1. Burosumab dose and dose justification: As a result of additional clinical data available since the time the original protocol was written, the dose of burosumab was changed. The starting dose of burosumab was changed to 0.8 mg/kg Q2W. The dose may then be increased to 1.2 mg/kg at any time during the study if a subject met the following dose adjustment criteria: 1) 2 consecutive serum phosphorus measurements were below the normal range; 2) serum phosphorus had increased by < 0.5 mg/dL from Baseline; and 3) the subject had not missed a dose of study drug that would have accounted for the decrease in serum phosphorus. Previously the protocol had specified a starting dose of 0.3 mg/kg Q2W for the first 2 doses and a target dose of 0.6 mg/kg Q2W. 2. Study Population: The inclusion criteria were modified to add PHEX mutation or VUS in either the patient or in a directly related family member with appropriate X-linked inheritance to confirm presence of XLH and to avoid including patients with syndromes that have clinical and biochemical phenotypic overlap with XLH. The criterion of intact fibroblast growth factor 23 (iFGF23) level ≥ 30 pg/mL by Kainos assay was eliminated because it was unnecessary in addition to genetic confirmation. The exclusion criteria were modified to add presence of nephrocalcinosis grade 4 on renal ultrasound (ie, stone formation). Presence of stone formation was added as an exclusion criterion based on regulatory agency request.

(continued) 3. Prohibited Medications: The washout period required for subjects receiving oral phosphate and active vitamin D standard therapy was reduced from 14 days to 7 days. Oral phosphate is typically given 4–5 times daily in XLH due to its rapid clearance from the body (Carpenter et al. 2011). Prescribing information for oral calcitriol notes a half life of 27.4 hours in children (Rocaltrol 2008); therefore, a 7-day washout was deemed sufficient to remove phosphate and active vitamin D from the body and minimizes the duration of time that a patient is off therapy. 4. Study Procedures and Assessments: a. Screening Visit 2 was removed from the Schedule of Events. Assessments previously indicated to be performed at Screening Visit 2 were rescheduled to be performed at the Baseline visit. This change was made to reduce the burden of multiple visits on subjects and their families. b. The Pediatric Orthopedic Society of North America Pediatric Outcomes Data Collection Instrument was removed as an assessment in the study because the questionnaire could be administered to subjects less than 2 years of age and most of the items were only relevant for subjects 5 years of age or older. Therefore, the amount of data to be collected from this instrument in this study of children 1 to 4 years old was likely minimal. c. The frequency and schedule of renal ultrasounds was modified. Renal ultrasounds were to be conducted at Screening, Week 40, and Week 64. Renal ultrasound assessment was moved from Baseline to Screening because renal stone formation had been added as an exclusion criterion. The Week 12 renal ultrasound was removed to minimize patient burden in these young patients. d. The frequency and schedule for measurement of FGF23 levels was modified to Baseline, Week 24, and Week 64. This change was made to minimize blood volumes collected and to align with the Phase 3 pediatric protocol.

(continued) e. Assessment of ADA was added at the Baseline Visit. ADA assessment was needed both before and after burosumab administration to distinguish between background signal and ADAs induced by administration of burosumab. f. The instructions for the measurement of BP were updated. BP was to be measured only in subjects who were ≥ 3 years of age. Previously, PB was measured one time each at the beginning and end of site visits in all subjects. At the Screening Visit, BP was to be measured 3 times, 30 seconds apart at the beginning of each visit; 3 additional BP measurements, 30 seconds apart, were to be obtained at the end of the study visit after all procedures had been performed. Elevated BP measurements were noted in some subjects in the Phase 2 pediatric UX023-CL201 study prior to administration of burosumab and in some subjects post administration of burosumab. To help ensure accurate pre-treatment and post-treatment BP measurements in this study, multiple assessments of BP were to be obtained at each site visit. The United States Department of Health and Human Services guidelines for Blood Pressure Measurement in Children was used as a reference. 5. Safety Measurements: Assessment of serum lipase in addition to serum amylase was added for all subjects. 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 burosumab studies at Baseline, mild elevations of amylase (<2x the upper limit of the reference range [ULRR]) have been noted. Post treatment mild shifts in amylase elevation (< 2xULRR) has been noted without association with GI symptoms. No AEs of pancreatitis have been observed. The additional testing of serum lipase were to aid in a determination of whether the elevations were from pancreatic or salivary gland sources.

