26 September 2019 
Protocol UX023T-CL201 Amendment 5 (dated 27 April 2018) has been modified by 
Amendment 6 to incorporate the following changes. Minor edits and typographical 
corrections have also been made as needed.  
1. Study duration: Section 7.1 and related sections were updated to extend the total 
treatment duration from up to 244 weeks or 31 December 2019, to up to 300 weeks or 
31 January 2021, or until commercial availability of KRN23 as prescribed by subjects’ 
treating physician, whichever is sooner. Accordingly, the End of Study (EOS) 
assessments were removed from Week 244, and the additional study visits along with the 
revised EOS assessments are now shown in the Schedule of Events Table 2.6.  
Rationale: The study is being extended to allow continuation of treatment in subjects 
until availability of another mechanism of KRN23 treatment, such as commercially 
available treatment. 
2. Timing of Safety Follow-up Telephone Call: The Schedule of Events Table 2.6, 
Section 7.1, and related sections were updated to indicate that the Safety Follow-up 
Telephone Call (TC) will occur approximately 6 weeks (+ 5 days) after a subject’s last 
dose of study drug to collect information on any ongoing or new adverse events (AEs), 
serious adverse events (SAEs), and concomitant medications. An additional Safety 
Follow-up TC will occur approximately 12 weeks (+ 5 days) after the subject’s last dose 
of study drug. If subjects have started receiving KRN23 (burosumab) via an alternative 
mechanism (eg, commercial treatment) by the time of the 6-week Safety Follow-up TC, 
the 12-week Safety Follow-up TC may not be necessary.  
Rationale: To clarify the timing of Safety Follow-up TCs with respect to subjects’ last 
dose of study drug. 
3. Supplemental Schedule of Events table: The supplemental Schedule of Events table 
that outlined the assessments to be performed following a dose optimization at or after 
Week 96, including serum KRN23, brief pain inventory (BPI), brief fatigue inventory 
(BFI), 36-item short form health survey (SF-36), and sit-to-stand (STS), was removed 
from the Schedule of Events and related sections throughout protocol. 
Rationale: To simplify the study assessments and minimize unnecessary repetition of 
assessments.  

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4. Schedule of Events Tables 2.4 and 2.5: Visits at Weeks 142, 166, 192, and 214 were 
removed from the Treatment Extension Period. 
Rationale: These visits were included in the protocol when dosing every 2 weeks (Q2W) 
was added to the study. However, the previous version of the protocol did not indicate 
that these additional visits are only for subjects who are undergoing Q2W dosing. This 
change is a clarification to avoid unnecessary site visits by all subjects.  
5. Sit-to-stand assessments during the Treatment Extension Period: STS assessments 
were removed from the Treatment Extension Period (Schedule of Events Table 2.4 and 
Table 2.5) for subjects who have an upward dose or frequency adjustment at or after 
Week 96. 
Rationale: To simplify the study assessments in subjects undergoing dose optimization at 
or after Week 96.  
6. Radiographic assessments: Section 7.5.4.3, the Schedule of Events, and related sections 
were updated to clarify that targeted radiographs will be completed at the anatomical 
location where a fracture or pseudofracture was identified at or after Screening every 
24 weeks starting at Week 72, until resolution, or up to Week 240.  
Rationale: To clarify the timing of follow-up of fractures or pseudofractures identified at 
or after Screening. Previously, radiographic assessments were not included after 
Week 144. 
7. Tumor imaging and tumor identification: Section 7.5.6.9 and the related assessments 
in the Schedule of Events (Table 2.6) were modified to clarify that for subjects with 
tumor-induced osteomalacia (TIO), if the tumor is visible and localized at Screening, it 
will be imaged at Screening and every 24 weeks through Week 144, and then every 
48 weeks (or at next scheduled visit) for the remainder of the study. For subjects with 
TIO whose tumor was not identifiable at Screening, evaluations every 48 weeks (or in 
alignment with regularly scheduled clinic visits) will be performed beginning at 
Week 120 in an attempt to locate the tumor. The preferred imaging technique is 
68Ga-DOTATATE positron emission tomography (PET)/computed tomography (CT). 
Imaging to locate the tumor may also be performed at unscheduled visits if there is 
clinical suspicion of new tumor development. If the tumor is located and determined to 
be unresectable, magnetic resonance imaging (MRI) or CT imaging (at the discretion of 
the Investigator) should occur within 21 (± 7) days of identification to assess tumor size, 
at an unscheduled visit if necessary, and thereafter according to the Schedule of Events. 
Rationale: To clarify tumor imaging and tumor identification assessments throughout the 
remainder of the study. 
8. Definition of maintenance dose: In Section 7.4.5 and related sections, a definition of 
maintenance dose was added (defined as a dose at which 2 consecutive trough serum 
phosphorous levels are within the normal range [2.5 – 4.0 mg/dL]). 
Rationale: To provide clarity on the criterion for a maintenance dose of KRN23.  

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9. KRN23 dose titration schemes:  
 
(a) Table 7.4.5.1 was revised to include only the initial KRN23 dose titration scheme; 
dosing procedures for subjects undergoing treatment of an underlying tumor were 
removed and placed in Section 7.4.5.1 and Table 7.4.5.3.  
 
(b) Table 7.4.5.2 and related text were updated to clarify the criteria and dose titration 
scheme for dose adjustments and increases in dose frequency at or after Week 96. 
Criteria for dose adjustments based on trough serum phosphorous levels were added. For 
subjects increasing to a KRN23 dose of 2.0 mg/kg Q2W based on the criteria in 
Table 7.4.5.2, additional predose serum phosphorus measurements were added every 
4 weeks (Q4W) for 12 weeks to ensure that subjects do not experience dose-limiting 
toxicity (DLT) (Section 7.5.6.13).  
 
(c) Section 7.4.5.1 and Table 7.4.5.3 were created to clarify dosing procedures and the 
dose titration scheme for subjects who undergo treatment of an underlying tumor. 
Language was added to clarify that serum phosphorus levels should be monitored every 
4 weeks for 24 weeks following the resumption of KRN23 treatment through 
unscheduled blood draws at peak time points. The KRN23 dose will be titrated based on 
peak serum phosphorous levels as indicated in Table 7.4.5.3. Thereafter, dosing decisions 
will be made based on trough serum phosphorus levels as indicated in Table 7.4.5.2, and 
serum phosphorus measurements will proceed according to the Schedule of Events. 
Rationale: (a, b, c) To clarify the study dosing procedures, dose titration schemes, and 
related assessments. 
10. Introduction: Previous and Ongoing Clinical Studies (Section 5.3.3), and Summary of 
Overall Risks and Potential Benefits (Section 5.4) were updated to reflect the current 
information from clinical studies of KRN23. 
Rationale: To update the protocol with the most current clinical data for KRN23.  
11. Stopping rules: Minor updates were made to the Stopping Rules (Section 7.3.3.1) to 
clarify the criteria under which study treatment will be stopped, and/or the subject will be 
discontinued from the study. 
Rationale: To more clearly define the Stopping Rules for this study.  
12. Medical Monitor: In Section 8.5.4.6, the study Medical Monitor was changed to Mary 
Scott Roberts, MD. 
Rationale: This was a minor administrative change to update the safety contact 
information to reflect the current Medical Monitor for the study.  
13. Study safety review team: References to the study safety review team in Section 7.1, 
Section 7.3.3.1, and Section 7.5.6.13 were changed to clarify that the Sponsor will 
perform these safety monitoring activities. Key safety data will be reviewed by the 
Sponsor periodically on an ongoing basis coincident with formal data snap shots. 
Rationale: To clarify the language regarding the safety monitoring activities performed 
by the Sponsor. 

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2 SYNOPSIS 
TITLE OF STUDY:  
A Phase 2 open-label trial to assess the efficacy and safety of KRN23, an antibody to 
FGF23, in subjects with tumor-induced osteomalacia (TIO) or epidermal nevus syndrome 
(ENS)-associated osteomalacia 
PROTOCOL NUMBER: 
UX023T-CL201 
STUDY SITES: 
Multiple study sites in the United States  
PHASE OF DEVELOPMENT: 
Phase 2 
RATIONALE FOR THIS STUDY: 
KRN23 is a fully human immunoglobulin G1 (IgG1) monoclonal antibody (mAb) that 
binds to and inhibits the activity of fibroblast growth factor 23 (FGF23), leading to an 
increase in serum phosphorus levels. There are multiple disorders (each with a unique 
underlying cause) that result in unusually high circulating levels of FGF23, which in turn 
result in renal phosphate wasting and reduced (or aberrantly normal in relationship to 
elevated FGF23) levels of 1,25-dihydroxyvitamin D (1,25[OH]2D). Across these disorders 
the clinical symptoms are similar and often include osteomalacia (and, in children, rickets), 
muscle weakness, fatigue, bone pain, and fractures. KRN23 has been studied in 1 of these 
disorders, X-linked hypophosphatemia (XLH). Positive results were observed in a 
nonclinical pharmacology model of XLH. In single- and repeat-dose clinical studies in 
subjects with XLH, subcutaneous (SC) administration of KRN23 consistently increased 
and sustained serum phosphorus levels and tubular reabsorption of phosphate (TRP) 
without a major impact on urine calcium levels or vitamin D metabolism. KRN23 
(burosumab) was approved by the Food and Drug Administration (FDA) on 17 April 2018 
for the treatment of XLH in adult and pediatric patients 1 year of age and older, and a 
positive European Commission conditional marketing authorization was received on 
23 February 2018 for the treatment of XLH with radiographic evidence of bone disease in 
children 1 year of age and older and adolescents with growing skeletons. 

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Similar to XLH, tumor-induced osteomalacia (TIO), also known as oncogenic 
osteomalacia, is an acquired condition in which tumors, whose pathology is usually 
phosphaturic mesenchymal tumors (PMT), cause excessive ectopic production of FGF23 
that leads to renal phosphate wasting and impaired vitamin D synthesis. The high levels of 
FGF23 result in a similar biochemical profile to XLH that includes low serum phosphorus, 
phosphaturia, an abnormally low ratio of renal tubular maximum phosphate reabsorption 
rate to glomerular filtration rate (TmP/GFR), elevated alkaline phosphatase (ALP), normal 
calcium, and low to normal levels of 1,25(OH)2D. In TIO, tumors that are typically benign 
cause excessive ectopic production of FGF23, and if the causal tumor can be completely 
removed, the syndrome remits. However, some tumors are considered inoperable because 
of the location of the tumor or extent of disease or an inability to localize the tumor.  
Epidermal nevus syndrome (ENS) are rare congenital syndromes characterized by the 
presence of epidermal nevi in association with 1 or more other developmental 
abnormalities of other organ systems including the nervous, skeletal, cardiovascular, and 
ocular systems. Hypophosphatemia may rarely be 1 of the skeletal manifestations of ENS 
presenting in children primarily as rickets and in adults as osteomalacia. In all 
ENS-associated osteomalacia (also known as cutaneous skeletal hypophosphatemia 
syndrome) cases in which serum FGF23 levels were assessed, they were found to be 
elevated. The source of the excess FGF23 in ENS-associated osteomalacia is unclear. 
While early studies suggested it may be from the skin lesions themselves, more recent 
studies suggest it may be skeletally derived. Compared with TIO, complete resection and 
surgical cure leading to removal of the source of excess FGF23 is less likely. Nonetheless, 
published case reports of ENS-associated osteomalacia indicate improvement with skin 
debridement surgery in some cases. In many cases, improvement, if any, is modest and 
transient.  
In both TIO and ENS-associated osteomalacia, when surgery is not curative or feasible, 
medical treatment comprises oral phosphate and/or active vitamin D replacement. Efficacy 
of these treatments is often limited; it does not treat the underlying disease; and its benefits 
must be balanced with monitoring for potential risks such as nephrocalcinosis, 
hypercalciuria, and hyperparathyroidism. 
This is a Phase 2 study designed to assess the efficacy, safety, pharmacokinetics (PK), and 
pharmacodynamics (PD) of KRN23 in subjects with TIO whose tumor is inoperable 
(defined as ‘the inability to localize the tumor or the impractical nature of surgery due to 
the extent of disease or the location of the tumor’) or ENS-associated osteomalacia, where 
skin lesion removal therapy is not considered a valid treatment option. It is hypothesized 
that KRN23 may provide clinical benefit in this patient population because of the common 
underlying feature in patients with TIO or ENS-associated osteomalacia and in patients 
with XLH: abnormally elevated FGF23 levels. 

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OBJECTIVES:  
The primary objectives of this study are to evaluate the following: 
• Effect of KRN23 treatment on increasing serum phosphorus levels in adults with 
TIO or ENS-associated osteomalacia  
• Effect of KRN23 treatment on improvement in TIO/ENS-associated osteomalacia 
as determined by the following histomorphometric indices: 
o Osteoid Thickness (O.Th) 
o Osteoid surface/Bone surface (OS/BS) 
o Osteoid volume/Bone volume (OV/BV) 
o Mineralization lag time (MLt) 
Secondary objectives of the study are to evaluate the following: 
• The PD profile of KRN23 as assessed by changes from Baseline over time in 
additional measures of serum phosphorus, serum FGF23, ALP, and 1,25(OH)2D; 
TRP and TmP/GFR (the ratio of renal tubular maximum phosphate reabsorption 
rate to glomerular filtration rate) 
• Effects of KRN23 on bone turnover markers, including bone-specific ALP 
(BALP), carboxy terminal cross-linked telopeptide of type I collagen (CTx), 
procollagen type 1 N-propeptide (P1NP), and osteocalcin 
• Functional outcomes including upper and lower extremity muscle strength, walking 
and reaching ability, and mobility 
• Patient-reported outcomes including self-reported pain, fatigue, and health-related 
quality of life 
The PK objective of the study is to: 
• Determine the PK profile of repeat SC injections of KRN23 at Baseline (Weeks 0, 
2, and 4) and 6 Months (Weeks 20, 22, and 24) in subjects with TIO or ENS-
associated osteomalacia 
Exploratory objectives of the study are to evaluate the following: 
• Changes in additional histomorphometry parameters in trans-iliac crest bone 
biopsies including both structural and dynamic measures 
• Changes in underlying skeletal disease/osteomalacia as assessed by skeletal 
survey/standard radiographs, dual-energy X-ray absorptiometry (DXA), 
99mTc-labelled bone scan, and high-resolution peripheral quantitative computed 
tomography (CT) (XtremeCT; where available) 
The safety objective of the study is to: 

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• Assess the safety of KRN23 administration in subjects with TIO or ENS-associated 
osteomalacia, based on adverse events (AEs), laboratory assessments, cardiac 
imaging, renal ultrasound, and immunogenic response 
STUDY DESIGN AND METHODOLOGY:  
UX023T-CL201 is a Phase 2 open-label study to determine the efficacy, safety, PD, and 
PK of repeat SC injections of KRN23 in adult subjects with TIO or ENS-associated 
osteomalacia. 
Subjects will be selected for Screening only if they are deemed to have inoperable disease 
(defined by an inability to localize the tumor or the impractical nature of surgery due to the 
extent of disease or the location of the tumor) or if they have ENS-associated osteomalacia 
and are not being considered for skin lesion removal treatment. Subjects who are eligible 
for Screening will discontinue oral phosphate and vitamin D metabolite therapy at least 
2 weeks prior to Screening and may not resume supplementation for the duration of the 
study. Subjects who are eligible for study entry will receive tetracycline (eg, tetracycline 
hydrochloride [HCl] and demeclocycline) prior to the Baseline Visit to facilitate 
histomorphometric analysis of the Baseline trans-iliac crest bone biopsy (refer to 
Section 7.5.4.3).  
The Baseline Visit will be conducted over approximately 4 days, including overnight stay 
if deemed necessary by the Investigator. Baseline safety and efficacy assessments 
(excluding bone biopsy) will occur on the first 1 to 2 days (Days −3 and −2). On the 
following day (Day −1), a trans-iliac crest bone biopsy will be performed (refer to 
Section 7.5.4.3). On the next day (Day 0, Week 0), subjects will receive their first SC 
injection(s) of KRN23.  
All enrolled subjects will begin treatment with KRN23 every 4 weeks (Q4W) at a starting 
dose of 0.3 mg/kg (Week 0). Doses of KRN23 will then be titrated in an effort to achieve a 
target fasting serum phosphorus range of 2.5 to 4.0 mg/dL (Table 7.4.5.1). All serum 
phosphorus assessments will be taken with subjects in the fasting state. If the subject’s 
peak serum phosphorus level at Week 2 remains below the target range, the subject’s dose 
may be increased at Week 4 to 0.6 mg/kg, at the discretion of the Investigator. Doses will 
then continue to be titrated in increments of 0.2 mg/kg at Weeks 8, 12, and 16 in individual 
subjects to achieve the target peak serum phosphorus range. Doses may be titrated at later 
visits, at the discretion of the Investigator, if there are concerns about safety or suboptimal 
efficacy or if a subject has not yet achieved the target range of serum phosphorus. 
The maximum dose allowed in this protocol is 2.0 mg/kg every 2 weeks (Q2W). If needed, 
the final dose adjustment increment may be less than the specified increment to reach the 
2.0 mg/kg dose. If a subject undergoes treatment of the underlying tumor (ie, radiation 
therapy or excision) at any point during the study, KRN23 treatment should be interrupted 
(Section 7.4.5.1). If the Investigator with the study Medical Monitor determines, based on 
serum phosphorus below the lower limit of normal, that the subject should resume KRN23 
treatment, the dose should be restarted at 0.3 mg/kg Q4W. Serum phosphorus levels 
should be subsequently monitored every 4 weeks for 24 weeks following the resumption of 
KRN23 treatment through unscheduled blood draws at peak (2 weeks postdose) time 

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points. The KRN23 dose will be titrated based on peak serum phosphorous levels as 
indicated in Table 7.4.5.3. Thereafter, dosing decisions will be made based on trough 
serum phosphorus levels (4 weeks ± 3 days postdose and prior to the subsequent dose) 
obtained at the previous study visit as indicated in Table 7.4.5.2, and serum phosphorus 
assessments will proceed according to the Schedule of Events (Table 2.1, Table 2.2, 
Table 2.3, Table 2.4, Table 2.5, and Table 2.6).  
Subjects will be enrolled consecutively. Key safety data will be reviewed periodically on 
an ongoing basis coincident with formal data snap shots. If a dose-limiting toxicity (DLT; 
a Grade ≥ 3 toxicity that is probably or possibly treatment related or a confirmed serum 
phosphorus level ≥ 6.5 mg/dL) is identified at any point, the study will be paused until all 
of the efficacy and safety data collected to date are reviewed to evaluate the overall 
risks/benefits of the study and to make a determination about whether it will continue. 
Screening, Baseline, and post-treatment PK, PD, efficacy, and safety assessments are 
shown by study visit in Table 2.1, Table 2.2, Table 2.3, Table 2.4, Table 2.5, and 
Table 2.6. 
Upon regulatory approval and commercial availability of KRN23 for the treatment of TIO, 
subjects will have their End of Study (EOS) Visit, and transition to prescription drug, as 
recommended by their treating physician. Until commercial availability, subjects may 
continue treatment with KRN23 for up to 252 weeks in the Treatment Extension Period, or 
until 31 January 2021, whichever is sooner, and then undergo their EOS Visit. Therefore, 
the duration of the Treatment Extension Period will vary for individual subjects, and will 
be determined by the time from the start of Week 49 through their EOS Visit. Upon 
completion of study drug treatment (ie, EOS Visit) or early withdrawal from this study (ie, 
Early Termination [ET] Visit), a Safety Follow-up Telephone Call (TC) will occur 
approximately 6 weeks (+ 5 days) after a subject’s last dose of study drug to collect 
information on any ongoing or new AEs, serious adverse events (SAEs), and concomitant 
medications. An additional Safety Follow-up TC will occur approximately 12 weeks 
(+ 5 days) after the subject’s last dose of study drug. If subjects have started receiving 
KRN23 (burosumab) via an alternative mechanism (eg, commercial treatment) by the time 
of the 6-week Safety Follow-up TC, the 12-week Safety Follow-up TC may not be 
necessary. The end of this study is defined as the last day protocol-specified assessments 
(including telephone contact) are conducted for the last subject.  
NUMBER OF SUBJECTS PLANNED:  
Approximately 15 adult subjects will be enrolled in the study. Subjects who withdraw or 
are removed from the study may be replaced on a case-by-case basis, at the discretion of 
Ultragenyx and the Investigator. 

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DIAGNOSIS AND CRITERIA FOR INCLUSION AND EXCLUSION:  
Individuals eligible to participate in this study must meet all of the following criteria at 
Screening: 
1. Have a clinical diagnosis of TIO/ENS-associated osteomalacia based on evidence of 
excessive FGF23 that is not amenable to cure by surgical excision of the offending 
tumor/lesion (documented by Investigator) 
2. Be ≥ 18 years of age 
3. Have a fasting serum phosphorus level < 2.5 mg/dL 
4. Have serum iFGF23 level ≥ 100 pg/ml by Kainos assay 
5. Have a ratio of renal tubular maximum reabsorption rate of phosphate to glomerular 
filtration rate (TmP/GFR) < 2.5 mg/dL 
6. Have an estimated glomerular filtration rate (eGFR) ≥ 60 mL/min (using Cockcroft-
Gault formula). Subjects with an eGFR ≥ 30 but < 60 mL/min will be considered 
eligible so long as in the opinion of the Investigator the decline in renal function is not 
related to nephrocalcinosis 
7. Have a corrected serum calcium level < 10.8 mg/dL 
[Corrected serum calcium = serum calcium in mg/dL + 0.8 × (4 − serum albumin in 
g/dL)] 
8. Females of child-bearing potential must have a negative urine pregnancy test at 
Screening and Baseline and be willing to have additional pregnancy tests during the 
study. Females considered not to be of childbearing potential include those who have 
not experienced menarche, are post-menopausal (defined as having no menses for at 
least 12 months without an alternative medical cause) or are permanently sterile 
because of total hysterectomy, bilateral salpingectomy, or bilateral oophorectomy 
9. Participants of child‐bearing potential or fertile males with partners of child-bearing 
potential who are sexually active must consent to use a highly effective method of 
contraception as determined by the site Investigator from the period following the 
signing of the informed consent through the final Safety Follow-up TC (as defined in 
Section 7.1) 
10. Be willing to provide access to prior medical records to determine eligibility including 
imaging, biochemical, and diagnostic, medical, and surgical history data 
11. Provide written informed consent after the nature of the study has been explained, and 
prior to any research-related procedures 
12. Be willing and able to complete all aspects of the study, adhere to the study visit 
schedule and comply with the assessments (in the opinion of the Investigator) 

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Individuals who meet any of the following exclusion criteria will not be eligible to 
participate in the study: 
1. Have a prior diagnosis of human immunodeficiency virus, hepatitis B, and/or 
hepatitis C 
2. Have a history of recurrent infection, a predisposition to infection, or a known 
immunodeficiency 
3. Are pregnant or breastfeeding at Screening or are planning to become pregnant (self or 
partner) at any time during the study 
4. Have participated in an investigational drug or device trial within 30 days prior to 
Screening or are currently enrolled in another study of an investigational product or 
device  
5. Have used a therapeutic mAb, including KRN23, within 90 days prior to Screening or 
have a history of allergic or anaphylactic reactions to any mAb 
6. Have or a have a history of any hypersensitivity to KRN23 excipients that, in the 
judgment of the Investigator, places the subject at increased risk for adverse effects 
7. Have used a pharmacologic vitamin D metabolite or its analog (eg, calcitriol, 
doxercalciferol, and paricalcitol), phosphate, or aluminum hydroxide antacids 
(eg, Maalox® and Mylanta®) within 2 weeks prior to Screening or during the study 
8. Have used medication to suppress parathyroid hormone (PTH) (eg, Sensipar®, 
cinacalcet, calcimimetics) within 2 months prior to Screening 
9. Have a history of malignancy within 5 years of study entry with the exception of 
PMT-MCT (Phosphaturic mesenchymal tumors of the mixed connective tissue type) 
tumors or non-melanoma skin cancers such as basal cell skin cancer 
10. Have donated blood or blood products within 60 days prior to Screening 
11. Have a history of allergic reaction to or have shown adverse reactions to a tetracycline 
(eg, tetracycline HCl and demeclocycline), benzodiazepines, fentanyl or lidocaine  
12. Have any condition, which in the opinion of the Investigator and Sponsor, could 
present a concern for either subject safety or difficulty with data interpretation 
INVESTIGATIONAL PRODUCT(S), 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 (30 mg) at a concentration of 30 mg/mL. KRN23 will be 
administered without dilution via SC injection to the abdomen, upper arm, or thigh; the 
injection site will be rotated with each injection, including to a different quadrant of the 
abdomen. No more than 1.5 mL may be administered in a single injection. If a subject 
needs more than 1.5 mL per administration, multiple injections must be administered and a 
different site must be used for each injection.  

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KRN23 will initially be administered Q4W. Doses will be titrated at Weeks 4, 8, 12, and 
16 in individual subjects to achieve a target peak serum phosphorus range of 2.5 to 
4.0 mg/dL. Doses may be titrated at later visits, at the discretion of the Investigator, if 
there are concerns about safety or suboptimal efficacy or if a subject has not yet achieved 
the target range of serum phosphorus. Dose frequency may be increased to Q2W if trough 
serum phosphorus levels remain < 2.5 mg/dL at a dose of 2.0 mg/kg Q4W. Doses should 
be interrupted and may be retitrated if a subject undergoes treatment of the underlying 
tumor (ie, radiation therapy or excision) at any point during the study. The maximum dose 
allowed in this protocol is 2.0 mg/kg Q2W. If needed, the final dose adjustment increment 
may be less than the specified increment to reach a 2.0 mg/kg dose. Following a downward 
dose adjustment, the Investigator together with the Medical Monitor will determine how 
and when to dose titrate up. 
REFERENCE THERAPY, DOSE AND MODE OF ADMINISTRATION:  
This is an open-label study in which all subjects will receive investigational product. 
No placebo or reference therapy will be administered. 
DURATION OF TREATMENT:  
The total KRN23 treatment duration on study will be up to 300 weeks, or up to 
31 January 2021, whichever is sooner, after which subjects will have their EOS Visit. 
Upon regulatory approval and commercial availability of KRN23 for the treatment of TIO, 
subjects will have their EOS Visit, and transition to prescription drug, as recommended by 
their treating physician. Subjects will undergo an ET Visit if 1 of the following occurs: the 
subject withdraws consent and discontinues from the study, the subject is discontinued 
from the study at the discretion of the Investigator or Ultragenyx, or the study is 
terminated.    
CRITERIA FOR EVALUATION: 
Primary Efficacy Evaluation: 
The study will have co-primary endpoints: 
• The proportion of subjects achieving mean serum phosphorus levels above the 
lower limit of normal (LLN; 2.5 mg/dL [0.81 mmol/L]) at the mid-point of the 
dose interval (2 weeks after dosing), as averaged across dose cycles between 
Baseline and Week 24 
• The change from Baseline in excess osteoid based on analysis of iliac crest bone 
biopsies after 48 weeks of KRN23 treatment using the following 
histomorphometric indices: 
o O.Th 
o OS/BS 

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o OV/BV 
o MLt 
Secondary Endpoints: 
• Additional measures to assess serum phosphorus levels over time include: 
o Proportion of subjects achieving mean serum phosphorus levels above the 
LLN (2.5 mg/dL [0.81 mmol/L]) at the end of the dosing cycle (4 weeks 
after dosing), as averaged across dose cycles between Baseline and 
Week 24 
o Mid-point of dosing cycle: mean change from Baseline and percent change 
from Baseline averaged across dose cycles between Baseline and Week 24 
o End of dosing cycle: mean change from Baseline averaged across dose 
cycles between Baseline and Week 24 
o Cumulative exposure: time-adjusted area under the curve between Baseline 
and Week 24 
• Change from Baseline over time in serum FGF23, ALP, 1,25(OH)2D; and urinary 
phosphorus, TRP, TmP/GFR  
• Change and percent change from Baseline over time in serum biochemical markers 
of bone turnover, including BALP, CTx, P1NP, and osteocalcin 
• Change from Baseline over time in muscle strength as assessed by hand-held 
dynamometry (HHD), sit-to-stand test (STS), weighted arm lift test (WAL), and 
6-minute walk test (6MWT) 
• Change from Baseline in brief pain inventory (BPI), brief fatigue inventory (BFI), 
and 36-item short form health survey (SF-36) over time 
Exploratory Endpoints: 
• Changes in other measures of structural and dynamic histomorphometry in trans-
iliac crest bone biopsies  
• Changes in bone condition and healing of prior long bone and pseudo-fractures as 
assessed by 99mTc-labelled bone scan 
• Changes in bone mineral density and bone mineral content as measured by DXA at 
the lumbar spine and hip 
• Changes in bone mineral density, bone mineral content, bone geometry, and 
microarchitecture in the cortical and trabecular compartments of the radius and 
tibia as measured by XtremeCT (when available) 

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Pharmacokinetics: 
• Serum KRN23 
Safety: 
Safety and tolerability will be evaluated by the incidence, frequency, and severity of 
treatment-emergent AEs and SAEs, as well as changes from Baseline to scheduled time 
points in the following general safety variables: 
• Vital signs and weight 
• Physical examinations 
• eGFR 
• Serum calcium, phosphorus, intact parathyroid hormone (iPTH), and urinary 
calcium and creatinine  
• Chemistry, hematology, and urinalysis, including additional KRN23/TIO 
biochemical parameters of interest (serum 25-hydroxyvitamin D [25(OH)D], 
lipase, amylase, creatinine, and FGF23) 
• Tumor imaging (TIO) or dermatologic assessment of skin lesions (ENS-associated 
osteomalacia) 
• Anti-KRN23 antibody formation  
• Dose-limiting toxicities, defined as: 
o Unexpected SAEs occurring during treatment considered to be either 
probably or possibly related to the investigational product. 
o A confirmed serum phosphorus level of ≥ 6.5 mg/dL (defined as 
hyperphosphatemia) at any time after dosing. 
• Concomitant medications 
• Urine pregnancy testing 
• Electrocardiogram (ECG) 
Ectopic Mineralization Safety Assessments include: 
• Echocardiogram (ECHO)  
• Renal ultrasound 
STATISTICAL METHODS:  
A full description of the statistical evaluations will be provided in the Statistical Analysis 
Plan (SAP). 

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Analysis Populations: 
Biopsy Analysis Set: The biopsy analysis set will include enrolled subjects with baseline 
and follow-up (either Week 48 or ET prior to Week 48) bone biopsy data. 
Full Analysis Set: All efficacy (except bone biopsy endpoints), safety, and PK/PD analyses 
will be performed on the set of all subjects who receive at least 1 dose of investigational 
product.  
Primary Efficacy Analysis: 
The proportion of subjects who achieve a serum phosphorus level above the LLN 
(2.5 mg/dL [0.81 mmol/L]), at 2 weeks after dosing (between baseline and Week 24, on 
average) will be provided, along with the 2-sided 95% confidence interval. Additional 
analyses of serum phosphorus including observed values, change from Baseline, percent 
change from Baseline over time, and area under the curve will be summarized from 
Baseline to Week 24. 
Histomorphometric indices O.Th, OS/BS, OV/BV, and MLt at Baseline and Week 48, and 
their change from Baseline at Week 48 will be summarized.  
Other Pharmacodynamics and Efficacy Analysis: 
PD and clinical efficacy endpoints will be summarized at each time point they are 
collected with descriptive statistics. For continuous variables, the mean, standard 
deviation, 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 also be summarized and evaluated. 
Safety Analysis: 
All subjects who receive any amount of study drug will be included in the safety analysis. 
All AEs will be coded using the Medical Dictionary for Regulatory Activities (MedDRA). 
The incidence and frequency of AEs will be summarized by System Organ Class, 
Preferred Term (PT), severity, and relationship to KRN23 treatment. A by-subject listing 
will be provided for those subjects who experience a SAE, including death, or experience 
an AE associated with early withdrawal from the study or study drug treatment. 
Clinical laboratory data will be summarized by the type of laboratory test. The frequency 
and percentage of subjects who experience abnormal clinical laboratory results (ie, outside 
of reference ranges) and/or clinically significant abnormalities will be presented for each 
clinical laboratory measurement. 

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Table 2.1: 
Schedule of Events – Screening and Baseline 
 
Screening 
Baseline2 
STUDY VISIT 
Screening Visit 
TC11 
TC21 
Visit 13 
STUDY WEEK or STUDY DAY 
Week −4 
Week −3 
Week −1 
Day −3 
Day −2 
Day −1 
Week / 
Day 04 
Informed Consent 
X 
 
 
 
 
 
 
Inclusion/Exclusion Criteria 
X 
 
 
X 
 
 
 
Medical History & Demographics 
X 
 
 
 
 
 
 
PHARMACODYNAMICS 
 
 
 
 
 
 
 
Serum Phosphorus5 
X 
 
 
X 
 
 
 
Serum FGF235 
X 
 
 
X 
 
 
 
Serum ALP6 
 
 
 
X 
 
 
 
Serum Creatinine5,6 
X 
 
 
X 
 
 
 
1,25(OH)2D5 
 
 
 
X 
 
 
 
2-Hour Urine5,6 
X 
 
 
X 
 
 
 
Bone turnover markers5,7 
 
 
 
X 
 
 
 
EFFICACY 
 
 
 
 
 
 
 
99mTc Bone Scan8 
 
 
 
 
X 
 
 
DXA8 
 
 
 
 
X 
 
 
Standard Radiographs9 
X 
 
 
 
 
 
 
Xtreme CT of Radius and Tibia10 
X 
 
 
 
 
 
 
Bone Biopsy11 
 
 
 
 
 
X 
 
BPI, BFI, SF-3612 
X 
 
 
 
X 
 
 

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Screening 
Baseline2 
STUDY VISIT 
Screening Visit 
TC11 
TC21 
Visit 13 
STUDY WEEK or STUDY DAY 
Week −4 
Week −3 
Week −1 
Day −3 
Day −2 
Day −1 
Week / 
Day 04 
HHD, STS, WAL, 6MWT12 
X 
 
 
 
X 
 
 
Ambulatory Status 
 
 
 
X19 
 
 
 
PHARMACOKINETICS 
 
 
 
 
 
 
 
Serum KRN23 
 
 
 
 
 
 
X 
SAFETY 
 
 
 
 
 
 
 
Vital Signs13 
 
 
 
X 
X 
X 
X 
Weight 
X 
 
 
 
X 
 
 
Height 
X 
 
 
 
 
 
 
Physical Examination 
X 
 
 
X 
 
 
 
Concomitant Medications 
X 
 
 
X 
 
 
 
Adverse Events 
X 
X 
X 
X 
X 
X 
X 
Chemistry14, Hematology15 
X 
 
 
X 
 
 
 
Anti-KRN23 Antibody16 
 
 
 
 
 
 
X 
Serum Calcium4 
X 
 
 
X 
 
 
 
Serum iPTH4 
X 
 
 
X 
 
 
 
25(OH)D 
X 
 
 
 
 
 
 
Urinalysis 
X 
 
 
X 
 
 
 
24-hour Urine17 
 
 
 
X 
 
 
 
ECHO, ECG8  
 
 
 
X 
 
 
 
Renal Ultrasound18 
X 
 
 
 
 
 
 

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Screening 
Baseline2 
STUDY VISIT 
Screening Visit 
TC11 
TC21 
Visit 13 
STUDY WEEK or STUDY DAY 
Week −4 
Week −3 
Week −1 
Day −3 
Day −2 
Day −1 
Week / 
Day 04 
Tumor Imaging20 
X 
 
 
 
 
 
 
Urine Pregnancy Test21 
X 
 
 
X 
 
 
 
DRUG ADMINISTRATION 
 
 
 
 
 
 
 
Tetracycline Labeling  
 
X 
X 
 
 
 
 
KRN2322 
 
 
 
 
 
 
X 
1 TC1 will be a telephone call to the subject within 1 week of the Screening Visit to communicate test results related to eligibility. If eligible for the study with 
only the FGF23 criterion pending, the subject will be instructed to begin taking a tetracycline (eg, tetracycline HCl and demeclocycline) on Days −20, −19, and 
−18 prior to the Baseline Visit. TC2 will be a second telephone call to the subject and should be conducted at least 7 days prior to the Baseline Visit to instruct 
the subject to begin taking a tetracycline on Days −8, −7, and −6 prior to the Baseline Visit.  
2 At the discretion of the Investigator, Baseline Day −3 and Day −2 assessments may be completed in any order to allow for flexibility in scheduling. 
All assessments from Days −3 and −2 must be completed prior to the bone biopsy, which must be completed on its own day with no other assessments and 
1 day prior to dosing on Day 0.  
3 Visit 1 may include overnight stay if deemed necessary by the Investigator. Discharge will occur approximately 24 hours after the first dose of KRN23 but 
may occur later in cases of prolonged recovery from the bone biopsy procedure 
4 All Day 0 assessments must be performed prior to administration of the first dose of KRN23. 
5 Blood and urine to be collected after a minimum overnight fasting time of 8 hours and prior to drug administration. 
6 Fasting 2-hour urine collections for TmP/GFR, TRP, and urinary calcium. Blood draw for serum creatinine should occur at 1 hour into the urine collection. 
7 Bone turnover markers will include serum measures of CTx, P1NP, BALP, and osteocalcin. 
8 May be completed within ± 5 days of the projected visit date to accommodate scheduling. 
9 At Screening, standard radiographs (skeletal survey) will be obtained of the lateral spine, AP chest, right and left hand/wrist, right and left humerus, right and 
left radius/ulna, right and left femur/pelvis, right and left tibia/fibula, and right and left foot as well as any location(s) where the subject is currently 
experiencing tenderness or pain that may reflect underlying pathology, or where the subject has a history of recent (< 3 months) fracture(s). 
10 May be performed any time after the subject has enrolled in the study (after meeting all eligibility criteria) until Baseline.  
11 A bone biopsy of the trans-iliac crest will be performed using general or local anesthesia as per institution practice(s) and performed by a physician trained and 
experienced in the procedure. The bone biopsy is not required at the Baseline Visit if a previous bone biopsy taken within 12 months of screening confirmed 

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the diagnosis of osteomalacia, the subjects’ clinical manifestations have not changed significantly since the time of the previous biopsy/diagnosis, and the 
tissue collected at that biopsy is made available for testing for this protocol.  
12 BPI, BFI, SF-36, HHD, STS, WAL, and 6MWT may be completed within ± 5 days of the projected visit date to accommodate scheduling. 
13 Vital sign measurements consist of seated systolic/diastolic blood pressure measured in millimeters of mercury (mm Hg), heart rate (beats per min), respiration 
rate (breaths per min), 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. 
14 Serum chemistry panels may include PD parameters (ie, serum phosphorus) and safety parameters of interest (ie, calcium) to avoid duplication of testing. See 
Table 7.5.6.4.1 for a complete list of Clinical Laboratory Assessments for Safety.  
15 Complete blood count, differential, and platelet count. 
16 If anti-KRN23 antibodies are identified in a given subject, additional samples may be obtained to perform further testing. 
17 24-hour urine collections for urinary phosphorus, calcium, creatinine, and eGFR; fasting 2-hour urine collections for TmP/GFR, TRP, and urinary 
calcium/creatinine ratio. 
18 Screening results will be treated as Baseline data. 
19 Ambulatory status at Baseline will be collected retrospectively 
20 Subjects with a TIO diagnosis only. If visible, the tumor will be imaged at Screening using the same radiologic imaging technique (eg, computed tomography 
[CT] or magnetic resonance imaging [MRI]) used to identify the tumor. In cases where the tumor was initially identified using another imaging technology, a 
baseline CT scan or MRI (whichever is more clinically appropriate) will be performed. During follow up, the same imaging technique (CT scan or MRI) that 
was used at Baseline will be utilized to assess the size of the tumor.  
21 For women of childbearing potential only, a serum pregnancy test will be performed in the event of a positive or equivocal urine pregnancy test. 
22 All enrolled subjects will begin treatment with KRN23 at a starting dose of 0.3 mg/kg (Week 0, Day 0, and no sooner than the day after the bone biopsy is 
performed). 
 
 

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Table 2.2: 
Schedule of Events – Treatment Period (Weeks 1 – 48) 
VISIT 
TYPE / NUMBER1 
V1 
 
HH
V1 
HH 
V2 
V3 
HH 
V4 
V5 
HH 
V6 
V7 
HH  
V8 
V9 
HH
V10 
HH 
V10.1 
HH 
V11 
V122 
HH
V13 
HH
V14 
V15 
HH
V16 
HH
V17 
TC33 
TC43 
V184 
STUDY WEEK 
DA
Y1 
1 
2 
4 
6 
8 
10 
12 
14 
16 
20 
21 
22 
24 
28 
32 
36 
40 
44 
45 
47 
48 
D1 
D2 
PHARMACODYNAMICS 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Serum Phosphorus5 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
X 
 
Serum FGF235 
X 
 
 
X 
 
 
 
X 
 
X 
 
 
 
X 
 
 
X 
 
 
 
 
X 
 
Serum ALP5 
 
 
 
 
 
 
 
X 
 
X 
 
 
 
X 
 
 
X 
 
 
 
 
X 
 
Serum Creatinine5,6 
 
 
 
X 
 
X 
 
X 
 
X 
 
 
 
X 
 
 
X 
 
 
 
 
X 
 
1,25(OH)2D5 
 
X 
X 
 
 
 
 
X 
 
X 
 
X 
 
X 
 
 
X 
 
 
 
 
X 
 
2-Hour Urine5,6 
 
 
 
X 
 
X 
 
X 
 
X 
 
 
 
X 
 
 
X 
 
 
 
 
X 
 
Bone Biomarkers5,7 
 
 
 
 
 
 
 
 
 
X 
 
 
 
X 
 
 
 
 
 
 
 
X 
 
EFFICACY 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
99mTc Bone Scan8 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
X 
 
DXA8 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
X 
 
Standard Radiographs9 
 
 
 
 
 
 
 
X 
 
 
 
 
 
X 
 
 
X 
 
 
 
 
X 
 
XtremeCT of Radius 
and Tibia8 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
Bone Biopsy10  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
BPI, BFI, SF-3611 
 
 
 
 
 
 
 
X 
 
 
 
 
 
X 
 
 
 
 
 
 
 
X 
 
HHD, STS, WAL, 
6MWT11 
 
 
 
 
 
 
 
X 
 
 
 
 
 
X 
 
 
 
 
 
 
 
X 
 

Protocol Number: UX023T-CL201 
Amendment 6 
26 September 2019 
 
 
 
 
Proprietary and Confidential 
Page 21 
VISIT 
TYPE / NUMBER1 
V1 
 
HH
V1 
HH 
V2 
V3 
HH 
V4 
V5 
HH 
V6 
V7 
HH  
V8 
V9 
HH
V10 
HH 
V10.1 
HH 
V11 
V122 
HH
V13 
HH
V14 
V15 
HH
V16 
HH
V17 
TC33 
TC43 
V184 
STUDY WEEK 
DA
Y1 
1 
2 
4 
6 
8 
10 
12 
14 
16 
20 
21 
22 
24 
28 
32 
36 
40 
44 
45 
47 
48 
D1 
D2 
PHARMACOKINETICS 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Serum KRN2312 
X 
 
X 
X 
 
X 
 
 
 
X 
X 
 
X 
X 
 
X 
X 
X 
 
 
 
X 
 
SAFETY 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Vital Signs13 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
X 
 
Weight 
 
 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
X 
 
 
 
 
X 
 
Physical Examination 
 
 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
X 
 
 
 
 
X 
 
Concomitant 
Medications 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
X 
 
Adverse Events 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
X 
 
Chemistry,14 
Hematology15 
 
 
 
X 
 
X 
 
X 
 
X 
X 
 
 
X 
X 
X 
X 
X 
X 
 
 
X 
 
Anti-KRN23 
Antibody16 
 
 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
X 
 
 
 
 
X 
 
Serum Calcium5 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
X 
 
Serum iPTH5 
X 
 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
X 
 
 
 
 
X 
 
25(OH)D 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
X 
 
Urinalysis 
 
 
 
X 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
 
 
 
 
X 
 
24-hour Urine17 
 
 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
X 
 
 
 
 
X 
 
ECHO, ECG8 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
X 
 
Renal Ultrasound8,18 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
X 
 
Tumor Imaging8,19 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
X 
 
Urine Pregnancy Test20 
 
 
 
X 
 
X 
 
X 
 
X 
X 
 
 
X 
X 
X 
X 
X 
X 
 
 
X 
 

Protocol Number: UX023T-CL201 
Amendment 6 
26 September 2019 
 
 
 
 
Proprietary and Confidential 
Page 22 
VISIT 
TYPE / NUMBER1 
V1 
 
HH
V1 
HH 
V2 
V3 
HH 
V4 
V5 
HH 
V6 
V7 
HH  
V8 
V9 
HH
V10 
HH 
V10.1 
HH 
V11 
V122 
HH
V13 
HH
V14 
V15 
HH
V16 
HH
V17 
TC33 
TC43 
V184 
STUDY WEEK 
DA
Y1 
1 
2 
4 
6 
8 
10 
12 
14 
16 
20 
21 
22 
24 
28 
32 
36 
40 
44 
45 
47 
48 
D1 
D2 
DRUG 
ADMINISTRATION 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Tetracycline Labeling 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
X 
 
 
KRN2321 
 
 
 
X 
 
X 
 
X 
 
X 
X 
 
 
X 
X 
X 
X 
X 
X 
 
 
X 
 
Dose Adjustment (as 
needed) 
 
 
 
X 
 
X 
 
X 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
1 Home health (HH) visits may also be conducted at the clinic depending on proximity of the subject to the investigational site and local availability of home 
health care services. The visit window is ± 3 days. 
2 The Week 24 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. 
3 TC3 will be a telephone call to the subject to instruct the subject to begin taking tetracycline (eg, tetracycline HCl and demeclocycline) on Days, −20, −19, 
and −18 prior to the Week 48 Day 2 visit. TC4 will be a second telephone call to the subject and should be conducted at least 7 days prior to the Week 48 
Day 2 visit to instruct the subject to begin taking a tetracycline on Days −8, −7, and −6 prior to the Week 48 Day 2 visit when the bone biopsy will be 
performed. Tetracycline will be given to the subject at the clinic during the Week 36 visit.  
4 The Week 48 visit (if applicable) may be up to 2 days in duration due to the volume of testing; required blood draws may be split across the 2 days. The 
bone biopsy must be completed on its own day with no other assessments. 
5 Blood and urine to be collected after a minimum overnight fasting time of 8 hours and prior to drug administration. 
6 Fasting 2-hour urine collections for TmP/GFR, TRP, and urinary calcium. Blood draw for serum creatinine should occur at 1 hour into the urine collection.  
7 Bone biomarkers will include serum measures of CTx, P1NP, BALP, and osteocalcin. 
8 May be completed within ± 5 days of the projected visit date to accommodate scheduling.  
9 Standard radiographs will be completed in the anatomical location where a fracture or pseudo-fracture is identified at Screening every 12 weeks (at 
Weeks 24, 36, and 48) until resolution. Unscheduled radiographs will be completed for any new fractures or pseudo-fractures identified during the Treatment 
Period approximately every 12 weeks from the date of fracture until resolution. 
10 A bone biopsy of the trans-iliac crest will be performed using general or local anesthesia as per institution practice(s) and performed by a physician trained 
and experienced in the procedure.  
11 BPI, BFI, SF-36, HHD, STS, WAL, and 6MWT may be completed within ± 5 days of the projected visit date to accommodate scheduling. 

Protocol Number: UX023T-CL201 
Amendment 6 
26 September 2019 
 
 
 
 
Proprietary and Confidential 
Page 23 
12 Analysis of serum KRN23 in samples drawn at Weeks 8, 32, 36, 40, and 48 may be performed retrospectively on available stable stored samples once 
appropriate approvals and consents are in place. 
13 Vital sign measurements consist of seated systolic/diastolic blood pressure measured in millimeters of mercury (mm Hg), heart rate (beats per min), 
respiration rate (breaths per min), 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. 
14 Serum chemistry panels may include PD parameters (ie, serum phosphorus) and safety parameters of interest (ie, calcium) to avoid duplication of testing. 
See Table 7.5.6.4.1 for a complete list of Clinical Laboratory Assessments for Safety.  
15 Complete blood count, differential, and platelet count. 
16 If anti-KRN23 antibodies are identified in a given subject, additional samples may be obtained to perform further testing. 
17 24-hour urine collections for urinary phosphorus, calcium, creatinine, and eGFR; fasting 2-hour urine collections for TmP/GFR, TRP, and urinary 
calcium/creatinine ratio. 
18 Screening results will be treated as Baseline data. 
19 Subjects with a TIO diagnosis only. If visible at Screening, the tumor will be imaged every 24 weeks using the same radiologic imaging technique (eg, CT 
scan or MRI) used to identify the tumor in order to assess the size of the tumor.  
20 For women of childbearing potential only, a serum pregnancy test will be performed in the event of a positive or equivocal urine pregnancy test. 
21 After the starting dose, doses of KRN23 will be titrated in an effort to achieve a target fasting serum phosphorus range of 2.5 to 4.0 mg/dL. If the subject’s 
peak serum phosphorus level at Week 2 remains below the target range, the subject’s dose may be increased at Week 4 to 0.6 mg/kg, at the discretion of the 
Investigator. Doses will then be titrated in increments of 0.2 mg/kg at Weeks 8, 12, and 16 in individual subjects to achieve a target peak serum phosphorus 
range. If needed, the final dose adjustment increment may be less than the specified increment to reach the 2.0 mg/kg dose. Doses may be titrated at later 
visits, at the discretion of the Investigator, if there are concerns about safety or suboptimal efficacy, or if a subject undergoes treatment of the underlying 
tumor. 

Protocol Number: UX023T-CL201 
Amendment 6 
26 September 2019 
 
 
 
 
Proprietary and Confidential 
Page 24 
Table 2.3: 
Schedule of Events – Treatment Extension Period1 (Weeks 49 – 120) 
VISIT TYPE/NUMBER2 
 
HH 
V19 
HH 
V20 
HH 
V21 
HH 
V22 
HH 
V23 
V24 
HH 
V25 
HH 
V26 
HH  
V27 
HH 
V28 
HH 
V29 
V30 
HH 
V31 
HH 
V32 
HH 
V33 
HH 
V34 
HH 
V35 
V36 
STUDY WEEK 
Q2W22 
52 
56 
60 
64 
68 
72 
76 
80 
84 
88 
92 
96 
100 
104 
108 
112 
116 
120 
PHARMACODYNAMICS 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Serum Phosphorus4 
 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
Serum FGF234 
 
 
 
 
 
 
X 
 
 
 
 
 
X 
 
 
 
 
 
X 
Serum ALP4 
 
 
 
 
 
 
X 
 
 
 
 
 
X 
 
 
 
 
 
X 
Serum Creatinine4,5 
 
 
 
 
 
 
X 
 
 
 
 
 
X 
 
 
 
 
 
X 
1,25(OH)2D4 
 
 
 
 
 
 
X 
 
 
 
 
 
X 
 
 
 
 
 
X 
2-Hour Urine4,5 
 
 
 
 
 
 
X 
 
 
 
 
 
X 
 
 
 
 
 
X 
Bone Biomarkers4,6 
 
 
 
 
 
 
X 
 
 
 
 
 
X 
 
 
 
 
 
X 
EFFICACY 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
99mTc Bone Scan7 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
DXA7 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
Standard Radiographs8 
 
 
 
 
 
 
X 
 
 
 
 
 
X 
 
 
 
 
 
X 
XtremeCT of Radius and 
Tibia7 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
BPI, BFI, SF-3610 
 
 
 
 
 
 
X 
 
 
 
 
 
X 
 
 
 
 
 
X 
Ambulatory Status11 
 
 
 
 
 
 
X 
 
 
 
 
 
X 
 
 
 
 
 
X 
PHARMACOKINETICS 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Serum KRN23 
 
 
 
 
 
 
X 
 
 
 
 
 
X 
 
 
 
 
 
X 
SAFETY 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Vital Signs12 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Weight 
 
 
 
 
 
 
X 
 
 
 
 
 
X 
 
 
 
 
 
X 

Protocol Number: UX023T-CL201 
Amendment 6 
26 September 2019 
 
 
 
 
Proprietary and Confidential 
Page 25 
VISIT TYPE/NUMBER2 
 
HH 
V19 
HH 
V20 
HH 
V21 
HH 
V22 
HH 
V23 
V24 
HH 
V25 
HH 
V26 
HH  
V27 
HH 
V28 
HH 
V29 
V30 
HH 
V31 
HH 
V32 
HH 
V33 
HH 
V34 
HH 
V35 
V36 
STUDY WEEK 
Q2W22 
52 
56 
60 
64 
68 
72 
76 
80 
84 
88 
92 
96 
100 
104 
108 
112 
116 
120 
Physical Examination 
 
 
 
 
 
 
X 
 
 
 
 
 
X 
 
 
 
 
 
X 
Concomitant Medications 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Adverse Events 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Chemistry,13 Hematology14 
 
 
 
X 
 
 
X 
 
 
 
 
 
X 
 
 
 
 
 
X 
Anti-KRN23 Antibody 
 
 
 
 
 
 
X 
 
 
 
 
 
X 
 
 
 
 
 
X 
Serum Calcium4 
 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
Serum iPTH4 
 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
25(OH)D 
 
 
 
 
 
 
X 
 
 
 
 
 
X 
 
 
 
 
 
X 
Urinalysis 
 
 
 
 
 
 
X 
 
 
 
 
 
X 
 
 
 
 
 
X 
24-hour Urine15 
 
 
 
 
 
 
X 
 
 
 
 
 
X 
 
 
 
 
 
X 
ECHO, ECG7 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
Renal Ultrasound7,16 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
Tumor Imaging7,17 
 
 
 
 
 
 
X 
 
 
 
 
 
X 
 
 
 
 
 
X 
Tumor Identification18 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
PHEX mutational 
analysis19 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
Urine Pregnancy Test20 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
DRUG ADMINISTRATION 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
KRN2321,22 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Footnotes for Table 2.3 follow Table 2.6. 

Protocol Number: UX023T-CL201 
Amendment 6 
26 September 2019 
 
 
 
 
Proprietary and Confidential 
Page 26 
Table 2.4: 
Schedule of Events – Treatment Extension Period1 (Weeks 121 – 192)  
VISIT TYPE/NUMBER2 
 
HH 
V37 
HH 
V38 
HH 
V39 
HH 
V40 
HH 
V41 
V43 
HH 
V44 
HH 
V45 
HH 
V46 
HH 
V47 
HH 
V48 
V50 
HH 
V51 
HH 
V52 
HH 
V53 
HH 
V54 
HH 
V55 
V57 
STUDY WEEK 
Q2W22 
124 
128 
132 
136 
140 
144 
148 
152 
156 
160 
164 
168 
172 
176 
180 
184 
188 
192 
PHARMACODYNAMICS 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Serum Phosphorus4 
 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
Serum FGF234 
 
 
 
 
 
 
X 
 
 
 
 
 
X 
 
 
 
 
 
X 
Serum ALP4 
 
 
 
 
 
 
X 
 
 
 
 
 
X 
 
 
 
 
 
X 
Serum Creatinine4,5 
 
 
 
 
 
 
X 
 
 
 
 
 
X 
 
 
 
 
 
X 
1,25(OH)2D4 
 
 
 
 
 
 
X 
 
 
 
 
 
X 
 
 
 
 
 
X 
2-Hour Urine4,5 
 
 
 
 
 
 
X 
 
 
 
 
 
X 
 
 
 
 
 
X 
Bone Biomarkers4,6 
 
 
 
 
 
 
X 
 
 
 
 
 
X 
 
 
 
 
 
X 
EFFICACY 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
99mTc Bone Scan7 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
XtremeCT of Radius and 
Tibia7  
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Skeletal Survey9 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Targeted radiographs8 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
X 
BPI, BFI, SF-3610 
 
 
 
 
 
 
X 
 
 
 
 
 
X 
 
 
 
 
 
X 
Ambulatory Status11 
 
 
 
 
 
 
X 
 
 
 
 
 
X 
 
 
 
 
 
X 
PHARMACOKINETICS 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Serum KRN23 
 
 
 
 
 
 
X 
 
 
 
 
 
X 
 
 
 
 
 
X 
SAFETY 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Vital Signs12 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Weight 
 
 
 
 
 
 
X 
 
 
 
 
 
X 
 
 
 
 
 
X 

Protocol Number: UX023T-CL201 
Amendment 6 
26 September 2019 
 
 
 
 
Proprietary and Confidential 
Page 27 
VISIT TYPE/NUMBER2 
 
HH 
V37 
HH 
V38 
HH 
V39 
HH 
V40 
HH 
V41 
V43 
HH 
V44 
HH 
V45 
HH 
V46 
HH 
V47 
HH 
V48 
V50 
HH 
V51 
HH 
V52 
HH 
V53 
HH 
V54 
HH 
V55 
V57 
STUDY WEEK 
Q2W22 
124 
128 
132 
136 
140 
144 
148 
152 
156 
160 
164 
168 
172 
176 
180 
184 
188 
192 
Physical Examination 
 
 
 
 
 
 
X 
 
 
 
 
 
X 
 
 
 
 
 
X 
Concomitant Medications 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Adverse Events 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Chemistry,13 
Hematology14 
 
 
 
 
 
 
X 
 
 
X 
 
 
X 
 
 
 
 
 
X 
Anti-KRN23 Antibody  
 
 
 
 
 
 
X 
 
 
 
 
 
X 
 
 
 
 
 
X 
Serum Calcium4 
 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
Serum iPTH4 
 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
25(OH)D 
 
 
 
 
 
 
X 
 
 
 
 
 
X 
 
 
 
 
 
X 
Urinalysis 
 
 
 
 
 
 
X 
 
 
 
 
 
X 
 
 
 
 
 
X 
24-hour Urine15 
 
 
 
 
 
 
X 
 
 
 
 
 
X 
 
 
 
 
 
X 
ECHO, ECG7 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
X 
Renal Ultrasound7,16 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
X 
Tumor Imaging7,17 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
X 
Tumor Identification18 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
Urine Pregnancy Test20 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
DRUG ADMINISTRATION 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
KRN2321,22 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Footnotes for Table 2.4 follow Table 2.6. 

Protocol Number: UX023T-CL201 
Amendment 6 
26 September 2019 
 
 
 
 
Proprietary and Confidential 
Page 28 
Table 2.5: 
Schedule of Events – Treatment Extension Period1 (Weeks 193 – 244) 
VISIT TYPE/NUMBER2 
 
HH 
V58 
HH 
V59 
HH 
V60 
HH 
V61 
HH 
V62 
V64 
HH 
V65 
HH 
V66 
HH 
V67 
HH 
V68 
HH 
V69 
V70 
HH 
V71 
STUDY WEEK 
HH 
Q2W22 
196 
200 
204 
208 
212 
216 
220 
224 
228 
232 
236 
240 
244 
PHARMACODYNAMICS 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Serum Phosphorus4 
 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
Serum FGF234 
 
 
 
 
 
 
X 
 
 
 
 
 
X 
 
Serum ALP4 
 
 
 
 
 
 
X 
 
 
 
 
 
X 
 
Serum Creatinine4,5 
 
 
 
 
 
 
X 
 
 
 
 
 
X 
 
1,25(OH)2D4 
 
 
 
 
 
 
X 
 
 
 
 
 
X 
 
2-Hour Urine4,5 
 
 
 
 
 
 
X 
 
 
 
 
 
X 
 
Bone Biomarkers4,6 
 
 
 
 
 
 
X 
 
 
 
 
 
X 
 
EFFICACY 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Targeted radiographs8 
 
 
 
 
 
 
X 
 
 
 
 
 
X 
 
BPI, BFI, SF-3610 
 
 
 
 
 
 
X 
 
 
 
 
 
X 
 
Ambulatory Status11 
 
 
 
 
 
 
X 
 
 
 
 
 
X 
 
PHARMACOKINETICS 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Serum KRN23 
 
 
 
 
 
 
X 
 
 
 
 
 
X 
 
SAFETY 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Vital Signs12 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Weight 
 
 
 
 
 
 
X 
 
 
 
 
 
X 
 
Physical Examination 
 
 
 
 
 
 
X 
 
 
 
 
 
X 
 
Concomitant Medications 
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 
Chemistry,13 Hematology14 
 
 
 
 
 
 
X 
 
 
X 
 
 
X 
 

Protocol Number: UX023T-CL201 
Amendment 6 
26 September 2019 
 
 
 
 
Proprietary and Confidential 
Page 29 
VISIT TYPE/NUMBER2 
 
HH 
V58 
HH 
V59 
HH 
V60 
HH 
V61 
HH 
V62 
V64 
HH 
V65 
HH 
V66 
HH 
V67 
HH 
V68 
HH 
V69 
V70 
HH 
V71 
STUDY WEEK 
HH 
Q2W22 
196 
200 
204 
208 
212 
216 
220 
224 
228 
232 
236 
240 
244 
Anti-KRN23 Antibody  
 
 
 
 
 
 
X 
 
 
 
 
 
X 
 
Serum Calcium4 
 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
Serum iPTH4 
 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
25(OH)D 
 
 
 
 
 
 
X 
 
 
 
 
 
X 
 
Urinalysis 
 
 
 
 
 
 
X 
 
 
 
 
 
X 
 
24-hour Urine15 
 
 
 
 
 
 
X 
 
 
 
 
 
X 
 
ECHO, ECG7 
 
 
 
 
 
 
X 
 
 
 
 
 
X 
 
Renal Ultrasound7,16 
 
 
 
 
 
 
X 
 
 
 
 
 
X 
 
Tumor Imaging7,17 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
Tumor Identification18 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
Urine Pregnancy Test20 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
DRUG ADMINISTRATION 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
KRN2321,22 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Footnotes for Table 2.5 follow Table 2.6. 

Protocol Number: UX023T-CL201 
Amendment 6 
26 September 2019 
 
 
 
 
Proprietary and Confidential 
Page 30 
Table 2.6: 
Schedule of Events – Treatment Extension Period1 (Weeks 248 – End of Study) and Safety Follow-up 
VISIT TYPE/NUMBER2 
 
HH 
V72 
HH 
V73 
HH 
V74 
HH 
V75 
V76 
HH 
V77 
HH 
V78 
HH 
V79 
HH 
V80 
HH 
V81 
V82 
HH 
V83 
HH 
V84 
V85 
Safety 
Follow-up 
TC23 
Safety 
Follow-up 
TC24 
STUDY WEEK 
HH 
Q2W22 
248 
252 
256 
260 
264 
268 
272 
276 
280 
284 
288 
292 
296 
W300/ 
EOS/ET3 
6 Weeks 
From Last 
Dose 
12 Weeks 
From 
Last Dose 
PHARMACODYNAMICS 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Serum Phosphorus4 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
Serum FGF234 
 
 
 
 
 
X 
 
 
 
 
 
X 
 
 
X 
 
 
Serum ALP4 
 
 
 
 
 
X 
 
 
 
 
 
X 
 
 
X 
 
 
Serum Creatinine4,5 
 
 
 
 
 
X 
 
 
 
 
 
X 
 
 
X 
 
 
1,25(OH)2D4 
 
 
 
 
 
X 
 
 
 
 
 
X 
 
 
X 
 
 
2-Hour Urine4,5 
 
 
 
 
 
X 
 
 
 
 
 
X 
 
 
X 
 
 
Bone Biomarkers4,6 
 
 
 
 
 
X 
 
 
 
 
 
X 
 
 
X 
 
 
EFFICACY 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
99mTc Bone Scan7 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
BPI, BFI, SF-3610 
 
 
 
 
 
X 
 
 
 
 
 
X 
 
 
X 
 
 
Ambulatory Status11 
 
 
 
 
 
X 
 
 
 
 
 
X 
 
 
X 
 
 
PHARMACOKINETICS 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Serum KRN23 
 
 
 
 
 
X 
 
 
 
 
 
X 
 
 
X 
 
 
SAFETY 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Vital Signs12 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
Weight 
 
 
 
 
 
X 
 
 
 
 
 
X 
 
 
X 
 
 
Physical Examination 
 
 
 
 
 
X 
 
 
 
 
 
X 
 
 
X 
 
 
Concomitant 
Medications 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 

Protocol Number: UX023T-CL201 
Amendment 6 
26 September 2019 
 
 
 
 
Proprietary and Confidential 
Page 31 
VISIT TYPE/NUMBER2 
 
HH 
V72 
HH 
V73 
HH 
V74 
HH 
V75 
V76 
HH 
V77 
HH 
V78 
HH 
V79 
HH 
V80 
HH 
V81 
V82 
HH 
V83 
HH 
V84 
V85 
Safety 
Follow-up 
TC23 
Safety 
Follow-up 
TC24 
STUDY WEEK 
HH 
Q2W22 
248 
252 
256 
260 
264 
268 
272 
276 
280 
284 
288 
292 
296 
W300/ 
EOS/ET3 
6 Weeks 
From Last 
Dose 
12 Weeks 
From 
Last Dose 
Adverse Events 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Chemistry,13 
Hematology14 
 
 
 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
Anti-KRN23 Antibody  
 
 
 
 
 
X 
 
 
 
 
 
X 
 
 
X 
 
 
Serum Calcium4 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
Serum iPTH4 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
25(OH)D 
 
 
 
 
 
X 
 
 
 
 
 
X 
 
 
X 
 
 
Urinalysis 
 
 
 
 
 
X 
 
 
 
 
 
X 
 
 
X 
 
 
24-hour Urine15 
 
 
 
 
 
X 
 
 
 
 
 
X 
 
 
X 
 
 
ECHO, ECG7 
 
 
 
 
 
X 
 
 
 
 
 
X 
 
 
X 
 
 
Renal Ultrasound7,16 
 
 
 
 
 
X 
 
 
 
 
 
X 
 
 
X 
 
 
Tumor Imaging7,17 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
X 
 
 
Tumor Identification18 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
X 
 
 
Urine Pregnancy Test20 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
DRUG 
ADMINISTRATION 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
KRN2321,22 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
1 During the Treatment Extension Period (Weeks 49 – 300), clinic visits will occur at approximately 24-week intervals.  
2 Home health (HH) visits may also be conducted at the clinic depending on proximity of the subject to the investigational site and local availability of home 
health care services. The visit window is ± 3 days. 
3 Upon regulatory approval and commercial availability of KRN23 for the treatment of TIO, subjects will have their End of Study (EOS) Visit, and transition 
to prescription drug, as recommended by their treating physician. Until commercial availability, subjects may continue treatment with KRN23 for up to 
252 weeks in the Treatment Extension Period, or until 31 January 2021, whichever is sooner, and then undergo their EOS Visit. Subjects will undergo an 

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Early Termination (ET) Visit if the subject withdraws consent and discontinues from the study, the subject is discontinued from the study at the discretion of 
the Investigator or Ultragenyx, or the study is terminated. The EOS Visit or ET Visit may be up to 2 days in duration due to the volume of testing; required 
blood draws may be split across 2 days. ECHO will not be performed at the EOS or ET Visit if the assessment was conducted within 3 months of 
termination. 99mTC bone scan will not be performed at the EOS or ET visit if the assessment was performed within 12 months of termination. BPI, BFI, 
SF-36, anti-KRN23 antibody assessment, and serum iPTH will not be performed at the EOS or ET Visit if they were conducted within 4 weeks of 
termination. 
4 Blood and urine to be collected after a minimum overnight fasting time of 8 hours and prior to drug administration.  
5 Fasting 2-hour urine collections for TmP/GFR, TRP, and urinary calcium. Blood draw for serum creatinine should occur at 1 hour into the urine collection.  
6 Bone biomarkers will include serum measures of CTx, P1NP, BALP, and osteocalcin.  
7 May be completed within ± 5 days of the projected visit date to accommodate scheduling.  
8 Targeted radiographs will be completed in the anatomical location where a fracture or pseudo-fracture was identified at Screening every 24 weeks starting at 
Week 72, until resolution or up to Week 240. The skeletal survey at Week 144 will be used to capture the 24-week follow-up targeted radiographs for 
identified fractures or pseudo-fractures.  
9 Skeletal survey includes standard radiographs of the chest, lateral spine, right and left hand/wrist, right and left humerus, right and left radius/ulna, right and 
left femur/pelvis, right and left tibia/fibula, and right and left foot 
10 BPI, BFI, and SF-36 may be completed within ± 5 days of the projected visit date to accommodate scheduling. 
11 Ambulatory assessment will be performed for each subject at the first site visit after proper approvals and consents are obtained and at all site visits 
thereafter.  
12 Vital sign measurements consist of seated systolic/diastolic blood pressure measured in millimeters of mercury (mm Hg), heart rate (beats per min), 
respiration rate (breaths per min), 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.  
13 Serum chemistry panels may include PD parameters (ie, serum phosphorus) and safety parameters of interest (ie, calcium) to avoid duplication of testing. 
See Table 7.5.6.4.1 for a complete list of Clinical Laboratory Assessments for Safety.  
14 Complete blood count, differential, and platelet count.  
15 24-hour urine collections for urinary phosphorus, calcium, creatinine, and eGFR; fasting 2-hour urine collections for TmP/GFR, TRP, and urinary 
calcium/creatinine ratio.  
16 Screening results will be treated as Baseline data.  
17 Subjects with a TIO diagnosis only. If visible at Screening, the tumor will be imaged every 24 weeks through Week 144 and then every 48 weeks for the 
remainder of the study using the same radiologic imaging technique (eg, CT scan or MRI) used to identify the tumor in order to assess the size of the tumor. 
For subjects in whom the tumor is identified during the study by 68Ga-DOTATATE positron emission tomography (PET)/computed tomography (CT) or 
another method, tumor imaging (CT or MRI, at the discretion of the Investigator) should be performed within 21 (± 7) days of identification to assess tumor 
size, at an unscheduled visit if necessary, and thereafter every 48 weeks per the Schedule of Events. If the MRI/CT imaging following tumor identification 

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has occurred within 3 months of the next scheduled MRI/CT assessment, the scheduled assessment will be skipped. Tumor imaging will not be performed at 
the EOS/ET Visit if it has been performed within the past 12 months. 
18 To be performed only in subjects with TIO for whom the tumor was not identified at Baseline or for subjects who have a clinical indication of a possible new 
tumor every 48 weeks (or in alignment with regularly scheduled clinic visits) after Week 120. The preferred imaging technique is 68Ga-DOTATATE 
PET/CT. Octreotide-SPECT (SPECT/CT) or FDG-PT/CT may be used if 68Ga-DOTATATE PET/CT is not available. (If none of these methods are 
available, another imaging technique may be used at Investigator discretion.) Tumor identification will not be performed at the EOS or ET visit if it has been 
performed within the past 12 months. 
19 A blood sample for PHEX mutational analysis will be collected at Week 96 or the next appropriate visit after appropriate approvals and consents have been 
obtained for any subject who experienced TIO symptoms beginning in childhood and for whom a causative tumor has not been identified. A PHEX 
mutational analysis previously performed by a qualified laboratory as part of routine medical care may be used if available.  
20 For women of childbearing potential only, a serum pregnancy test will be performed in the event of a positive or equivocal urine pregnancy test. 
21 After the starting dose, doses of KRN23 will be titrated in an effort to achieve a target fasting serum phosphorus range of 2.5 to 4.0 mg/dL (see 
Table 7.4.5.1). If the subject’s peak serum phosphorus level at Week 2 remains below the target range, the subject’s dose may be increased at Week 4 to 
0.6 mg/kg, at the discretion of the Investigator. Doses will then be titrated in increments of 0.2 mg/kg at Weeks 8, 12, and 16 in individual subjects to 
achieve a target peak serum phosphorus range. If needed, the final dose adjustment increment may be less than the specified increment to reach the 
2.0 mg/kg dose. Doses may be titrated at later visits, at the discretion of the Investigator, if there are concerns about safety or suboptimal efficacy, or if a 
subject undergoes treatment of the underlying tumor (see Table 7.4.5.2 and Table 7.4.5.3).  
22 Dosing frequency may be increased to Q2W dosing if the subject reaches a dose of 2.0 mg/kg Q4W and serum phosphorus levels remain below the lower 
limit of normal on 2 consecutive trough measurements (see Table 7.4.5.2). Additional HH visits will be scheduled for Q2W dose administration if necessary. 
Vital signs, adverse events, and concomitant medications will also be collected at these additional HH visits. 
23 The site personnel will initiate a Safety Follow-up telephone call (TC) approximately 6 weeks (+ 5 days) after the last dose of study drug to collect 
information on any ongoing or new AEs, SAEs, or concomitant medications. An additional Safety Follow-up TC will occur at 12 weeks (+ 5 days) after the 
last dose of study drug (see footnote 24). If subjects have started receiving KRN23 (burosumab) via an alternative mechanism (eg, commercial treatment) by 
the time of the 6-week Safety Follow-up TC, the 12-week Safety Follow-up TC may not be necessary.  
24 Only for subjects not continuing KRN23 (burosumab) therapy under commercial use or another mechanism at the time of the 6-week Safety Follow-up TC. 
The site personnel will initiate a Safety Follow-up TC at 12 weeks (+ 5 days) after the last dose of study drug to collect information on any ongoing or new 
AEs, SAEs, or concomitant medications. 

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3 TABLE OF CONTENTS 
1 TITLE PAGE .......................................................................................................................1 
2 SYNOPSIS ...........................................................................................................................5 
3 TABLE OF CONTENTS ...................................................................................................34 
4 LIST OF ABBREVIATIONS AND DEFINITION OF TERMS ......................................39 
5 INTRODUCTION .............................................................................................................42 
5.1 Study Rationale .........................................................................................................42 
5.2 Overview of the Disease ...........................................................................................43 
5.3 Brief Overview of the Development of the Product .................................................44 
5.3.1 
Brief Description of the Investigational Product .........................................44 
5.3.2 
Nonclinical Studies ......................................................................................45 
5.3.3 
Previous and Ongoing Clinical Studies .......................................................46 
5.4 Summary of Overall Risks and Potential Benefits ....................................................50 
6 STUDY OBJECTIVES ......................................................................................................51 
7 INVESTIGATIONAL PLAN ............................................................................................53 
7.1 Overall Study Design and Plan .................................................................................53 
7.2 Discussion of Study Design, Including Choice of Control Group ............................55 
7.3 Selection of Study Population ...................................................................................55 
7.3.1 
Inclusion Criteria .........................................................................................55 
7.3.2 
Exclusion Criteria ........................................................................................56 
7.3.3 
Removal of Subjects from Therapy or Assessment ....................................57 
7.3.3.1 
Stopping Rules .............................................................................58 
7.4 Treatments .................................................................................................................58 
7.4.1 
Treatments Administered ............................................................................58 
7.4.2 
Identity of Investigational Product(s) ..........................................................59 
7.4.2.1 
Investigational Test Product ........................................................59 
7.4.2.2 
Placebo or Active Comparator .....................................................59 

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7.4.3 
Method of Assigning Subjects to Treatment Groups ..................................59 
7.4.4 
Selection of Doses in the Study ...................................................................59 
7.4.5 
Selection and Timing of Dose for Each Subject .........................................60 
7.4.5.1 
Dosing in Subjects Undergoing Treatment of Underlying 
Tumor ...........................................................................................63 
7.4.6 
Blinding .......................................................................................................64 
7.4.7 
Prior and Concomitant Therapy ..................................................................64 
7.4.7.1 
Prohibited Medications ................................................................64 
7.4.7.2 
Permitted Medications .................................................................65 
7.4.8 
Treatment Compliance ................................................................................65 
7.5 Study Procedures and Assessments ..........................................................................65 
7.5.1 
Schedule of Events ......................................................................................66 
7.5.2 
Primary Efficacy Assessments ....................................................................66 
7.5.3 
Additional Pharmacodynamic Measurements .............................................67 
7.5.4 
Clinical Assessments ...................................................................................67 
7.5.4.1 
Clinical Outcomes Measurements ...............................................68 
7.5.4.2 
Patient Reported Outcomes Measurements .................................69 
7.5.4.3 
Bone Health Measurements .........................................................69 
7.5.4.4 
Ambulatory Assessment ..............................................................70 
7.5.5 
Pharmacokinetic Measurements ..................................................................70 
7.5.6 
Safety Measurements ..................................................................................70 
7.5.6.1 
Medical History ...........................................................................70 
7.5.6.2 
Concomitant Medications/Therapies ...........................................71 
7.5.6.3 
Adverse Events ............................................................................71 
7.5.6.4 
Clinical Laboratory Tests for Safety ............................................72 
7.5.6.5 
Anti-KRN23 Antibody Screening................................................73 
7.5.6.6 
Renal Ultrasound and Glomerular Filtration Rate .......................74 
7.5.6.7 
Echocardiogram ...........................................................................74 

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7.5.6.8 
Electrocardiogram ........................................................................74 
7.5.6.9 
Tumor Imaging ............................................................................74 
7.5.6.10 
Vital Signs and Weight ................................................................75 
7.5.6.11 
Physical Examination...................................................................75 
7.5.6.12 
Pregnancy Testing and Contraception .........................................76 
7.5.6.13 
Dose Limiting Toxicity ................................................................77 
7.5.7 
Appropriateness of Measurements ..............................................................77 
7.6 Statistical Methods and Determination of Sample Size ............................................78 
7.6.1 
Efficacy Endpoints ......................................................................................79 
7.6.1.1 
Primary Efficacy Endpoints .........................................................79 
7.6.1.2 
Secondary Endpoints ...................................................................79 
7.6.1.3 
Exploratory Endpoints .................................................................80 
7.6.2 
Statistical and Analytical Plans ...................................................................80 
7.6.2.1 
Analysis Populations ....................................................................80 
7.6.2.2 
Statistical Principles .....................................................................80 
7.6.2.3 
Demography, Baseline Characteristics, and Disposition .............80 
7.6.2.4 
Efficacy Analyses ........................................................................81 
7.6.2.5 
Safety Analyses ............................................................................82 
7.6.2.6 
Exposure ......................................................................................83 
7.6.2.7 
Anti-KRN23 Antibody Assessment .............................................83 
7.6.3 
Determination of Sample Size .....................................................................83 
8 STUDY CONDUCT ..........................................................................................................84 
8.1 Ethics .........................................................................................................................84 
8.1.1 
Institutional Review Board ..........................................................................84 
8.1.2 
Ethical Conduct of Study ............................................................................84 
8.1.3 
Subject Information and Consent ................................................................84 
8.2 Investigators and Study Administrative Structure ....................................................85 

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8.3 Investigational Product Accountability .....................................................................85 
8.4 Data Handling and Record Keeping .........................................................................86 
8.4.1 
Case Report Forms and Source Documents ................................................86 
8.4.2 
Data Quality Assurance ...............................................................................86 
8.4.3 
Record Retention .........................................................................................87 
8.5 Reporting and Follow-up of Adverse Events ............................................................87 
8.5.1 
Definition of Adverse Events ......................................................................87 
8.5.2 
Severity of Adverse Events .........................................................................88 
8.5.3 
Relationship of Adverse Events to Study Drug ...........................................89 
8.5.4 
Adverse Event Reporting to Ultragenyx .....................................................90 
8.5.4.1 
General .........................................................................................90 
8.5.4.2 
Serious Adverse Events, Serious Adverse Drug Reactions, 
and Requirements for Immediate Reporting ................................90 
8.5.4.3 
Urgent Safety Reporting ..............................................................91 
8.5.4.4 
Adverse Drug Reaction Reporting ...............................................91 
8.5.4.5 
Pregnancy in Subject or Partner ...................................................92 
8.5.4.6 
Safety Contact Information ..........................................................92 
8.6 Financing and Insurance ...........................................................................................92 
8.7 Publication Policy .....................................................................................................92 
9 REFERENCES ..................................................................................................................93 
10 SIGNATURE PAGE .........................................................................................................95 
 
LIST OF TABLES 
Table 2.1: 
Schedule of Events – Screening and Baseline .....................................16 
Table 2.2: 
Schedule of Events – Treatment Period (Weeks 1 – 48) .....................20 
Table 2.3: 
Schedule of Events – Treatment Extension Period1 (Weeks 
49 – 120) ..............................................................................................24 

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Table 2.4: 
Schedule of Events – Treatment Extension Period1 (Weeks 
121 – 192) ............................................................................................26 
Table 2.5: 
Schedule of Events – Treatment Extension Period1 (Weeks 
193 – 244) ............................................................................................28 
Table 2.6: 
Schedule of Events – Treatment Extension Period1 (Weeks 
248 – End of Study) and Safety Follow-up .........................................30 
Table 5.3.3.1: 
Summary of Clinical Studies with KRN23 ..........................................47 
Table 7.4.5.1: 
KRN23 Initial Dose Titration Scheme .................................................61 
Table 7.4.5.2: 
KRN23 Dose Titration Scheme for Dose Adjustments and 
Increases in Dose Frequency from Q4W to Q2W At or After 
Week 96 ...............................................................................................62 
Table 7.4.5.1.1: 
KRN23 Dose Titration Scheme Following Treatment of an 
Underlying Tumor ...............................................................................63 
Table 7.5.6.4.1: 
Clinical Laboratory Assessments .........................................................73 
  

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4 LIST OF ABBREVIATIONS AND DEFINITION OF TERMS 
Abbreviations 
1,25(OH)2D 
1,25-dihydroxyvitamin D 
25(OH)D 
25-hydroxyvitamin D 
6MWT 
6-minute walk test 
ADA 
Anti-drug antibody 
AE 
Adverse event 
ALP 
Alkaline phosphatase 
BALP 
Bone-specific alkaline phosphatase 
BFI 
Brief fatigue inventory 
BPI 
Brief pain inventory 
BS 
Bone surface 
BV 
Bone volume 
CFR 
Code of Federal Regulations 
CRF 
Case Report Form 
CT 
Computed tomography 
CTCAE 
Common Terminology Criteria for Adverse Events 
CTx 
Carboxy terminal cross-linked telopeptide of type 1 collagen 
DLT 
Dose-limiting toxicity 
DXA 
Dual-energy X-ray absorptiometry 
ECG 
Electrocardiogram 
ECHO 
Echocardiogram 
EDC 
Electronic Data Capture 
eGFR 
Estimated glomerular filtration rate 
ENS 
Epidermal nevus syndrome 
EOS 
End of study 
ET 
Early Termination 
EudraCT 
European Union Drug Regulating Authorities Clinical Trials 
FDA 
Food and Drug Administration 
FGF23 
Fibroblast growth factor 23 
GCP 
Good Clinical Practice 
GFR 
Glomerular filtration rate 
HCl 
Hydrochloride 
HH 
Home Health 
HHD 
Hand-held dynamometry 
HIPAA 
Health Insurance Portability and Accountability Act 
ICF 
Informed Consent Form 
ICH 
International Conference on Harmonisation of Technical Requirements 
for Registration of Pharmaceuticals for Human Use 
IgG1 
Immunoglobulin G1 
IND 
Investigational New Drug (Application) 
iPTH 
Intact parathyroid hormone 
IRB 
Institutional Review Board 

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IV 
Intravenous(ly) 
KHK 
Kyowa Hakko Kirin Pharma, Inc. (the Sponsor’s development partner 
for KRN23) 
KRN23 
Investigational product, an anti-FGF23 antibody 
LLN 
Lower limit of normal 
LVH 
Left ventricular hypertrophy 
mAb 
Monoclonal antibody 
MedDRA 
Medical Dictionary for Regulatory Activities 
MLt 
Mineralization lag time 
MRI 
Magnetic resonance imaging 
NOAEL 
No adverse effect level 
OS 
Osteoid surface 
O.Th 
Osteoid thickness 
OV 
Osteoid volume 
P1NP 
Procollagen type 1 N-propeptide 
PD 
Pharmacodynamics 
PET 
Positron emission tomography 
PHEX 
Phosphate-regulating gene with Homology to Endopeptidases located on 
the X chromosome 
PK 
Pharmacokinetics 
PMT 
Phosphaturic mesenchymal tumor 
PT 
Preferred Term 
PTH 
Parathyroid hormone 
QTc 
Corrected QT interval 
Q2W 
Every 2 weeks 
Q4W 
Every 4 weeks 
RLS 
Restless legs syndrome 
SAE 
Serious adverse event 
SAP 
Statistical Analysis Plan 
SC 
Subcutaneous(ly) 
SF-36 
36-item short form health survey 
STS 
Sit-to-stand (test) 
SUSAR 
Suspected unexpected serious adverse reaction  
TC 
Telephone call 
TIO 
Tumor-induced osteomalacia (also known as oncogenic osteomalacia) 
TmP/GFR 
Ratio of renal tubular maximum phosphate reabsorption rate to 
glomerular filtration rate 
TRP 
Tubular reabsorption of phosphate 
USA 
United States of America 
WAL 
Weighted arm lift (test) 
XLH 
X-linked hypophosphatemia 
 
 

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Definition of Terms 
°C 
Degrees Celsius 
dL 
Deciliter 
g 
Gram 
kDa 
Kilodalton 
kg 
Kilogram 
L 
Liter 
mg 
Milligram 
mL 
Milliliter 
mmol 
Millimole 
 

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5 INTRODUCTION 
5.1 
Study Rationale 
KRN23 is a fully human immunoglobulin G1 (IgG1) monoclonal antibody (mAb) that binds 
to and inhibits the activity of fibroblast growth factor 23 (FGF23), leading to an increase in 
serum phosphorus levels. There are multiple disorders (each with a unique underlying cause) 
that result in unusually high circulating levels of FGF23, which in turn results in renal 
phosphate wasting and reduced (or aberrantly normal in relationship to the elevated FGF23 
levels) levels of 1,25-dihydroxy vitamin D (1,25[OH]2D). Across these disorders the clinical 
symptoms are similar and often include osteomalacia (and, in children, rickets), muscle 
weakness, fatigue, bone pain, and fractures. KRN23 has been studied in 1 of these disorders, 
X-linked hypophosphatemia (XLH), in which a mutation in the Phosphate-regulating gene 
with Homology to Endopeptidases located on the X chromosome (PHEX; 
a phosphate-regulating gene with highest expression in bone cells) leads to elevated levels of 
FGF23. In the Hyp mouse model, a relevant murine model of XLH, treatment with a mouse 
anti-FGF23 mAb normalized or ameliorated many of the characteristic abnormalities 
associated with XLH (Aono et al. 2009; Aono et al. 2011). In single- and repeat-dose clinical 
studies in subjects with XLH, subcutaneous (SC) administration of KRN23 consistently 
increased and sustained serum phosphorus levels and tubular reabsorption of phosphate 
(TRP) without a major impact on urine calcium levels or vitamin D metabolism. 
KRN23 (burosumab) was approved by the Food and Drug Administration (FDA) on 
17 April 2018 for the treatment of XLH in adult and pediatric patients 1 year of age and 
older, and a positive European Commission conditional marketing authorization was 
received on 23 February 2018 for the treatment of XLH with radiographic evidence of bone 
disease in children 1 year of age and older and adolescents with growing skeletons. 
Similar to XLH, tumor-induced osteomalacia (TIO), also known as oncogenic osteomalacia, 
is an acquired condition in which tumors, whose pathology is usually phosphaturic 
mesenchymal tumors (PMT), cause excessive ectopic production of FGF23 that leads to 
renal phosphate wasting and impaired vitamin D synthesis. The high levels of FGF23 result 
in a similar biochemical profile to XLH that includes low serum phosphorus, phosphaturia, 
an abnormally low ratio of renal tubular maximum phosphate reabsorption rate to glomerular 
filtration rate (TmP/GFR), elevated alkaline phosphatase (ALP), normal calcium, and low to 
normal levels of 1,25(OH)2D. In TIO, tumors that are typically benign cause excessive 
ectopic production of FGF23, and if the causal tumor can be completely removed, the 
syndrome remits. In patients for whom the tumor is inoperable, the current standard of care 
consists of oral phosphate and/or vitamin D replacement. Efficacy of this treatment is often 
limited; it does not treat the underlying disease; and its benefits must be balanced with 
monitoring for potential risks such as nephrocalcinosis, hypercalciuria, and 
hyperparathyroidism. Epidermal nevus syndrome (ENS) are rare congenital syndromes 
characterized by the presence of epidermal nevi in association with 1 or more other 
developmental abnormalities of other organ systems including the nervous, skeletal, 
cardiovascular, and ocular systems. Hypophosphatemia may rarely be 1 of the skeletal 
manifestations of ENS presenting in children primarily as rickets and in adults as 

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osteomalacia. In all ENS-associated osteomalacia (also known as cutaneous skeletal 
hypophosphatemia syndrome) cases in which serum FGF23 levels were assessed, they were 
found to be elevated (Lim et al. 2014). The source of the excess FGF23 in ENS-associated 
osteomalacia is unclear. Although some previous studies had suggested that the source of 
excess FGF23 was from skin lesions, more recent studies have failed to detect FGF23 protein 
or FGF23 mRNA from samples of skin lesions. Thus, it is possible that an as-yet unknown 
substance produced from the skin may induce FGF23 excess or that FGF23 excess in this 
syndrome may be from dysplastic bone or other skeletal lesions that are often part of the 
constellation of congenital malformations associated with the underlying somatic mosaic 
mutation that forms the basis of ENS-associated osteomalacia. Compared with TIO, 
complete resection and surgical cure leading to removal of the source of excess FGF23 is less 
likely.  
Treatment with oral phosphate and calcitriol as well as excision of these skin lesions have 
produced mixed reports of efficacy (Olivares et al. 1999). In many cases, improvement, if 
any, is modest and transient. 
This is a Phase 2 study designed to assess the efficacy, safety, pharmacokinetics (PK), and 
pharmacodynamics (PD) of KRN23 in subjects with TIO whose tumor is inoperable (defined 
by an inability to localize the tumor or the impractical nature of surgery due to the extent of 
disease or the location of the tumor) or ENS-associated osteomalacia, where skin lesion 
removal therapy is not considered a valid treatment option. It is hypothesized that KRN23 
may provide clinical benefit in this patient population because of the common underlying 
feature: abnormally elevated FGF23 levels. 
5.2 
Overview of the Disease 
TIO, also known as oncogenic osteomalacia, is an acquired condition in which typically 
benign tumors cause excessive ectopic production of FGF23 that leads to renal phosphate 
wasting and impaired calcitriol synthesis. The high levels of FGF23 result in a similar 
biochemical profile to XLH that includes low serum phosphorus, phosphaturia, an 
abnormally TmP/GFR, elevated ALP, normal calcium, and low to normal levels of 
1,25(OH)2D (Drezner 1999). However, because the FGF23 levels observed in TIO far exceed 
those seen in XLH, the clinical syndrome resulting from the renal phosphate wasting is often 
more severe and characterized by poor bone mineralization, fractures, and muscle and bone 
pain. The tumors characteristic of TIO are typically small, slow-growing masses that may be 
located in various areas, including long bones, soft tissues, nasal sinuses, and the groin. 
Most tumors are benign, phosphaturic mesenchymal connective tissue tumors, also known as 
PMTs, although a few cases of malignant tumors have been reported (Folpe et al. 2004; 
Weidner et al. 1987). TIO-related tumors can particularly difficult to find, even with the use 
of high-resolution imaging techniques (Jan de Beur et al. 2002). When the tumor can be 
identified and surgically removed, FGF23 levels decline dramatically and the clinical 
syndrome remits within days to weeks. If the tumor cannot be located, or if the tumor resides 
in an area that precludes surgical excision because of the risk of damage to neighboring 
structures, conventional therapy is the same as with XLH, ie, phosphorus supplementation in 

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combination with calcitriol. In some cases, calcitriol alone is administered 
(Geller et al. 2007). The efficacy of this treatment is limited given the magnitude of the 
FGF23 levels and the severity of the resulting phosphate wasting. Its benefits should be 
weighed against the need for frequent monitoring to mitigate the risks of nephrocalcinosis, 
hypercalciuria, and hyperparathyroidism. 
Epidermal nevus syndromes are rare congenital syndromes, characterized by the presence of 
epidermal nevi in association with 1 or more other developmental abnormalities of other 
organ systems including the nervous, skeletal, cardiovascular, and ocular systems 
(Stavrianeas et al. 2004). The epidermal nevi are non-neoplastic overgrowth of various 
components of skin cells (eg, sebaceous cells- linear sebaceous nevus) that are usually 
distributed linearly along the lines of Blaschko, corresponding to the movement of skin cells 
during embryogenesis. While these epidermal nevi may be limited to the skin, the additional 
systemic abnormalities almost exclusively occur in the setting of extensive skin surface area 
involvement (10 – 60% of the body surface area) consistent with early embryonic somatic 
mutation in multipotent progenitor cells. Specific genetic defects and timing of mutation 
during fetal development influence the varied phenotypes of ENS (Lim et al. 2014). 
Hypophosphatemia may rarely be 1 of the skeletal manifestations of ENS presenting in 
children primarily as rickets and in adults as osteomalacia. In all ENS-associated 
osteomalacia cases in which serum FGF23 levels were assessed, they were found to be 
elevated (Lim et al. 2014). Standard of care with oral phosphate and calcitriol as well as 
excision of these skin lesions have produced mixed reports of efficacy (Olivares et al. 1999). 
In many cases, improvement, if any, is modest and transient.  
5.3 
Brief Overview of the Development of the Product 
A brief overview of existing information on KRN23 is provided here. Comprehensive 
information on KRN23 is contained in the Investigator’s Brochure provided by Ultragenyx, 
which should be reviewed prior to initiating the study. 
5.3.1 
Brief Description of the Investigational Product 
KRN23 is a fully human IgG1 mAb that binds to and inhibits the activity of FGF23. KRN23 
is expressed in Chinese hamster ovary dihydrofolate reductase deficient cells. The secreted 
KRN23 antibody is recovered from the culture medium and purified using a series of 
chromatographic and filtration steps. Based on the amino acid sequence, the predicted 
molecular mass of KRN23 is approximately 140 kDa.  
FGF23 reduces serum phosphorus levels by 2 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. 

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KRN23 has the potential to block or reduce FGF23 action and improve phosphate 
metabolism in patients with TIO or ENS-associated osteomalacia. 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 the ratio of the 
tubular maximum reabsorption rate of phosphate to glomerular filtration rate (TmP/GFR) in 
the kidney and increases the production of 1,25(OH)2D, which also enhances intestinal 
absorption of phosphate. The action on both 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 
patients with TIO or ENS-associated osteomalacia. 
5.3.2 
Nonclinical Studies 
The Sponsor’s development partner, Kyowa Hakko Kirin Pharma, Inc. (KHK), has 
conducted a series of nonclinical pharmacology, PK, and toxicology studies in rabbits and 
cynomolgus monkeys to support the use of KRN23 in clinical studies. Findings of potential 
clinical significance and relevance to this protocol are summarized below; additional 
information is provided in the Investigator’s Brochure. 
• KRN23 binds to human, rabbit, and monkey FGF23 with comparable affinities. In a 
Good Laboratory Practice 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, thus no untoward 
direct-effects of KRN23 are expected in any tissues of normal humans, rabbits, or 
cynomolgus monkeys 
• In a 40-week toxicity study in male and female adult cynomolgus monkeys, KRN23 was 
administered every 2 weeks at doses of 0 (control), 0.03, 0.3, 3, and 30 mg/kg 
intravenously (IV) and 30 mg/kg SC. The main observed histopathological change was 
metastatic mineralization of various soft tissues, including the kidney, eyeball, lung, 
manus, skeletal muscle, and submandibular gland in the 3.0 mg/kg IV and 30 mg/kg SC 
and IV groups. Mineralization in the kidney and eyeball did not show obvious 
reversibility after a 13-week recovery period. The no adverse effect level (NOAEL) was 
0.03 mg/kg for males and 0.3 mg/kg (IV) for females based on the histopathologic 
finding metastatic mineralization; in males mineralization and hyperstosis of cortical 
bone were more severe in males than 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 IV 
• Prolonged and excessive elevation of serum phosphate beyond normal levels was 
associated with soft tissue and organ mineralization including the kidney where 
nephrocalcinosis was observed at the highest doses tested (IV and SC); reversibility of 
mineralization could not be established 

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• The most prominent pharmacologic actions of KRN23 were dose-dependent changes in 
serum inorganic phosphorus and 1,25(OH)2D in rabbits and in 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 of administration 
• 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 in juvenile, adult, and pregnant cynomolgus monkeys 
suggest that the primary toxicological effects of KRN23 are associated with prolonged 
and excessive antagonism of the normal regulatory actions of FGF23 on renal TRP and 
vitamin D metabolism 
5.3.3 
Previous and Ongoing Clinical Studies 
Table 5.3.3.1 summarizes previous and ongoing clinical studies of KRN23. Details of study 
parameters and PK, PD, clinical efficacy, and safety results where available are provided in 
the Investigator’s Brochure.  

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Table 5.3.3.1: Summary of Clinical Studies with KRN23 
Study Number 
Study Design 
Number of 
Subjects 
Dosage and Regimen 
Key Endpoints 
Study 
Status 
XLH in Adults and Children 
KRN23-US-02 
Phase 1, Double-
blind, Randomized, 
Placebo-controlled 
Single-dose, 
Dose-escalation 
Study 
Adults 
38 enrolled 
38 dosed 
38 completed 
Single-dose KRN23 
IV: 0, 0.003, 0.01, 0.03, 0.1, and 0.3 mg/kg (n=17) 
SC: 0, 0.1, 0.3, 0.6 and 1.0 mg/kg (n=12) 
Placebo: (n=9) 
- Safety of single-
dose administered 
IV or SC 
- PK profile, PD 
effect, 
hypersensitivity  
Completed 
KRN23-INT-001 
Phase 1/2, Open-
label, Repeat-dose, 
Dose-escalation 
Study 
 
Adults 
32 enrolled  
29 dosed  
26 completed 
Up to 4 doses of KRN23 (0.05, 0.1, 0.3 and 0.6 mg/kg) 
SC every 28 days over a 120-day period.  
Placebo: (n=1) 
- Safety and 
efficacy of repeat-
doses 
administered SC  
- PD, PK, and QoL 
measures 
Completed 
KRN23-INT-002 
Phase 1/2 Extension 
of KRN23-INT-001 
Study 
 
Adults 
23 enrolled 
23 dosed 
19 completed 
Up to 12 doses of KRN23 (0.05, 0.1, 0.3, 0.6, and 
1.0 mg/kg) SC every 28 days over a 120-day period. 
Placebo: (n=1) 
- Safety and 
efficacy of repeat-
doses 
administered SC  
- PD, PK, and QoL 
Completed 
KRN23-001 
Phase 1, Open-label 
Single-dose Study 
Japanese and 
Korean Adults 
18 enrolled 
18 dosed 
18 completed 
Single-dose KRN23  
SC: 0.3, 0.6 and 1.0 mg/kg 
- Safety and PD 
- PK 
Completed 
UX023-CL203  
Phase 2b Long-term, 
Open-label Extension 
of Studies 
KRN23-INT-001 and 
KRN23-INT-002 
Adults 
20 enrolled 
20 dosed 
KRN23: 0.3, 0.6, or 1.0 mg/kg SC Q4W for a 
minimum of 164 weeks and a maximum of 192 weeks. 
- Safety  
- Efficacy  
- PD, bone health, 
immunogenicity 
Ongoing; 
enrollment 
closed 

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Study Number 
Study Design 
Number of 
Subjects 
Dosage and Regimen 
Key Endpoints 
Study 
Status 
UX023-CL303  
Phase 3, 
Randomized, 
Double-Blind, 
Placebo-Controlled, 
Fixed Dose Study 
Adults  
(18 – 65 yrs) 
134 enrolled 
134 dosed 
KRN23: 1.0 mg/kg SC (rounded to the nearest 10 mg; 
max 90 mg) Q4W for up to 96 weeks (subjects in Japan 
or Korea) or 149 weeks (subjects in US and EU) or 
until availability of another mechanism of KRN23 
Placebo: subjects in the placebo group will receive 
placebo for 24 weeks, and will then cross over to 
KRN23 1 mg/kg. 
- Efficacy 
- PD effect 
- Pain (BPI) and 
other PROs 
- Safety 
 
Ongoing; 
enrollment 
closed 
UX023-CL304 
Phase 3, Open-label, 
Fixed Dose Study 
Adults 
(25 – 65 yrs) 
14 enrolled 
14 dosed 
KRN23 1 mg/kg SC (rounded to the nearest 10 mg; 
max 90 mg) Q4W for up to 96 weeks (non-US 
subjects) or 141 weeks (US subjects). 
- Bone 
histomorphometry 
- PD, PROs 
- Safety 
Ongoing; 
enrollment 
closed 
UX023-CL201 
Phase 2, Open-label 
Repeat-dose, Dose–
finding Study 
Children  
(5 – 12 yrs)  
52 enrolled 
52 dosed 
52 completed 
KRN23 SC Q2W (0.1 – 2.0 mg/kg) or Q4W (0.2 – 2.0 
mg/kg) for a 16-week dose Titration Period and a 48-
week Treatment Period, followed by KRN23 SC Q2W 
for a 96-week Treatment Extension Period. For US 
subjects, an additional 56-week Treatment Extension 
Period is included. 
KRN23 dose is adjusted Q4W during the Titration 
Period in 0.3 mg/kg increments, and titration may 
continue during the Treatment Period until the target 
serum phosphorus range is reached. For subjects 
receiving KRN23 Q4W, dosing is adjusted at 60% of 
their Q4W dose during the Treatment Extension period 
to maintain serum phosphorus in the target range. 
- Dose and dose 
regimen 
- Safety and PD of 
repeat-doses  
- Efficacy 
- PK and QoL 
Completed 
UX023-CL205 
Phase 2, Open-label 
Study 
Children 
(1 – 4 yrs)  
13 enrolled 
13 dosed 
KRN23 SC Q2W at a starting dose of 0.8 mg/kg to a 
maximum of 1.2 mg/kg for 64 weeks, with an 
additional 96-week Treatment Extension Period. 
 
- Safety and PD 
- Efficacy 
- Functional 
disability and pain 
- PK 
Ongoing; 
enrollment 
closed 

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Study Number 
Study Design 
Number of 
Subjects 
Dosage and Regimen 
Key Endpoints 
Study 
Status 
UX023-CL301 
Phase 3, Open-label, 
Active-controlled 
Study 
Children 
(1 to ≤ 12 yrs)  
61 enrolled 
61 dosed 
KRN23 SC Q2W up to 64 weeks. Target dose of 
0.8 mg/kg. Dose may be increased to 1.2 mg/kg at any 
time during the study if serum phosphorus increased by 
< 0.5 mg/dL from Baseline. The maximum allowable 
dose is 90 mg.  
Active control: oral phosphate and active vitamin D 
individualized for each subject at Investigator’s 
discretion within expert guidelines. 
For subjects in the US, Canada, EU, and Australia, a 
76-week Treatment Extension Period is included, 
during which subjects in the active-comparator 
controlled group will crossover to receive KRN23 
treatment.  
- Efficacy 
- Safety and PD 
- Functional 
disability and pain  
- PK and QoL 
Ongoing; 
enrollment 
closed 
KRN23-003 
Phase 3, Open-label 
Study 
Children (1 to 
≤ 12 yrs) 
15 enrolled 
15 dosed 
KRN23 SC Q2W up to Week 88 or until commercial 
product is available, whichever comes first. Target 
dose of 0.8 mg/kg. Dose may be increased to 1.2 mg/kg 
at any time during the study if serum phosphorus 
increased by ≤ 0.5 mg/dL from Baseline.  
- Safety 
- Efficacy 
- PK 
- PD 
Ongoing; 
enrollment 
closed 
KRN23-004 
Phase 3, Open-label, 
Long-term Extension 
Study  
28 planned  
 
Adults:  
18 enrolled 18 
dosed 
 
Children:  
1 enrolled  
1 dosed  
Adults: KRN23 1 mg/kg SC (max 90 mg) Q4W, until 
commercial product is available, or the end of 
September 2020, whichever comes first. 
Children: Target dose of 0.8 mg/kg (minimum 10 mg) 
Q2W, until commercial product is available, or the end 
of September 2020. Dose may be increased to 
1.2 mg/kg or 2.0 mg/kg at any time during study if 
serum phosphorus increased by ≤ 0.5 mg/dL from 
Baseline. 
- Safety 
- Efficacy 
- PD effect 
- PK 
 
Ongoing; 
enrollment 
open 
BUR-02 
Phase 3, Open-label, 
Long-term Extension 
Study 
38 adults 
planned 
24 enrolled 
22 dosed  
KRN23 1 mg/kg SC (max 90 mg) Q4W for up to 120 
weeks. 
- Safety 
- Efficacy 
- PROs 
Ongoing; 
enrollment 
open 
TIO and ENS-associated Osteomalacia in Adults 
KRN23-002 
Phase 2, Open-label 
Study 
Japanese and 
Korean Adults  
13 enrolled 
KRN23 SC Q4W 0.3 – 2.0 mg/kg for up to 140 weeks 
or until commercial product is available, whichever 
comes first. 
- Efficacy 
- Safety 
- PK, PD 
Ongoing; 
enrollment 
closed 

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5.4 
Summary of Overall Risks and Potential Benefits 
The efficacy and safety of KRN23 in XLH has been established in a total of 13 completed 
and ongoing clinical studies (Section 5.3.3), which include a broad patient population 
ranging from 1 year of age to adults. In total, more than 200 adults and children with XLH 
have received KRN23 at various doses (up to 2 mg/kg every 2 weeks) and for durations up to 
214 weeks. These studies have demonstrated that KRN23 treatment blocks FGF23 and leads 
to a sustained increase in serum phosphorus levels and restoration of phosphate homeostasis, 
thereby improving key manifestations of XLH in children and adults. In children with XLH, 
KRN23 treatment substantially improved rickets, growth, physical function, and pain. 
In adults with XLH, KRN23 treatment improved skeletal health, including osteomalacia; 
improved the healing of fractures and pseudofractures; improved physical function; and 
reduced subject-reported stiffness and pain.  
Across all studies in XLH, KRN23 was well tolerated and demonstrated an acceptable safety 
profile with no significant safety concerns. Most adverse events were mild to moderate in 
severity and no KRN23-related deaths have occurred. In the adult placebo-controlled study in 
XLH, most frequent adverse events related to KRN23 were injection-site reactions in 
children and restless legs syndrome (RLS) in adults. Injection-site reaction events were mild 
in severity and readily managed. RLS events were generally mild to moderate in severity and 
often occurred in the setting of medical or family history of RLS. In adults, serum 
phosphorus levels above the normal range occurred in < 10% of subjects and were transient, 
mild, and reversible. No clinically meaningful changes related to potential ectopic 
mineralization were observed. Although ectopic mineralization is a known risk related to 
XLH disease, and is exacerbated by the current standard of care consisting of oral phosphate 
and/or 1,25(OH)2D supplementation, KRN23 does not appear to be associated with 
progression of cardiac or renal ectopic mineralization beyond the natural course of 
pre-existing disease. 
In conclusion, KRN23 inhibits the effects of FGF23, restoring phosphate, vitamin D, and 
bone metabolism homeostasis. By targeting FGF23 and correcting hypophosphatemia, it is 
expected that the underlying osteomalacia will be treated in subjects with TIO and 
ENS-associated osteomalacia, leading to improved clinical outcomes including a potential 
reduction in pain, fatigue, and fracture risk, as well as the impact of these factors on the 
health-related quality of life of adult patients with TIO. To date, KRN23 has a favorable 
safety profile without evidence of increased ectopic mineralization or other safety concerns 
associated with excess FGF23. Overall, based on the scientific rationale, unmet medical 
need, and results from nonclinical studies and clinical studies to date, investigation of 
KRN23 is warranted in patients with TIO/ENS-associated osteomalacia for whom complete 
surgical tumor/lesion resection is not a viable treatment option. 

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6 STUDY OBJECTIVES 
The primary objectives of this study are to evaluate the following: 
• Effect of KRN23 treatment on increasing serum phosphorus levels in adults with TIO or 
ENS-associated osteomalacia  
• Effect of KRN23 treatment on improvement in TIO/ENS-associated osteomalacia as 
determined by the following histomorphometric indices: 
o Osteoid thickness (O.Th) 
o Osteoid surface/Bone surface (OS/BS) 
o Osteoid volume/Bone volume (OV/BV) 
o Mineralization lag time (MLt) 
Secondary objectives of the study are to evaluate the following:  
• The PD profile of KRN23 as assessed by changes from Baseline over time in additional 
measures of serum phosphorus, serum FGF23, alkaline phosphatase (ALP), and 
1,25(OH)2D; TRP and TmP/GFR (the ratio of renal tubular maximum phosphate 
reabsorption rate to glomerular filtration rate) 
• Effects of KRN23 on bone turnover markers, including bone-specific ALP (BALP), 
carboxy terminal cross-linked telopeptide of type I collagen (CTx), procollagen type 1 
N-propeptide (P1NP), and osteocalcin 
• Functional outcomes including upper and lower extremity muscle strength, walking and 
reaching ability, and mobility 
• Patient-reported outcomes including self-reported pain, fatigue, and health-related quality 
of life 
The PK objective of the study is to: 
• Determine the PK profile of repeat SC injections of KRN23 at Baseline (Weeks 0, 2, 
and 4) and 6 months (Weeks 20, 22, and 24) in subjects with TIO or ENS-associated 
osteomalacia 
Exploratory objectives of the study are to evaluate the following: 
• Changes in additional histomorphometry parameters in trans-iliac crest bone biopsies 
including both structural and dynamic measures 
• Changes in underlying skeletal disease/osteomalacia as assessed by skeletal 
survey/standard radiographs, dual-energy X-ray absorptiometry (DXA), 99mTc-labelled 
bone scan, and high-resolution peripheral quantitative computed tomography (CT) 
(XtremeCT; where available) 

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The safety objective of the study is to: 
• Assess the safety of KRN23 administration in subjects with TIO or ENS-associated 
osteomalacia, based on adverse events (AEs), laboratory assessments, cardiac imaging, 
renal ultrasound, and immunogenic response  
 
 

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7 INVESTIGATIONAL PLAN 
7.1 
Overall Study Design and Plan 
UX023T-CL201 is an open-label, Phase 2 study of KRN23 in adult subjects with TIO or 
ENS-associated osteomalacia. Approximately 15 subjects with TIO or ENS-associated 
osteomalacia with inoperable disease (defined as ‘the inability to localize the tumor or the 
impractical nature of surgery due to the extent of disease or the location of the tumor’), will 
be enrolled. The study will include an initial 48-week Treatment Period, a Treatment 
Extension Period of up to 252 weeks, and a Safety Follow-up Period of up to 12 weeks from 
the last dose of study drug to determine the efficacy, safety, PK, and PD of repeat SC 
injections of KRN23.  
Subjects will be brought in for a Screening Visit and asked to provide written informed 
consent. An extensive review of historical records and images will be conducted to confirm 
the diagnosis and to determine the extent of the lesion and severity of disease. Subjects will 
be selected for Screening only if they are deemed to be inoperable for cure. A historical 
tumor image may be used as the Screening image if it was obtained within 12 months of 
Screening. 
Subjects who are eligible for Screening will discontinue oral phosphate and vitamin D 
metabolite therapy at least 2 weeks prior to the Screening Visit and may not resume 
supplementation for the duration of the study. After Screening biochemistry parameters 
confirm eligibility, subjects will be provided a tetracycline (eg, tetracycline hydrochloride 
[HCl] and demeclocycline) to take prior to the Baseline Visit to facilitate histomorphometric 
analysis of the trans-iliac crest bone biopsy (refer to Section 7.5.4.3). Note that the bone 
biopsy is not required at the Baseline Visit if a previous bone biopsy performed within 
12 months of Screening confirmed the diagnosis of osteomalacia, the subjects’ clinical 
manifestations have not changed significantly since the time of the previous 
biopsy/diagnosis, and the tissue collected at that biopsy is made available for testing for this 
protocol.  
The Baseline Visit will be conducted over approximately 4 days, including overnight stay if 
deemed necessary by the Investigator. Fasting blood samples and urine collections (of 2- and 
24-hour durations), as well as predose Baseline safety and efficacy assessments (excluding 
bone biopsy) will occur on the first 1 to 2 days of the Baseline Visit. On the day following 
these assessments, a trans-iliac crest bone biopsy will be performed (refer to Section 7.5.4.3). 
No other assessments are to be performed or any study drug administered on that day. On the 
day following the biopsy (Day 0, Week 0), subjects will receive their first SC injection(s) of 
KRN23.  
All enrolled subjects will begin treatment with KRN23 every 4 weeks (Q4W) at a starting 
dose of 0.3 mg/kg (Week 0). Doses of KRN23 will then be titrated in an effort to achieve a 
target fasting serum phosphorus range of 2.5 to 4.0 mg/dL (details are described in 
Section 7.4.5). If the subject’s peak serum phosphorus level at Week 2 remains below the 

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target range, the subject’s dose may be increased at Week 4 to 0.6 mg/kg, at the discretion of 
the Investigator. Doses will then continue to be titrated in increments of 0.2 mg/kg at 
Weeks 8, 12, and 16 in individual subjects to achieve the target peak serum phosphorus 
range. Doses may be titrated at later visits, at the discretion of the Investigator, if there are 
concerns about safety or suboptimal efficacy, or if a subject has not yet achieved the target 
range of serum phosphorus (refer to Section 7.4.5). Doses of KRN23 will be adjusted 
downward if serum phosphorous levels range from 4.0 to 4.5 mg/dL. Doses of KRN23 will 
be skipped if serum phosphorous levels exceed 4.5 mg/dL. Doses will be interrupted and may 
be retitrated if a subject undergoes treatment of the underlying tumor (ie, radiation therapy or 
excision) at any point during the study (refer to Section 7.4.5).  
Subjects will be enrolled consecutively. The incidence, frequency, and severity of AEs and 
serious AEs (SAEs); AEs leading to discontinuation; deaths; clinically significant laboratory 
parameters (serum chemistry, hematology, and urinalysis); as well as serum intact 
parathyroid hormone (iPTH), phosphorus, 1,25(OH)2D, creatinine, calcium:creatinine ratio, 
and serum and urinary calcium will be reviewed periodically on an ongoing basis coincident 
with formal data snap shots. If a dose-limiting toxicity (DLT; a Grade ≥ 3 toxicity that is 
probably or possibly treatment related or a confirmed serum phosphorus level ≥ 6.5 mg/dL) 
is identified at any point, the study will be paused until all of the efficacy and safety data 
collected to date are reviewed to evaluate the overall risks/benefits of the study and to make a 
determination about whether it will continue. 
Upon regulatory approval and commercial availability of KRN23 for the treatment of TIO, 
subjects will have their End of Study (EOS) Visit, and transition to prescription drug, as 
recommended by their treating physician. Until commercial availability, subjects may 
continue treatment with KRN23 for up to 252 weeks in the Treatment Extension Period, or 
until 31 January 2021, whichever is sooner, and then undergo their EOS Visit. Therefore, the 
duration of the Treatment Extension Period will vary for individual subjects, and will be 
determined by the time from the start of Week 49 through their EOS Visit. Upon completion 
of study drug treatment (ie, EOS Visit) or early withdrawal from study (ie, Early Termination 
[ET] Visit), a Safety Follow-up telephone call (TC) will occur approximately 6 weeks 
(+ 5 days) after a subject’s last dose of study drug to collect information on any ongoing or 
new AEs, SAEs, and concomitant medications. An additional Safety Follow-up TC will 
occur approximately 12 weeks (+ 5 days) after the subject’s last dose of study drug. If 
subjects have started receiving KRN23 (burosumab) via an alternative mechanism 
(eg, commercial treatment) by the time of the 6-week Safety Follow-up TC, the 12-week 
Safety Follow-up TC may not be necessary. The end of this study is defined as the last day 
that protocol-specified assessments (including telephone contact) are conducted for the last 
subject.  
Screening, Baseline, and post-treatment PK, PD, efficacy, and safety assessments are shown 
by study visit in Table 2.1, Table 2.2, Table 2.3, Table 2.4, Table 2.5, and Table 2.6. 

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7.2 
Discussion of Study Design, Including Choice of Control Group 
This is a Phase 2 study and is the first study of KRN23 in subjects with TIO or 
ENS-associated osteomalacia. Therefore, this is an open-label study in which there is no 
control arm, and all adult subjects will receive investigational product. Subjects will be 
enrolled sequentially; to minimize any safety risks the first 3 subjects must complete at least 
the first 2 doses with no safety or tolerability issues before the next 12 subjects may be 
enrolled.  
7.3 
Selection of Study Population 
This is the first clinical study of KRN23 in subjects with TIO or ENS-associated 
osteomalacia. This study will be conducted in approximately 15 adult subjects with a clinical 
diagnosis of TIO or ENS-associated osteomalacia who are likely to benefit from treatment 
with KRN23 because they are deemed to have inoperable disease (defined by an inability to 
localize the tumor or the impractical nature of surgery due to the extent of disease or 
the location of the tumor) or if they have ENS-associated osteomalacia and are not being 
considered for skin lesion removal treatment.  
7.3.1 
Inclusion Criteria 
Subjects eligible to participate in this study must meet all of the following criteria at 
Screening:  
1. Have a clinical diagnosis of TIO/ENS-associated osteomalacia based on evidence of 
excessive FGF23 that is not amenable to cure by surgical excision of the offending 
tumor/lesion (documented by Investigator) 
2. Be ≥ 18 years of age 
3. Have a fasting serum phosphorus level < 2.5 mg/dL 
4. Have serum iFGF23 level ≥ 100 pg/mL by Kainos assay 
5. Have a TmP/GFR < 2.5 mg/dL 
6. Have an estimated glomerular filtration rate (eGFR) ≥ 60 mL/min (using Cockcroft-Gault 
formula). Subjects with an eGFR ≥ 30 but < 60 mL/min will be considered eligible so 
long as in the opinion of the Investigator the decline in renal function is not related to 
nephrocalcinosis 
7. Have a corrected serum calcium level < 10.8 mg/dL  
[Corrected serum calcium = serum calcium in mg/dL + 0.8 × (4 – serum albumin in 
g/dL)] 

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8. Females of child-bearing potential must have a negative urine pregnancy test at Screening 
and Baseline and be willing to have additional pregnancy tests during the study. 
Females considered not to be of childbearing potential include those who have not 
experienced menarche, are post-menopausal (defined as having no menses for at least 
12 months without an alternative medical cause) or are permanently sterile because of 
total hysterectomy, bilateral salpingectomy, or bilateral oophorectomy 
9. Participants of child‐bearing potential or fertile males with partners of child-bearing 
potential who are sexually active must consent to use a highly effective method of 
contraception as determined by the site Investigator from the period following the signing 
of the informed consent through the final Safety Follow-up TC (as defined in Section 7.1) 
10. Be willing to provide access to prior medical records to determine eligibility including 
imaging, biochemical, and diagnostic, medical, and surgical history data 
11. Provide written informed consent after the nature of the study has been explained, and 
prior to any research-related procedures 
12. Be willing and able to complete all aspects of the study, adhere to the study visit schedule 
and comply with the assessments (in the opinion of the Investigator) 
7.3.2 
Exclusion Criteria 
Subjects meeting any of the following criteria must not be enrolled in the study: 
1. Have a prior diagnosis of human immunodeficiency virus, hepatitis B, and/or hepatitis C 
2. Have a history of recurrent infection, a predisposition to infection, or a known 
immunodeficiency 
3. Are pregnant or breastfeeding at Screening or are planning to become pregnant (self or 
partner) at any time during the study 
4. Have participated in an investigational drug or device trial within 30 days prior to 
Screening or are currently enrolled in another study of an investigational product or 
device 
5. Have used a therapeutic mAb, including KRN23, within 90 days prior to Screening, or 
have a history of allergic or anaphylactic reactions to any mAb 
6. Have or have a history of any hypersensitivity to KRN23 excipients that, in the judgment 
of the Investigator, places the subject at increased risk for adverse effects 
7. Have used a pharmacologic vitamin D metabolite or its analog (eg, calcitriol, 
doxercalciferol, and paricalcitol), phosphate, or aluminum hydroxide antacids 
(eg, Maalox® and Mylanta®) within 2 weeks prior to Screening or during the study 
8. Have used medication to suppress parathyroid hormone (PTH) (eg, Sensipar, cinacalcet, 
calcimimetics) within 2 months prior to Screening 

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9. Have a history of malignancy within 5 years of study entry with the exception of 
PMT-MCT (Phosphaturic mesenchymal tumors of the mixed connective tissue type) 
tumors or non-melanoma skin cancers such as basal cell skin cancer 
10. Have donated blood or blood products within 60 days prior to Screening 
11. Have a history of allergic reaction to or have shown adverse reactions to a tetracycline 
(eg, tetracycline HCl and demeclocycline), benzodiazepines, fentanyl, or lidocaine 
12. Have any condition, which in the opinion of the Investigator and Sponsor, could present a 
concern for either subject safety or difficulty with data interpretation 
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 because of poor enrollment or noncompliance, as applicable. 
Subjects may be removed from the study for the following reasons: 
• Occurrence of an unacceptable AE 
• Any clinical deterioration or worsening of serum biochemistries 
• 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 
• Pregnancy in subject 
In addition, a subject may be removed if a previously unidentified causal tumor is identified 
and determined to be amenable to complete resection, consistent with the inclusion criterion 
requiring a tumor that is not amenable to cure by surgical excision. 
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). AEs should be followed until the abnormality stabilizes, resolves, or 
until a decision is made that it is not likely to resolve. If AEs do not return to baseline 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 ET Visit procedures within 4 weeks of discontinuation (Table 2.6).  

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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 and the Principal 
Investigator. 
7.3.3.1 
Stopping Rules 
Individual subjects who experience a Grade 3 or higher SAE that is unexpected and possibly, 
probably, or definitely related to KRN23 (Section 8.5.3) will be assessed by the Investigator 
and reviewed with the Medical Monitor to determine if any actions are needed. In these 
cases, a full clinical investigation will be performed to make a decision regarding what 
actions to take, including whether to recommend stopping the study drug and/or 
discontinuing the subject from the study and informing the Institutional Review Board/Ethics 
Committee (IRB). Subjects who experience unacceptable toxicity as determined by the full 
clinical investigation will be withdrawn from study treatment.  
Individual subjects will be monitored for ectopic mineralization by renal ultrasound and 
echocardiogram (ECHO). If new or clinically significant worsening in mineralization is 
considered clinically meaningful by the Investigator and/or Sponsor and related to study 
drug, the subject will be discontinued from the study. 
In addition, while the study is open for enrollment, after the first 3 subjects have completed 
the Week 8 assessments, those 3 subjects will continue on the study and the safety data 
collected to date will be reviewed by the Sponsor to determine whether to continue adding 
subjects to the study. If a dose limiting toxicity is identified, the study will be paused while 
all of the efficacy and safety data collected to date are reviewed to evaluate the overall 
risk-benefit of the study and make a determination about whether it will continue. 
7.4 
Treatments 
7.4.1 
Treatments Administered 
This is an open-label study of the investigational product KRN23. All subjects will receive 
KRN23 treatment for up to 300 weeks, or until 31 January 2021, whichever is sooner, after 
which subjects will have their EOS Visit. Upon regulatory approval and commercial 
availability of KRN23 for the treatment of TIO, subjects will have their EOS Visit, and 
transition to prescription drug, as recommended by their treating physician. Subjects will 
undergo an ET Visit if 1 of the following occurs: the subject withdraws consent and 
discontinues from the study, the subject is discontinued from the study at the discretion of the 
Investigator or Ultragenyx, or the study is terminated. KRN23 will be administered Q4W. 
All enrolled subjects will begin treatment with KRN23 at a starting dose of 0.3 mg/kg 
(Week 0). Doses of KRN23 will then be titrated Q4W in an effort to achieve a target fasting 
serum phosphorus range of 2.5 to 4.0 mg/dL (as described in Section 7.4.5). All serum 
phosphorus assessments will be taken with subjects in the fasting state. 
If the subject’s peak serum phosphorus level at Week 2 remains below the target range, the 
subject’s dose may be increased at Week 4 to 0.6 mg/kg, at the discretion of the Investigator. 

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Doses will then continue to be titrated in increments of 0.2 mg/kg at Weeks 8, 12, and 16 in 
individual subjects to achieve the target peak serum phosphorus range. Doses may be 
titrated at later visits, at the discretion of the Investigator, if there are concerns about safety or 
suboptimal efficacy or if a subject has not yet achieved the target range of serum phosphorus 
(refer to Section 7.4.5).  
Doses of KRN23 will be adjusted downward if serum phosphorous levels range from 4.0 to 
4.5 mg/dL. Doses of KRN23 will be skipped if serum phosphorous levels exceed 4.5 mg/dL. 
Doses will be interrupted and may be retitrated if a subject undergoes treatment of the 
underlying tumor (ie, radiation therapy or excision) at any point during the study (refer to 
Section 7.4.5). Following a downward dose adjustment, the Investigator together with the 
Medical Monitor will determine how and when to dose titrate up. 
The maximum dose allowed in this protocol is 2.0 mg/kg every 2 weeks (Q2W) (refer to 
Section 7.4.5). If needed, the final dose adjustment increment may be less than the specified 
increment to reach the 2.0 mg/kg dose.  
7.4.2 
Identity of Investigational Product(s) 
7.4.2.1 
Investigational Test Product 
KRN23 is supplied as a sterile, clear, colorless, and preservative-free solution in single-use 
5-mL vials containing 1 mL of KRN23 (30 mg) at a concentration of 30 mg/mL. KRN23 
should be securely stored at 2 to 8°C and protected from light. It should not be frozen. 
KRN23 will be administered SC without dilution. Subjects will receive study drug via SC 
injection to the abdomen, upper arm, or thigh; the injection site will be rotated with each 
injection, including to a different quadrant of the abdomen. No more than 1.5 mL may be 
administered in a single injection. If a subject needs more than 1.5 mL per administration, 
multiple injections must be administered and a different site must be used for each injection.  
7.4.2.2 
Placebo or Active Comparator 
This is an open-label study in which all subjects will receive investigational product. 
No placebo or reference therapy will be administered. 
7.4.3 
Method of Assigning Subjects to Treatment Groups 
All subjects will receive the same investigational product, KRN23, and will follow the same 
dose regimen. Therefore, there is no randomization in this study. 
7.4.4 
Selection of Doses in the Study 
In the first-in-human, single-dose, dose-escalation study of KRN23 (KRN-US-02), IV and 
SC doses were evaluated in subjects with XLH. SC doses ranged from 0.1 to 1.0 mg/kg, and 
meaningful increases in serum phosphorus, TmP/GFR, and serum 1,25(OH)2D levels were 
observed beginning at the 0.3 mg/kg dose level.  

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In a Phase 1/2 multiple-dose, dose-escalation study (KRN23-INT-001), 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 Q4W in subjects with XLH. The 
proportion of KRN23-treated subjects with serum phosphorus levels in the target range 
(> 2.5 to ≤ 4.0 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 were individually selected for each 
subject (up to 1.0 mg/kg every 4 weeks) based on serum phosphorus response (target range 
> 2.5 to ≤ 4.0 mg/dL) and safety considerations. Doses were relatively stable in the extension 
study and were generally either 0.6 or 1.0 mg/kg. Doses up to 1.0 mg/kg administered 
every 4 weeks were well tolerated over a period of 48 weeks.  
In the ongoing pediatric study in patients with XLH, KRN23 doses up to 2.0 mg/kg 
administered Q2W or Q4W are permitted.  
Based on these initial results in subjects with XLH, a starting dose of 0.3 mg/kg, with 
additional KRN23 injections Q4W, was selected for this study. Although the maximum dose 
administered to date in adults with XLH is 1.0 mg/kg Q4W, the maximum dose in this study 
is 2.0 mg/kg Q2W. This dose was selected because it is anticipated that doses > 1.0 mg/kg 
may be needed to bring serum phosphorus levels up to the lower end of the normal range in 
subjects with TIO. Compared to subjects with XLH, FGF23 levels are much higher in 
subjects with TIO and ENS-associated osteomalacia and the associated hypophosphatemia is 
more severe. It is important to note that dose escalation will be limited based on individual 
subject serum phosphorus response (see Section 7.4.5), and no off-target effects have been 
observed to date in nonclinical or clinical studies. Specific safety monitoring procedures, 
based on the target effects of KRN23, have been selected to mitigate safety risk to subjects 
(see Section 7.5.6). 
7.4.5 
Selection and Timing of Dose for Each Subject 
KRN23 will initially be administered Q4W. All subjects will receive a KRN23 starting dose 
of 0.3 mg/kg (at Week 0). Doses of KRN23 will then be titrated in an effort to achieve a 
target fasting peak serum phosphorus range of 2.5 to 4.0 mg/dL based on peak serum 
phosphorus samples obtained 2 weeks after drug administration (described in Table 7.4.5.1). 
If the subject’s peak serum phosphorus level at Week 2 remains below the target range, the 
subject’s dose may be increased at Week 4 to 0.6 mg/kg, at the discretion of the Investigator. 
Doses will then continue to be titrated in increments of 0.2 mg/kg at Weeks 8, 12, and 16 in 
individual subjects to achieve the target peak serum phosphorus range.  

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Table 7.4.5.1: KRN23 Initial Dose Titration Scheme  
Study Week 
Peak Serum Phosphorus Level1 
Dose Adjustment 
Week 2 
< 2.5 mg/dL 
Increase the dose by 0.3 mg/kg to 
0.6 mg/kg at Week 4 
Weeks 8, 12, and 16 
< 2.5 mg/dL 
Increase the dose by 0.2 mg/kg2 
2.5 – 4.0 mg/dL 
Repeat the current dose 
> 4.0 – 4.5 mg/dL 
Reduce the dose by 0.2 mg/kg 
> 4.5 mg/dL 
Skip dose 
1 Peak fasting serum phosphorus level is the phosphorus level at 2 weeks post dose. Peak fasting serum 
phosphorus levels will be measured through Week 16 and at Week 22 or at unscheduled visits if needed. 
Thereafter, dosing decisions will be made based on trough serum phosphorus levels (4 weeks after dose and 
prior to the subsequent dose) obtained at the previous study visit as indicated in Table 7.4.5.2. Local labs may 
be obtained on the day of dosing (prior to the injection) if confirmation of serum phosphorus level is needed 
to determine whether to maintain the current dose level or to titrate the dose. 
2 If a subject’s fasting peak serum phosphorus level has not increased (defined as a change ≤ 0.2 mg/dL) after 
2 consecutive dose escalations, even if the target peak serum phosphorus range has not been achieved, then 
the current dose will be considered that subject’s maintenance dose and will not be escalated further. 
 
Doses may be titrated at later visits, following the initial dose titration phase, at the discretion 
of the Investigator, if there are concerns about safety, suboptimal efficacy, or if a subject has 
not yet achieved the target range of serum phosphorus. To optimize serum phosphorus levels 
throughout the dose cycle, Investigators may increase the dose of KRN23 in 0.5 mg/kg 
increments in those subjects whose trough serum phosphorus level (4 weeks postdose, just 
prior to the next dose) is below the lower limit of normal (< 2.5 mg/dL) on 2 consecutive 
measurements performed at 4-week intervals (Table 7.4.5.2). Trough levels of serum 
phosphorus may be evaluated through unscheduled assessments, if necessary, until a new 
maintenance dose is established (defined as a dose at which 2 consecutive trough serum 
phosphorous levels are within the normal range [2.5 – 4.0 mg/dL]). Dose titration may 
continue up to a dose of 2.0 mg/kg Q4W, until fasting trough serum phosphorus is 
≥ 2.5 mg/dL (Table 7.4.5.2).  
If, after a subject reaches a dose of 2.0 mg/kg Q4W, the trough serum phosphorus level 
remains < 2.5 mg/dL on 2 consecutive trough assessments performed at 4-week intervals 
beginning after the second administration of the 2 mg/kg dose, the dosing frequency may be 
increased to Q2W (Table 7.4.5.2). Subjects transitioning to Q2W dosing should initially 
receive 60% of their established Q4W total dose level (equivalent to 1.2 mg/kg). 
Predose serum phosphorus levels will then be followed through assessments every 4 weeks 
(prior to subsequent doses) for 12 weeks. If, after 12 weeks from the first Q2W dose, predose 
serum phosphorus remains < 2.5 mg/dL, the dose may be increased to 2.0 mg/kg Q2W. 
Predose serum phosphorus levels will then be followed through assessments every 4 weeks 
(prior to subsequent doses) for 12 weeks to ensure that subjects do not experience DLT 
(Section 7.5.6.13). 

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Following a downward dose adjustment, the Investigator together with the Medical Monitor 
will determine how and when to dose titrate up. 
The maximum dose allowed in this study is 2.0 mg/kg Q2W.  
KRN23 will continue to be dosed Q4W or Q2W throughout the study, either at home using 
home health services or at the study site. 
Table 7.4.5.2: KRN23 Dose Titration Scheme for Dose Adjustments and Increases in 
Dose Frequency from Q4W to Q2W At or After Week 96 
Criteria for Dose Adjustments Based on Trough Serum Phosphorous Levels 
Current Dose and 
Frequency 
Trough Serum Phosphorus 
Level1 
Dose/Frequency Adjustment 
< 2.0 mg/kg, Q4W 
2 consecutive levels  
< 2.5 mg/dL at current dose 
Increase the dose by 0.5 mg/kg, up to 
2.0 mg/kg Q4W  
2.5 – 4.0 mg/dL 
Repeat the current dose 
> 4.0 – 4.5 mg/dL 
Reduce the dose by 0.5 mg/kg2 
> 4.5 mg/dL 
Skip dose 
2.0 mg/kg, Q4W 
2 consecutive levels  
< 2.5 mg/dL, 
 beginning after the second 
administration of the 2 mg/kg 
dose 
Initiate Q2W dosing at 60% of the Q4W total 
dose (equivalent to 1.2 mg/kg) 
1.2 mg/kg, Q2W 
Levels remain < 2.5 mg/dL 
after 12 weeks on initial Q2W 
dose3 
Increase dose to 2.0 mg/kg Q2W4 
1 Trough serum phosphorous levels will be measured every 4 weeks, just prior to the next dose. Serum 
phosphorus levels may be measured at unscheduled visits if necessary. 
2 Following a downward dose adjustment, the Investigator together with the Medical Monitor will determine 
how and when to dose titrate up. 
3 Dosing decisions will be based on fasting trough serum phosphorus levels obtained every 4 weeks (prior to 
dosing) for 12 weeks. Local labs may be obtained on the day of dosing (prior to the injection) if confirmation 
of serum phosphorus level is needed to determine whether to maintain the current dose level or to titrate the 
dose.  
4 Predose serum phosphorus levels will be followed through assessments every 4 weeks (prior to subsequent 
doses) for 12 weeks after initiation of 2.0 mg/kg Q2W dosing to ensure that subjects do not experience DLT 
(Section 7.5.6.13). 

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7.4.5.1 
Dosing in Subjects Undergoing Treatment of Underlying Tumor 
If a subject undergoes treatment of the underlying tumor (ie, radiation therapy or excision) at 
any point during the study, KRN23 treatment should be interrupted. If the Investigator with 
the study Medical Monitor determines, based on serum phosphorus levels below the lower 
limit of normal, that the subject should resume KRN23 treatment, the dose should be 
restarted at 0.3 mg/kg Q4W. Serum phosphorus levels should be subsequently monitored 
every 4 weeks for 24 weeks following the resumption of KRN23 treatment through 
unscheduled blood draws at peak (2 weeks postdose ± 3 days) time points. The KRN23 dose 
will be titrated based on peak serum phosphorous levels as indicated in Table 7.4.5.3. 
Thereafter, dosing decisions will be made based on trough serum phosphorus levels 
(4 weeks ± 3 days postdose and prior to the subsequent dose) obtained at the previous study 
visit as indicated in Table 7.4.5.2, and serum phosphorus measurements will proceed 
according to the Schedule of Events (Table 2.1, Table 2.2, Table 2.3, Table 2.4, Table 2.5, 
and Table 2.6). 
Table 7.4.5.1.1: 
KRN23 Dose Titration Scheme Following Treatment of an 
Underlying Tumor 
Criteria for Resuming KRN23 Treatment 
Initial Dose  
If the Investigator with the study Medical Monitor 
determines, based on serum phosphorous below the lower 
limit of normal (< 2.5 mg/dL) that the subject should resume 
KRN23 treatment. 
The dose should be initiated at 0.3 mg/kg Q4W. 
Subsequent Criteria for Dose Adjustments Based on Peak Serum Phosphorous Levels1 
Visit 
Peak Serum Phosphorous Level 
Dose Adjustment 
After initial dose 
If below target range of 
2.5 – 3.5 mg/dL 
Increase the dose by 0.3 mg/kg to 0.6 mg/kg 
at 4 weeks post resuming KRN23 
After subsequent doses 
through 24 weeks post 
resuming KRN23 
< 2.5 mg/dL 
Increase the dose by 0.2 mg/kg 
2.5 – 4.0 mg/dL 
Repeat the current dose 
> 4.0 – 4.5 mg/dL 
Reduce the dose by 0.2 mg/kg 
> 4.5 mg/dL 
Skip dose 
1 Peak fasting serum phosphorus level is the phosphorus level 2 weeks after a KRN23 dose. Peak fasting serum 
phosphorus levels will be measured through 24 weeks post resuming KRN23, with dosing decisions made 
based on peak serum phosphorous levels as indicated. Unscheduled visits can be utilized for assessments as 
needed. Thereafter (> 24 weeks after resuming KRN23), dosing decisions will be made based on trough 
serum phosphorus levels (4 weeks ± 3 days postdose and prior to the subsequent dose) obtained at the 
previous study visit as indicated in Table 7.4.5.2. Local labs may be obtained on the day of dosing (prior to 
the injection) if confirmation of serum phosphorus level is needed to determine whether to maintain the 
current dose level or to titrate the dose. 

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7.4.6 
Blinding 
This is an open-label study in which all subjects will receive investigational product, and 
doses will be individually titrated. Therefore, no blinding or masking procedures of the 
investigational product are necessary. 
7.4.7 
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 7.4.7.1. All concomitant medications taken during the study will be 
recorded in the CRF with indication, dose information, and dates of administration. 
Any changes to concomitant medication will also be documented. Any intervention to treat 
the underlying tumor (ie, radiation therapy or resection) should also be recorded. The 
Investigator should notify the Medical Monitor before initiating treatment of the underlying 
tumor.  
7.4.7.1 
Prohibited Medications 
To be eligible for the study, subjects must agree to discontinue use of certain medications for 
the indicated timeframe prior to dosing with KRN23. These medications will remain 
prohibited throughout the conduct of the study. Any subject who resumes or requires the use 
of any of these medications during the Treatment Period or Treatment Extension Period will 
be discontinued from the study. 
One exception is in the case of a subject who needs to discontinue treatment with KRN23 for 
more than 4 weeks to undergo treatment of the underlying tumor. In this case, treatment with 
oral phosphate and/or pharmacologic vitamin D metabolites may be necessary. Initiation of 
oral phosphate/vitamin D should not begin before 4 weeks after the last dose of KRN23. 
Before resuming KRN23 treatment, 14-day washout of oral phosphate/vitamin D should 
occur, and serum phosphorus below the lower limit of normal should be confirmed (refer to 
Section 7.4.5). 
• Pharmacologic vitamin D metabolites or analogs (eg, calcitriol, doxercalciferol, and 
paricalcitol): 14-day washout required prior to Screening and during study 
• Oral phosphate: 14-day washout required prior to Screening and during study 
• Aluminum hydroxide antacids (eg, Maalox® and Mylanta®): 14-day washout required 
prior to Screening and during study  
• Chronic use of systemic corticosteroids (short courses acceptable if indicated) 
• PTH suppressors (eg, Sensipar®, cinacalcet) 
• Chemotherapeutic agents 

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• 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. 
7.4.7.2 
Permitted Medications 
Other than the medications specifically prohibited in this protocol, subjects may receive 
concomitant medications as required. If serum 25-hydroxy vitamin D (25[OH]D) levels fall 
below 20 ng/mL, oral supplementation with vitamin D, eg, multivitamins (non-active vitamin 
D metabolites) 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. 
7.4.8 
Treatment Compliance 
Trained personnel will administer study drug by SC injection at the investigational site or 
during home health visits as indicated in the Schedule of Events (Table 2.1, Table 2.2, 
Table 2.3, Table 2.4, Table 2.5, and Table 2.6). Each administration of study drug will be 
recorded on the CRF. If a subject does not receive a dose within 21 days of a scheduled dose, 
that dose should be skipped and the next dose will be administered at the next scheduled 
dosing visit. 
7.5 
Study Procedures and Assessments 
Subjects will be brought in for a Screening Visit and asked to provide written informed 
consent. Prior to the visit, extensive review of historical records and images will be 
conducted to confirm the diagnosis, and to determine the extent of the lesion and severity of 
disease. Subjects will be selected for Screening only if they are deemed to be inoperable for 
cure.  
Subjects who are eligible for Screening will discontinue oral phosphate and vitamin D 
metabolite therapy at least 2 weeks prior to the Screening Visit and may not resume 
supplementation for the duration of the study. After Screening biochemistry parameters to 
confirm eligibility, subjects will be provided a tetracycline (eg, tetracycline HCl and 
demeclocycline) to take prior to the Baseline Visit to facilitate histomorphometric analysis of 
the trans-iliac crest bone biopsy. Subjects will be contacted by telephone within 1 week of 
the Screening Visit and directed to take a tetracycline on Days −20, −19, and −18 prior to the 
Baseline Visit. A second telephone call to the subject will occur at least 7 days prior to the 
Baseline Visit and will direct the subject to begin taking a tetracycline on Days −8, −7, and 
−6 prior to the Baseline Visit. XtremeCT of the radius and tibia will be performed between 
the Screening and Baseline Visit (when available). 
All enrolled subjects will begin treatment with KRN23 Q4W at a starting dose of 0.3 mg/kg 
(Week 0). Doses of KRN23 will then be titrated in an effort to achieve a target fasting serum 
phosphorus range of 2.5 to 4.0 mg/dL (details are described in Section 7.4.5).  

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If the subject’s peak serum phosphorus level at Week 2 remains below the target range, the 
subject’s dose may be increased at Week 4 to 0.6 mg/kg, at the discretion of the Investigator. 
Doses will then continue to be titrated in increments of 0.2 mg/kg at Weeks 8, 12, and 16 in 
individual subjects to achieve the target peak serum phosphorus range. Doses may be titrated 
at later visits, at the discretion of the Investigator, if there are concerns about safety or 
suboptimal efficacy (refer to Section 7.4.5). Doses will also be titrated if a subject undergoes 
treatment of the underlying tumor (ie, radiation therapy or excision) at any point during the 
study (refer to Section 7.4.5). 
The Baseline Visit will be conducted over approximately 4 days, including overnight stay if 
deemed necessary by the Investigator. Fasting blood samples, urine collections (of 2- and 
24-hour durations), imaging, and assessments of upper and lower extremity strength and 
function, walking and reaching ability, mobility and self-reported pain, disability and quality 
of life will occur on the first 1-2 days of the Baseline Visit. On the day following these 
assessments, a trans-iliac crest bone biopsy will be performed; the bone biopsy is not 
required at the Baseline Visit if a previous bone biopsy confirmed the diagnosis of 
osteomalacia, the subjects’ clinical manifestations have not changed significantly since the 
time of the previous biopsy/diagnosis, and the tissue collected at that biopsy is made 
available for testing for this protocol. No other assessments are to be performed and no study 
drug is to be administered on that day. The first dose of study drug will be administered the 
day after the biopsy is performed. Subcutaneous injections will be given in the Clinical 
Research Unit with the volume to be determined based on the weight measurement obtained 
on Day −2 (the day prior to dosing) or Day 0 (the day of dosing). Blood samples for PK and 
PD analyses will be obtained on Day 1 (24 hours following the initial dose). Subjects will be 
released from the Clinical Research Unit on Day 1 following the completion of all Day 1 
assessments. Release may be delayed at the discretion of the Investigator if prolonged 
recovery from the biopsy procedure is needed. 
Subjects will receive KRN23 treatment for up to 300 weeks, or up to 31 January 2021, 
whichever is sooner, after which subjects will have their EOS Visit. Upon regulatory 
approval and commercial availability of KRN23 for the treatment of TIO, subjects will have 
their EOS Visit, and transition to prescription drug, as recommended by their treating 
physician (Table 2.6). 
7.5.1 
Schedule of Events 
Parameters to be assessed, along with timing of assessments, are provided in Table 2.1, 
Table 2.2, Table 2.3, Table 2.4, Table 2.5, and Table 2.6. 
7.5.2 
Primary Efficacy Assessments 
First line treatment for TIO is complete tumor resection. However, when either the 
tumor cannot be localized or cannot be completely resected, the current standard of care 
is treatment with phosphorus supplementation, usually along with active vitamin D. 
The primary goals of this treatment are to:  

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• Maintain serum phosphorus levels at the lower end of the age-appropriate normal range 
• Improve or heal osteomalacia, thereby improving its associated symptoms, including 
fractures, bone and muscle pain, and muscle weakness and loss of function. 
Thus, the primary efficacy assessments in the study are as follows: 
• Serum phosphorus: KRN23 binds to and inhibits FGF23. FGF23 plays an important role 
as a specific regulator of serum phosphorus levels. Increasing serum phosphorus directly 
bears on the hypophosphatemia and consequent osteomalacia that characterize TIO and 
ENS-associated osteomalacia. Serum phosphorus levels will be measured pre- and 
post-treatment as indicated in the Schedule of Events (Table 2.1, Table 2.2, Table 2.3, 
Table 2.4, Table 2.5, and Table 2.6). 
• Trans-iliac crest bone biopsy: To assess O.Th, OS/BS, OV/BV, MLt as well as other 
parameters, a bone biopsy will be performed pre- and post-treatment as indicated in the 
Schedule of Events (Table 2.1 and Table 2.2). Note that the bone biopsy is not required at 
the Baseline Visit if a previous bone biopsy performed within 12 months of Screening 
confirmed the diagnosis of osteomalacia, the subjects’ clinical manifestations have not 
changed significantly since the time of the previous biopsy/diagnosis, and the tissue 
collected at that biopsy is made available for testing for this protocol. Bone biopsy 
histomorphometry will be interpreted centrally by trained personnel who are blinded to 
other subject data. 
7.5.3 
Additional Pharmacodynamic Measurements 
In addition to the effects on serum phosphorus, the PD effect of KRN23 will be assessed in 
adults with TIO or ENS-associated osteomalacia, by measuring the following: 
• Urinary phosphorus 
• Serum FGF23 
• Serum ALP 
• Serum 1,25(OH)2D 
• TmP/GFR and TRP 
• Biomarkers of bone remodeling (from blood), including BALP, CTx, P1NP, and 
osteocalcin 
7.5.4 Clinical Assessments 
Clinical efficacy measures will evaluate the effect of KRN23 on bone health and functional 
outcomes in adults with TIO or ENS-associated osteomalacia. Efficacy measures will assess 
bone health (Section 7.5.4.3), clinical outcomes (Section 7.5.4.1), and subject reported 

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outcomes (Section 7.5.4.2). Refer to the Study Reference Manual for additional details on 
clinical efficacy measures. 
7.5.4.1 
Clinical Outcomes Measurements 
Gross motor impairment, including diminished walking ability, pain, and muscle weakness 
are potential complications associated with TIO-related skeletal deformities. Endpoints to 
establish clinical outcomes associated with KRN23 treatment include upper and lower 
extremity strength and function, walking, and reaching ability and mobility.  
Hand-Held Dynamometry (HHD): To assess muscle strength, HHD will be administered 
pre- and post-treatment as indicated in the Schedule of Events (Table 2.1 and Table 2.2). 
Formal training will be conducted with the trained clinicians administering the HHD testing 
to standardize technique and minimize variability. The maximum voluntary isometric 
contraction against a dynamometer will be used to measure bilateral strength in the following 
muscle groups: elbow flexors, elbow extensors, knee flexors and knee extensors. Absolute 
values will be recorded, and the percent of predicted values will be calculated using 
published normative data based on age and gender (Bohannon 1997; Peters et al. 2011). 
Sit-to-stand (STS): To assess lower extremity strength and mobility, the STS test will be 
administered pre- and post-treatment as indicated in the Schedule of Events (Table 2.1, 
Table 2.2). Formal training will be conducted with the trained clinicians administering the 
STS test to standardize technique and minimize variability. Absolute values will be recorded. 
Weighted Arm Lift (WAL): To assess upper extremity strength, mobility and reaching ability, 
the WAL test will be administered pre- and post-treatment as indicated in the Schedule of 
Events (Table 2.1 and Table 2.2). Formal training will be conducted with the trained 
clinicians administering the WAL test to standardize technique and minimize variability. 
Absolute values will be recorded. 
6-Minute Walk Test (6MWT): The 6MWT will be administered by a trained clinician 
(preferably a licensed physical therapist) 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 premeasured course for 6 consecutive minutes. The total distance walked at 
the end of 6 minutes will be recorded in meters. The percent predicted values for the 6MWT 
will be calculated using published normative data based on age, gender, and height 
(Gibbons et al. 2001). 
The 6MWT will be administered at Screening for practice purposes to minimize training 
effects. The 6MWT will also be administered at Baseline (Day –2), and Weeks 12, 24, and 
48. Assistive devices may be used; any use will be noted on the CRF. 

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7.5.4.2 
Patient Reported Outcomes Measurements 
Pain, fatigue, and physical and mental health and quality of life will be assessed using 
validated self-report measures, including the brief pain inventory (BPI), the brief fatigue 
inventory (BFI) and the 36-item short form health survey (SF-36). 
BPI: The BPI will be administered at pre- and post-treatment time points as indicated in the 
Schedule of Events (Table 2.1, Table 2.2, Table 2.3, Table 2.4, Table 2.5, and Table 2.6) to 
assess pain severity and the impact of pain on daily functioning as measured by subject 
self-report.  
BFI: The BFI will be administered at pre- and post-treatment time points as indicated in the 
Schedule of Events (Table 2.1, Table 2.2, Table 2.3, Table 2.4, Table 2.5, and Table 2.6) to 
assess fatigue severity and the impact of fatigue on daily functioning as measured by subject 
self-report.  
SF-36: The SF-36 will be administered at pre- and post-treatment time points as indicated in 
the Schedule of Events (Table 2.1, Table 2.2, Table 2.3, Table 2.4, Table 2.5, and Table 2.6) 
to assess physical and mental health based on summary and subscale scores in: vitality, 
physical functioning, bodily pain, general health perceptions, physical role functioning, 
emotional role functioning, social role functioning, and mental health. 
7.5.4.3 
Bone Health Measurements 
99mTc-labelled Bone Scans: Whole body bone scans will be performed to evaluate bone 
condition and areas of bone damage, including current or prior long bone fractures and the 
presence of pseudo-fractures. Scans will be performed pre- and post-treatment as indicated in 
the Schedule of Events (Table 2.1, Table 2.2, Table 2.3 and Table 2.6), and pre- and 
post-treatment scans will be compared by a central reader who is blinded to time point and 
subject data.  
Dual-energy X-ray absorptiometry: Bone mineral density and content of the lumbar spine 
and hip will be assessed by DXA at pre- and post-treatment time points as indicated in the 
Schedule of Events (Table 2.1, Table 2.2, and Table 2.3).  
Radiographic Assessments: At Screening, skeletal survey (ie, standard radiographs) will be 
obtained of the lateral spine, AP chest, right and left hand/wrist, right and left humerus, right 
and left radius/ulna, right and left femur/pelvis, right and left tibia/fibula, and right and left 
foot as well as any location(s) where the subject is currently experiencing tenderness or pain 
that may reflect underlying pathology, or where the subject has a history of recent 
(< 3 months) fracture(s), or in bones where the bone scan suggests the presence of 
pseudo-fracture, non-vertebral fracture, vertebral fracture or other finding likely deemed 
related to osteomalacia. During follow-up, if a subject develops new symptoms of hip pain, 
rib pain or leg/femur pain, targeted radiographs will be ordered to assess for the presence of 
new fractures or pseudo-fractures. Follow-up targeted radiographs will be completed in the 
anatomical location where a fracture or pseudo-fracture was identified every 12 weeks during 

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the first 48 weeks (at Weeks 24, 36, and 48) and every 24 weeks starting at Week 72, until 
resolution or up to Week 240, as indicated in the Schedule of Events (Table 2.1, Table 2.2, 
Table 2.3, Table 2.4, Table 2.5, and Table 2.6). In addition, at Week 144 (Table 2.4) a 
skeletal survey will be performed. The skeletal survey includes standard radiographs of the 
chest, lateral spine, right and left hand/wrist, right and left humerus, right and left 
radius/ulna, right and left femur/pelvis, right and left tibia/fibula, and right and left foot. 
The skeletal survey at Week 144 will be used to capture the 24-week follow-up targeted 
radiographs for identified fractures or pseudo-fractures.  
Radiographs will be interpreted locally for the identification of new abnormalities, and 
assessed centrally for changes over time. Central readers will be blinded to other subject data. 
XtremeCT: XtremeCT scan of the radius and tibia will be performed (when available) 
pre- and post-treatment as indicated in the Schedule of Events (Table 2.1, Table 2.2, 
Table 2.3 and Table 2.4). As an exploratory efficacy measure, XtremeCT will be used to 
assess bone mineral density and content at the cortical and trabecular compartment. 
XtremeCT administration procedures will be standardized and results will be read locally by 
trained site personnel who are blinded to other subject data. 
7.5.4.4 
Ambulatory Assessment 
To assess ambulatory status, subjects will be asked whether they typically walk within the 
community unassisted, need to use an assistive device (eg, cane, crutches, walker), or cannot 
walk. Ambulatory status at Baseline will be recorded retrospectively. Prospective assessment 
of ambulatory status will occur at all site visits beginning from the first site visit after 
appropriate approvals and consents are obtained and then as indicated on the Schedule of 
Events (Table 2.3, Table 2.4, Table 2.5, and Table 2.6).  
7.5.5 
Pharmacokinetic Measurements 
To assess KRN23 concentration and possible accumulation, serum levels of KRN23 will be 
evaluated as a PK parameter in this study. Predose and postdose blood samples will be 
obtained as indicated in the Schedule of Events (Table 2.1, Table 2.2, Table 2.3, Table 2.4, 
Table 2.5, and Table 2.6). Stored stable samples may be retrospectively evaluated once 
proper approvals and consents are obtained. 
7.5.6 
Safety Measurements 
7.5.6.1 
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 TIO/ENS-associated 
osteomalacia and standard of care treatment. 

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Subjects must be willing to provide access to prior medical records for the collection of 
historical biochemical and radiographic data, as well as disease history. The specific 
diagnosis of TIO/ENS-associated osteomalacia will be recorded, along with date of onset, 
clinical presentation, and date and method of diagnosis.  
TIO/ENS-associated osteomalacia treatment history (including any prior attempts of surgical 
removal) and relevant concomitant medications will be recorded (start date, stop date, dose, 
dose regimen). Treatments may include calcitriol and oral phosphate. Medications include 
investigational, prescription, over-the-counter, herbal and nutritional supplements. 
Any relevant concomitant therapy, including physical/occupational therapy will be recorded. 
PHEX mutation analysis will be performed at Week 96 or at the next visit after appropriate 
approvals and consents are obtained for any subject who experienced symptoms of TIO since 
childhood and for whom the causative tumor has not been identified. If available, 
PHEX mutation analysis previously performed by a qualified laboratory as part of standard 
medical care may be used. The Investigator will communicate any genetic testing results to 
the subject. 
7.5.6.2 
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. 
Concomitant medications and therapies will also be assessed during all Home Health visits 
and during the Safety Follow-up Period (described in Section 7.1). Medications 
(investigational, prescription, over-the-counter, and herbal) and nutritional supplements taken 
during the 30 days prior to Screening will be reviewed and recorded. Therapies (physical 
therapy, occupational therapy as well as mobility and walking devices, including ankle foot 
orthoses, braces, cane, crutches, walker, wheelchair etc.) utilized during the 30 days prior to 
Screening will also be reviewed and recorded. At each subsequent visit, change in 
medications and therapies since the previous visit will be recorded.  
7.5.6.3 
Adverse Events 
All AEs will be recorded from the time the subject signs the informed consent through the 
EOS/ET Visit or Safety Follow-up TC (described in Section 7.1). The determination, 
evaluation, reporting, and follow-up of AEs will be performed as outlined in Section 8.5. 
At each visit, subjects will be asked about any new or ongoing AEs since the previous visit. 
Assessments of AEs will occur at each visit to the investigational site and at all home health 
visits. 
Clinically significant changes from Baseline in physical examination findings, vital signs, 
clinical laboratory parameters, renal ultrasounds, eGFR, ECHO and electrocardiograms 
(ECGs) will be recorded as AEs or SAEs, if appropriate. 

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7.5.6.4 
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 (ie, ALP and serum 
phosphorus) in the routine Chem-20 panel are also designated as PD/efficacy parameters in 
this study (Section 7.5.3). KRN23 biochemical parameters of interest include serum 
25-hydroxyvitamin D, lipase, amylase, total calcium, creatinine, FGF23, iPTH; and urinary 
calcium and creatinine. Reflexive testing for serum amylase isoenzymes will be performed if 
serum amylase levels are elevated by ≥ 2x the upper limit of the reference range. 
Blood and urine samples will be collected at Screening, Baseline, and regular intervals 
throughout the study as indicated in the Schedule of Events (Table 2.1, Table 2.2, Table 2.3, 
Table 2.4, Table 2.5, and Table 2.6). The local lab at the investigational site will be used to 
measure laboratory safety parameters required for study eligibility (except FGF23). Fasting 
for a minimum of 8 hours (overnight) is required prior to each blood draw; the duration of 
fasting will be recorded on the CRF. Twenty-four-hour urine collection is required to assess 
urinary phosphorus:creatinine and calcium:creatinine ratios; urinary phosphorus (a PD 
parameter, Section 7.5.3) will also be obtained from 24-hour urine samples.  
Clinical laboratory parameters to be assessed for safety are provided in Table 7.5.6.4.1. 
See Study Reference Manual for details on sample collection and processing. 

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Table 7.5.6.4.1: 
Clinical Laboratory Assessments 
Chemistry 
Hematology 
Urinalysis 
25(OH) D 
Hematocrit 
Appearance 
1,25(OH)2 D 
Hemoglobin 
Color 
Alanine aminotransferase  
Platelet count 
pH 
Alkaline phosphatase1 
Red blood cell count 
Specific gravity 
Amylase2 
White blood cell count 
Ketones 
Amylase isoenzymes2 
Mean corpuscular volume 
Protein 
Aspartate aminotransferase 
Mean corpuscular hemoglobin 
Glucose 
Bilirubin (direct and total) 
Mean corpuscular hemoglobin 
concentration 
 
Blood urea nitrogen 
 
 
Calcium (total) 
 
 
Chloride 
 
 
Carbon dioxide 
 
24-hour Urine 
Cholesterol (total) 
 
Calcium 
Creatinine 
 
Creatinine 
Gamma-glutamyl transpeptidase  
 
Phosphorus/creatinine ratio 
Glucose 
 
 
FGF23 
 
 
Intact parathyroid hormone  
 
 
Lactate dehydrogenase  
 
 
Lipase 
 
2-hour Urine 
Phosphorus1 
 
Calcium/creatinine ratio 
Potassium 
 
Phosphorus 
Protein (albumin and total) 
 
Creatinine 
Sodium 
 
 
Uric acid 
 
Pregnancy Test 
(if applicable) 
1 Also designated as PD/efficacy parameter. 
2 Will be assessed reflexively if amylase levels are ≥ 2x the upper limit of the reference range. 
 
Subjects who experience an SAE considered to be 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. 
7.5.6.5 
Anti-KRN23 Antibody Screening 
To determine the immunogenicity profile of KRN23, blood samples will be obtained for 
analysis of anti-KRN23 antibodies (anti-drug antibodies [ADA]) at predose and postdose 
time points as indicated in the Schedule of Events (Table 2.1, Table 2.2, Table 2.3, Table 2.4, 
Table 2.5, and Table 2.6). The concentration of anti-KRN23 antibodies in human serum will 
be determined using a validated solid phase extraction with acid dissociation assay and a 
3-tiered strategy: screening assay and specificity confirmation assay followed by titer 
measurement. 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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7.5.6.6 
Renal Ultrasound and Glomerular Filtration Rate 
Renal ultrasounds will be conducted at predose and postdose time points as indicated in the 
Schedule of Events (Table 2.1, Table 2.2, Table 2.3, Table 2.4, Table 2.5, and Table 2.6). 
Ultrasonographic findings of nephrocalcinosis will be graded on a 5-point scale 
(Verge et al. 1991). Central readings will be performed for all Screening and post-treatment 
renal ultrasounds to evaluate changes in calcifications and all other renal abnormalities from 
Baseline (ie, Screening assessment). Results obtained at Screening will serve as Baseline 
data. Central readers will be blinded to all other subject data. 
The eGFR will be calculated via urine collections at predose and postdose time points as 
indicated in the Schedule of Events (Table 2.1, Table 2.2, Table 2.3, Table 2.4, Table 2.5, 
and Table 2.6). Results obtained at Screening will serve as Baseline data. 
7.5.6.7 
Echocardiogram 
ECHO will be performed at predose and postdose time points as indicated in the Schedule of 
Events (Table 2.1, Table 2.2, Table 2.3, Table 2.4, Table 2.5, and Table 2.6). The goal is 
twofold: 1) assess for evidence of ectopic mineralization in the heart and aorta, and 
2) evaluate for signs of left ventricular hypertrophy (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 a central 
reading procedure to ensure consistent criteria across the study are used to assess ECHO 
parameters by trained personnel. Clinically significant abnormalities detected on ECHO will 
be promptly reported to the Principal Investigator for action as appropriate, including 
determining if an AE should be recorded in the CRF. 
7.5.6.8 
Electrocardiogram 
A standardized 12-lead ECG will measure PR, QRS, QT, and corrected QT intervals (QTc) 
at predose and postdose time points as indicated in the Schedule of Events (Table 2.1, 
Table 2.2, Table 2.3, Table 2.4, Table 2.5, and Table 2.6). 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 a single central reader. 
The ECG results will be assessed for any clinically significant abnormality or relevant 
changes from Baseline, and these will be recorded as AEs on the CRF. 
7.5.6.9 
Tumor Imaging 
For subjects with TIO, if the tumor is visible and localized at Screening, it will be imaged at 
Screening and every 24 weeks through Week 144 and then every 48 weeks (or at next 
scheduled visit) for the remainder of the study (Table 2.1, Table 2.2, Table 2.3, Table 2.4, 
Table 2.5, and Table 2.6) using the same radiologic imaging technique (either CT scan or 
magnetic resonance imaging [MRI]) used initially to identify the tumor. Screening images 
will be used as Baseline. If a subject has a historical scan obtained within 12 months of 
Screening, the historical scan may be used as the Screening image. In cases where the tumor 

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was initially identified using another imaging technology, a Baseline CT scan or MRI 
(whichever is more clinically appropriate) will be performed. During follow-up, the same 
imaging technique (CT scan or MRI) that was used at Screening will be utilized to assess 
tumor size. The radiologist will indicate whether tumor size and volume have changed over 
time. If applicable, tumor imaging will be assessed using the mint Lesion™ software.  
For subjects with TIO whose tumor was not identifiable at Screening, evaluations every 
48 weeks (or in alignment with regularly scheduled clinic visits) will be performed beginning 
at Week 120 in an attempt to locate the tumor (Table 2.3, Table 2.4, Table 2.5, and 
Table 2.6). The preferred imaging technique is 68Ga-DOTATATE positron emission 
tomography (PET)/CT. Octreotide-SPECT (SPECT/CT) or FDG-PT/CT may be used if 
68Ga-DOTATATE PET/CT is not available. (If none of these methods are available, another 
imaging technique may be used at Investigator discretion.) Imaging to locate the tumor may 
also be performed at unscheduled visits if there is clinical suspicion of new tumor 
development.  
If the tumor is located and determined to be unresectable, MRI or CT imaging (at the 
discretion of the Investigator) should occur within 21 (± 7) days of identification to assess 
tumor size, at an unscheduled visit if necessary, and thereafter according to the Schedule of 
Events (Table 2.1, Table 2.2, Table 2.3, Table 2.4, Table 2.5, and Table 2.6). If the MRI/CT 
imaging following tumor identification has occurred within 3 months of the next scheduled 
MRI/CT assessment, that assessment will be skipped and the Schedule of Events will be 
followed thereafter. A subject whose tumor is identified and determined to be amenable to 
complete surgical resection may be removed from study (Section 7.3.3).  
7.5.6.10 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 at predose and postdose time points as indicated in the Schedule of Events 
(Table 2.1, Table 2.2, Table 2.3, Table 2.4, Table 2.5, and Table 2.6) before any additional 
assessments are completed and after the subject has rested for 5 minutes. At each site visit, 
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. 
7.5.6.11 Physical Examination 
Complete physical examinations will be performed at predose and postdose time points as 
indicated in the Schedule of Events (Table 2.1, Table 2.2, Table 2.3, Table 2.4, Table 2.5, 
and Table 2.6). During the Treatment Extension Period, physical examinations will be 
performed at site visits only. 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. 

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7.5.6.12 Pregnancy Testing and Contraception 
Female subjects of childbearing potential will have urine pregnancy tests at the time points 
specified in the Schedule of Events (Table 2.1, Table 2.2, Table 2.3, Table 2.4, Table 2.5, and 
Table 2.6). Female subjects with a positive pregnancy test at Screening do not meet 
eligibility criteria for enrollment and will not be enrolled in the study. 
Additional pregnancy tests will be performed at any visit in which pregnancy status is in 
question. A serum pregnancy test will be performed in the event of a positive or equivocal 
urine pregnancy test result, or can be performed if pregnancy test by urine is not feasible. 
Pregnancy in subject or partner must be reported (Section 8.5.4.5); pregnant subjects will be 
discontinued from the study.  
Experience with KRN23 in pregnant women is limited. The study drug may involve risks to a 
pregnant female or unborn baby that are currently unknown.  
Female participants of child-bearing potential who have not undergone a total hysterectomy 
or bilateral salpingo-oophorectomy and are sexually active must consent to use a highly 
effective method of contraception as listed below from the period following the signing of 
the informed consent through Safety Follow-up (as described in Section 7.1). Sexually active 
male participants with female partners of childbearing potential must consent to use a highly 
effective method of contraception listed below from the period following the signing of 
informed consent through 12 weeks after stopping the study drug. Examples of highly 
effective methods (CTFG 2014) include: 
• Combined (estrogen and progestogen containing) hormonal contraception associated with 
inhibition of ovulation (eg, oral, intravaginal, transdermal) 
• Progestogen-only hormonal contraception associated with inhibition of ovulation (eg, 
oral, injectable, implantable) 
• Intrauterine device or intrauterine hormone-releasing system  
• Bilateral tubal occlusion 
• Male sterilization, also called vasectomy  
• Sexual abstinence (ie, 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) 

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7.5.6.13 Dose Limiting Toxicity 
A DLT is defined as the occurrence of any of the following: 
• A Grade ≥ 3 toxicity that is 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 
Sponsor. The outcome of this investigation will determine the subject’s continuation or 
withdrawal from the study, as described in Section 7.3.3.1.  
7.5.7 
Appropriateness of Measurements 
The assessments and timing of assessments used in this study and the variables analyzed are 
typical of those used to evaluate skeletal defects, hypophosphatemia, renal function, and 
vitamin D metabolism in patients with TIO and ENS-associated osteomalacia. The primary 
goal of treatment in TIO and ENS-associated osteomalacia patients with inoperable or 
incompletely resected tumors/lesions is to normalize serum phosphorus levels and correct or 
minimize osteomalacia, fractures, and bone and muscle pain.  
Trans-iliac crest bone biopsies will be performed at Baseline and at Week 48 for assessment 
of bone histology and histomorphometry to evaluate tissue level changes in bone remodeling. 
By performing the procedure before and after treatment with KRN23, each subject will serve 
as an individual control.  
The trans-iliac crest bone biopsy is a well-established tool in research and clinical use for 
evaluating bone tissue in metabolic bone diseases such as renal osteodystrophy, 
osteomalacia, and osteoporosis. Cellular activity and the amount of bone can be accurately 
quantified by histomorphometry, providing information that cannot be obtained through 
other imaging or biochemical studies (Sullivan et al. 1992). Osteomalacia is characterized by 
an accumulation of osteoid tissue, reflecting a prolonged and defective mineralization 
process (Arnstein et al. 1967). Specific histomorphometric parameters chosen to evaluate 
changes in osteomalacia with KRN23 treatment include osteoid thickness, osteoid 
surface/bone surface, and osteoid volume/bone volume, which are static parameters 
providing information about the amount of unmineralized bone (Dempster et al. 2013). 
In addition, mineralization lag time, a dynamic modeling parameter representing the mean 
time interval between the formation of osteoid and its subsequent mineralization, will be 
evaluated (Dempster et al. 2013). In TIO, surgical resection of the tumor has been shown to 
lead to complete resolution of osteomalacia by quantitative histomorphometry on bone 
biopsy (Shane et al. 1997). 

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Hypophosphatemia is the cause of the consequent osteomalacia and other symptoms that 
result in clinical manifestations of TIO and ENS-associated osteomalacia. Serum phosphorus 
will be measured throughout the study to evaluate changes in response to KRN23 treatment. 
FGF23 plays an important role in phosphate homeostasis, and KRN23 binds to and inhibits 
FGF23; serum FGF23 levels will be monitored throughout the 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 levels and TmP/GFR are routinely measured as a part of medical management of 
TIO. Biomarkers of bone formation (P1NP, ALP, BALP, osteocalcin) and resorption (CTx) 
may provide an indication of treatment effect. The relatively extensive panel of biomarkers 
has been included in this 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, DXA, and XtremeCT will be used to evaluate healing of osteomalacia, prior 
fractures, and bone mineral density and bone mineral content. HHD, STS, WAL, and 6WMT 
will be used as performance measures and have been successfully used in other clinical 
development programs with similar diseases. BPI will be used as an assessment of overall 
pain. BFI will be used as an assessment of general fatigue. The SF-36 was included to assess 
physical and mental function and health-related quality of life.  
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. Tumor imaging will be used to assess any changes in localized tumor size in subjects 
with TIO. Since elevated free FGF23 has been associated with LVH in patients with chronic 
kidney disease, ECHO and ECGs will examine the potential risk in TIO and ENS-associated 
osteomalacia subjects.  
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.  

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7.6.1 
Efficacy Endpoints 
All efficacy parameters will be summarized at Baseline and at each observed time that they 
are collected. 
7.6.1.1 
Primary Efficacy Endpoints 
The study will have co-primary endpoints: 
• The proportion of subjects achieving mean serum phosphorus levels above the lower 
limit of normal (LLN; 2.5 mg/dL [0.81 mmol/L]) at the mid-point of the dose interval 
(2 weeks after dosing), as averaged across dose cycles between Baseline and Week 24 
• The change from Baseline in excess osteoid based on analysis of iliac crest bone biopsies 
after 48 weeks of KRN23 treatment using the following histomorphometric indices: 
o O.Th 
o OS/BS 
o OV/BV 
o MLt 
7.6.1.2 
Secondary Endpoints 
• Additional measures to assess serum phosphorus levels over time include: 
o Proportion of subjects achieving mean serum phosphorus levels above the LLN 
(2.5 mg/dL [0.81 mmol/L]) at the end of the dosing cycle (4 weeks after dosing), as 
averaged across dose cycles between Baseline and Week 24 
o Mid-point of dosing cycle: mean change from Baseline and percent change from 
Baseline averaged across dose cycles between Baseline and Week 24 
o End of dosing cycle: mean change from Baseline averaged across dose cycles 
between Baseline and Week 24 
o Cumulative exposure: time-adjusted area under the curve between Baseline and 
Week 24 
• Change from Baseline over time in serum FGF23, ALP, 1,25(OH)2D; and urinary 
phosphorus, TRP, TmP/GFR 
• Change and percent change from Baseline over time in serum biochemical markers of 
bone turnover, including BALP, CTx, P1NP, and osteocalcin 
• Change from Baseline over time in muscle strength as assessed by HHD, STS test, WAL 
test, and 6MWT 
• Change from Baseline in BPI, BFI, and SF-36 over time 

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7.6.1.3 
Exploratory Endpoints 
• Changes in other measures of structural and dynamic histomorphometry in trans-iliac 
crest bone biopsies  
• Changes in bone condition and healing of prior long bone and pseudo-fractures as 
assessed by 99mTc-labelled bone scan 
• Changes in bone mineral density and bone mineral content as measured by DXA at the 
lumbar spine and hip 
• Changes in bone mineral density, bone mineral content, bone geometry, and 
microarchitecture in the cortical and trabecular compartments of the radius and tibia as 
measured by XtremeCT (when available) 
7.6.2 
Statistical and Analytical Plans 
7.6.2.1 
Analysis Populations 
Biopsy Analysis Set: The biopsy analysis set will include enrolled subjects with Baseline and 
follow-up (either Week 48 or ET prior to Week 48) bone biopsy data.  
Full Analysis Set: All efficacy (except bone biopsy endpoints), safety, and PK/PD analyses 
will be performed on the set of all subjects who receive at least 1 dose of investigational 
product. 
7.6.2.2 
Statistical Principles 
Descriptive statistics will be used to summarize the data. For continuous variables, the mean, 
the standard deviation, 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. 
Analyses of the data will be performed when the first 3 subjects have completed their 
Week 12 visit. An additional analysis will occur using all available data when the first 
subject completes the post-treatment bone biopsy and may occur at other time points. 
The final analysis will be performed at the end of the study. 
7.6.2.3 
Demography, Baseline Characteristics, and Disposition 
Demographics (age, sex, and race) and other baseline disease characteristics will be 
summarized using descriptive statistics for the Safety Analysis Set.  
The number of subjects screened, enrolled, treated, and completed will be summarized. 
Subject discontinuation from the study, and from treatment, will each be summarized 
including reason for discontinuation. 

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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. 
7.6.2.4 
Efficacy Analyses 
7.6.2.4.1 
Primary Efficacy Analysis 
The proportion of subjects who achieve a serum phosphorus level above the LLN (2.5 mg/dL 
[0.81 mmol/L]), at 2 weeks after dosing (between baseline and Week 24, on average) will be 
provided, along with the 2-sided 95% confidence interval. Additional analyses of serum 
phosphorus including observed values, change from Baseline, percent change from Baseline 
over time, and area under the curve will be summarized from Baseline to Week 24. 
Histomorphometric indices O.Th, OS/BS, OV/BV, and MLt at Baseline and Week 48, and 
their change from Baseline at Week 48 will be summarized.  
7.6.2.4.2 
Secondary and Exploratory Efficacy Analyses 
Secondary and exploratory efficacy parameters will be summarized at Baseline and at each 
time point they are collected. The changes from Baseline (absolute and percent) will be 
described across subjects in terms of the mean and standard deviation and may be tested 
using the generalized estimating equation method, if the model converges. The models for 
change from Baseline (absolute and percent) will include Baseline, and time (weeks of 
treatment) as a categorical variable. 
Correlations among PD parameters and efficacy endpoints may also be assessed. 
The number and percent of subjects with postdose serum phosphorus levels will be 
summarized by the following ranges:  
• ≤ 2.5 mg/dL (0.81 mmol/L)  
• > 2.5 mg/dL (0.81 mmol/L) but ≤ 4.0 mg/dL (1.13 mmol/L) 
• > 4.0 mg/dL (1.13 mmol/L)  
Individual PD-time plots may be presented for each subject as well as mean PD-time plots. 
Additional analyses using statistical models may be performed. The relationship between 
various PD parameters as well as KRN23 concentrations may be examined. 

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7.6.2.5 
Safety Analyses 
All subjects in the Safety Analysis Data Set will be included in all summaries of safety 
endpoints.  
The safety measures in this study are: 
• Incidence and frequency of AEs, treatment-related AEs, and SAEs 
• Clinically significant changes from Baseline in vital signs, weight, physical examination 
findings, and clinical laboratory tests 
• ECHO, ECG, and renal ultrasound 
• Tumor imaging or dermatologic assessment of skin lesions 
• Concomitant medications 
• Anti-KRN23 antibodies 
7.6.2.5.1 
Adverse Events 
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 (ie, 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. The numbers (frequency) and incidence rates of AEs and SAEs will be 
summarized. Special attention will be given to those subjects who died, discontinued 
treatment because of an AE, or experienced a SAE (eg, summaries, listings, and narrative 
preparation may be provided, as appropriate). 
7.6.2.5.2 
Clinical Laboratory Evaluations 
Clinical laboratory data will be summarized by the type of laboratory test. Reference ranges 
and markedly abnormal results (specified in the SAP) will be used in the summary of 
laboratory data. 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 (ie, outside of reference ranges) and/or clinically significant abnormalities 
will be presented for each clinical laboratory measurement. A list of reference ranges 
standardized across clinical laboratories will be provided. 

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7.6.2.5.3 
Vital Signs 
Vital signs will be summarized and listed by individual subject. Summaries of vital signs 
data over time and changes from Baseline over time will be provided. 
7.6.2.5.4 
Echocardiograms and Electrocardiograms 
Echocardiogram and ECG data will be listed and summarized by individual subject and study 
population. Individual subject results will be examined in relation to Baseline recordings. 
Summaries of PR, QRS, QT and QTc intervals over time and changes from Baseline over 
time will be provided. 
7.6.2.5.5 
Renal Ultrasound 
Renal ultrasound data will be listed and summarized for each subject and study population.  
7.6.2.5.6 
Prior and Concomitant Medications 
The World Health Organization drug dictionary will be used to classify prior and 
concomitant medications by therapeutic class and PT. Prior medications include 
medications that were taken before the first administration of study drug, including those 
reported before dosing at the Baseline (Day 0) study visit. Concomitant medications include 
medications that were taken at any time after the start of treatment within this study until the 
End-of-Treatment visit. 
7.6.2.6 
Exposure 
Exposure to KRN23 will be summarized using the number of doses and total amount of 
KRN23 administered to each subject during the study. 
7.6.2.7 
Anti-KRN23 Antibody Assessment 
The anti-KRN23 antibody data, including ADA titer and neutralizing activity, will be listed 
and summarized by individual subject and study population. 
7.6.3 Determination of Sample Size 
Assuming the proportion of subjects with a phosphorus level above the lower limit of normal 
at 2 weeks after dosing, as averaged across dose cycles between Baseline and Week 24 is 
60%, a sample size of 15 subjects will provide a 95% confidence interval with the half width 
no greater than 24.8%. A reduction in excess osteoid is expected to be shown in all subjects 
with paired biopsies, with an estimated ≥ 50% reduction from Baseline in osteoid thickness. 
The sample size and study duration are believed to be sufficient to enable characterization of 
KRN23 effects on serum phosphorus levels, excess osteoid histomorphometric indices, and 
the safety profile of KRN23. 

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8 STUDY CONDUCT 
8.1 
Ethics 
8.1.1 Institutional Review Board  
The IRB must be a properly constituted board or committee operating in accordance with 
21 Code of Federal Regulations (CFR) Part 56, “Institutional Review Boards.” This protocol, 
any protocol amendments, the associated Informed Consent Forms (ICFs), and the informed 
consent procedures must be submitted to the IRB for review and must be approved before the 
enrollment of any subject into the study. Investigational product 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 for the protocol and any protocol amendments, as applicable. 
All subject recruitment and/or advertising information must be submitted to the IRB and 
Ultragenyx or its designee for review and approval prior to implementation. IRB 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 should be notified immediately and the 
amendment forwarded to the IRB 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 Assembly General Assembly (Helsinki, 1964) and subsequent amendments and 
clarifications adopted by the General Assemblies. The Investigator will make every effort 
that the study described in this protocol is conducted in full conformance with those 
principles, current FDA regulations, International Conference on Harmonisation of Technical 
Requirements for Registration of Pharmaceuticals for Human Use (ICH) Good Clinical 
Practice (GCP) guidelines, and local ethical and regulatory requirements. Should a conflict 
arise, the 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 investigational 
product, as described in this protocol and the Investigator’s Brochure, 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. Ultragenyx or its designee must receive a copy of the IRB’s approval of the ICF 
before the shipment of investigational product 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 

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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 
from it at any time. 
The method of obtaining and documenting informed consent and the contents of the ICF will 
comply with ICH GCP guidelines, the requirements of 21 CFR Part 50, “Protection of 
Human Subjects,” the Health Insurance Portability and Accountability Act (HIPAA) 
regulations, and all other applicable regulatory requirements. Subjects will be given a copy of 
the signed ICF and will be provided any new information during the course of the study that 
might affect their continued participation in the study. The Investigator or a qualified 
designee will be available to answer each subject's questions throughout the study, and all of 
the subject’s questions must be answered to the subject’s satisfaction. If the protocol is 
amended and the ICF is revised, each subject will be required to provide written informed 
consent again using the revised ICF. 
Receipt of written informed consent will be documented in each potential subject’s CRF. 
The signed ICF will remain in each subject's study file and must be available to the Study 
Monitor(s) at all times. 
8.2 
Investigators and Study Administrative Structure 
Each Investigator must provide Ultragenyx and/or its designee a completed and signed 
Form FDA 1572 and a Financial Disclosure Form. All subinvestigators must be listed on 
Form FDA 1572 and Financial Disclosure Forms must be completed for all subinvestigators 
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, to inspect clinical site facilities, and to inspect study records, including proof 
of IRB 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 in accordance 
with regulatory authority requirements. 
8.3 
Investigational Product Accountability 
While at the clinical site, investigational product must be stored in a secure limited access 
location at controlled temperature as described in the Investigator’s Brochure and according 
to product packaging. The storage facility must be available for inspection by the study 
monitor at any time during the study.  

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A drug accountability record must be maintained for all investigational product received, 
dispensed, returned, and/or lost during the study. This record must be kept current and made 
available to the Study Monitor for inspection. Following the close-out of the study, all 
unused investigational product must be returned to Ultragenyx and/or its designee unless 
other instructions have been provided for final disposition of the investigational product.  
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 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 laboratory test reports and other subject records. Instances of missing or 
uninterpretable 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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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, 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 25 years after the end of the clinical trial or in accordance with national law. 
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 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.  
All AEs will be collected from the time the subject signs informed consent through up to 
12 weeks (approximately 5 times the elimination half-life) following the last dose of study 
drug (unless the subject starts treatment with commercial KRN23 [burosumab], see 
Section 7.1). 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 12 weeks following the last dose of study drug should have a comment in the 
source document by the Investigator whether the event has recovered, recovered with 
sequelae, or stabilized. 
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. 

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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 Sponsor, places the 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. 
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 Sponsor, results in any of the following 
outcomes:  
• Death 
• A life-threatening AE 
• Inpatient hospitalization or prolongation of existing hospitalization 
• Persistent or significant incapacity or disability (substantial disruption of the ability to 
conduct normal life functions) 
• A congenital anomaly/birth defect 
Note that hospitalizations planned prior to study enrollment (eg, 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 subject and may require medical or surgical intervention 
to prevent 1 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 Common Terminology 
Criteria for Adverse Events (CTCAE) version 4.0. 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 are 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 
subject 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 subject’s normal daily activities and generally 
require systemic drug therapy or other treatment; they are usually incapacitating 

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• Life-threatening (Grade 4): Events that place the subject at immediate risk of death or 
are disabling 
• Death (Grade 5): Events that result in death 
To make sure there is no confusion or misunderstanding of the difference between the terms 
“serious” and “severe,” which are not synonymous, the following note of clarification is 
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. 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. 
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, eg, 
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. 

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An alternative explanation is less likely, eg, 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, eg, concomitant 
drug(s), concomitant disease(s), known consequences of the disease under investigation 
or the relationship in time is very suggestive (eg, it is confirmed by dechallenge and 
rechallenge) 
8.5.4 
Adverse Event Reporting to Ultragenyx 
8.5.4.1 
General 
All AEs (ie, 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 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 their 
EOS/ET Visit or final Safety Follow-up TC, as defined in Section 7.1. 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 a subject’s EOS/ET Visit or final Safety Follow-up TC (Section 7.1) should 
have a comment in the source document by the Investigator whether the event has recovered, 
recovered with sequelae, or stabilized. 
8.5.4.2 
Serious Adverse Events, Serious Adverse Drug Reactions, and Requirements 
for Immediate Reporting 
Any SAE that occurs at any time during the study, including a clinically significantly 
abnormal laboratory test result that is considered serious, must be reported within 24 hours of 
knowledge of the event to Ultragenyx or its designee. These requirements apply equally to all 
subjects, regardless of the study phase or the at-risk subject's treatment assignment or dosage. 
The reporting requirement for SAEs is from the time of signing of the ICF through the 
EOS/ET Visit or final Safety Follow-up TC, as defined in Section 7.1. 
SAEs will be reported by completing and submitting SAE report forms to Ultragenyx or its 
designee. Initial SAE reports must be followed by detailed descriptions. These should include 
copies of hospital case records and other documents when requested. Telephone reports must 
be confirmed promptly by facsimile. Follow-up SAE information must be submitted in a 
timely manner as additional information becomes available. All SAEs regardless of 
relationship to study drug must be followed to resolution or stabilization if improvement is 
not expected. 

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Any death occurring from signing of the ICF through the EOS/ET Visit or final Safety 
Follow-up TC (Section 7.1) must be reported to Ultragenyx or its designee within 24 hours of 
knowledge of the death, whether or not it is considered treatment-related.  
The Investigator also must notify the IRB/EC of the occurrence of the SAE, in writing, as 
soon as is practicable and in accordance with IRB/EC requirements and local law. A copy of 
this notification must be provided to Ultragenyx or its designee. 
8.5.4.3 
Urgent Safety Reporting 
The regulations governing clinical studies state that the Sponsor and Investigator are required 
to take appropriate urgent safety measures to protect subjects against any immediate hazards 
that may affect the safety of subjects, and that the appropriate regulatory bodies should be 
notified according to their respective regulations. According to the European Union (EU) 
Clinical Trial Directive 2001/20/EC, “…in the light of the circumstances, notably the 
occurrence of any new event relating to the conduct of the trial or the development of the 
investigational medicinal product where that new event is likely to affect the safety of the 
subjects, the Sponsor and the Investigator shall take appropriate urgent safety measures to 
protect the subjects against any immediate hazard. The Sponsor shall forthwith inform the 
competent authorities of those new events and the measures taken and shall ensure that the 
Ethics Committee (EC) is notified at the same time.” The reporting period for urgent safety 
issues is the period from the signing of the ICF through the EOS/ET Visit or final Safety 
Follow-up TC, as defined in Section 7.1. Investigators are required to report any urgent 
safety measures to Ultragenyx within 24 hours. 
8.5.4.4 
Adverse Drug Reaction Reporting 
Ultragenyx or its designee will submit suspected unexpected serious adverse reactions 
(SUSAR) to appropriate Regulatory Authorities (including Competent Authorities in all 
Member States concerned), Ethics Committees, and Investigators as per local laws and 
regulations. Fatal and life-threatening SUSARs will be submitted no later than 7-calendar 
days of first knowledge of the event and follow-up information submitted within an 
additional 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 (eg, 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 EOS/ET Visit or 
final Safety Follow-up TC, as defined in Section 7.1. 

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Protocol Number: UX023T-CL201 
Amendment 6 
26 September 2019 
 
 
Proprietary and Confidential 
Page 93 
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