(continued) 6. Data Monitoring Committee: Details of the DMC were updated. Specifically, the amended protocol stated that the independent DMC was to include members with expertise in metabolic bone disease, cardiology, and nephrology and the conduct of clinical trials in children. The FDA requested the inclusion of DMC members with expertise in pediatric cardiology and nephrology in addition to metabolic bone disease. 7. Record Retention: The record retention language was updated to state that all study records must have been retained for at least 25 years after the end of the clinical trial or in accordance with national law. This administrative change was made to reflect changes to European Union clinical trial regulations and current regulations by other health authorities.

1. Study Objectives: The additional study objective was modified from “Pre-dose KRN23 drug concentration levels” to “KRN23 drug concentration levels (PK)” to clarify that burosumab drug concentration levels were to be assessed throughout the study. 2. Overall Study Design and Plan: The provision to maintain gender balance was modified from “no more than 7 subjects” to “no more than 70% of subjects”. The original protocol planned sample size was 10 subjects, therefore 7 subjects (ie, 70% of the study population) were originally selected. The change more accurately reflected the total enrollment of 13 subjects (9 male; 69%). 3. Study Duration: An Extension Period of 96 weeks was added for continued assessment of the long-term safety and efficacy of burosumab in younger children. 4. Removal of Subjects: Language was added to allow orthopedic surgery during the Extension Period if recommended by the investigator or consulting physician. In addition, subjects who developed hyperparathyroidism were allowed to remain on study, but use of medication to suppress parathyroid hormone (eg, Sensipar®, cinacalcet, calcimimetics) was not permitted at any time. Subjects were to be removed from study if treatment for hyperparathyroidism became medically necessary.

(continued) 5. Treatment: Updates were made to allow for a parent or caregiver to administer burosumab to the subject after proper training by study personnel in SC injection technique and documentation of proficiency. Additional updates were made to describe the timing of dose adjustments during the Extension Period and to describe methods for monitoring treatment compliance in the home setting via telephone contact and physical inventory of empty vials at site visits for study drug accountability. Allowing subjects’ parents or caregivers to administer burosumab in the home setting was expected to reduce the burden on the subjects. Instructions for Use (IFU) were thoughtfully developed with input from XLH patients and were used to guide parents and caregivers through the injection process. The IFU was provided to sites and IRBs for approval prior to the initiation of parent/caregiver administration. To avoid potential errors with any dose adjustments, dose changes during the Extension Period were to be initially implemented at the clinic visits. Site personnel collected information on treatment compliance in the home setting and monitored the home administration via telephone contact. 6. Study Procedures and Assessments: Changes to study procedures are described below; a new Schedule of Events table was included to describe visits and assessments during the Extension Period.

(continued) a. During the Extension Period, clinic visits were to occur at approximately 12-week intervals (±5 days). Home health or telephone visits were to occur every 2 weeks. For telephone visits, study sites scheduled biweekly telephone calls with the subjects’ parent/caregiver to confirm administration of study drug, and for collection of AEs and concomitant medication information. Site personnel initiated a safety follow-up telephone call 5 weeks (+5 days) after the Week 160 visit to determine if the subject was receiving burosumab therapy under commercial use or another mechanism and to collect information on any ongoing or new AEs, serious TEAEs, and concomitant medications for subjects not receiving burosumab. The additional safety visit (10 weeks ± 5 days after Week 160) applied to subjects who discontinued treatment early or chose not to continue burosumab therapy as commercial product or through another mechanism once the study ended. These additional clinic visits and telephone calls were included in the Extension Period to monitor long-term safety, compliance, and efficacy at an interval deemed appropriate for the age of the population and duration of treatment. b. As previously communicated by memorandum (20 October 2016), updates were made to remove TmP/GFR and TRP (tubular reabsorption of phosphate) as estimates of renal phosphate reabsorption due to the breadth of available data and burden of obtaining urine samples in this study population (under 5 years of age). c. As previously communicated by memorandum (20 October 2016), the Week 22 serum calcium assessment was removed from the Schedule of Events. d. As previously communicated by memorandum (05 April 2016), updates were made such that blood pressure was to be obtained for subjects aged 3 years or above (at study entry or beginning when the subject turned 3 years of age). The provision for training on blood pressure measurements at the site initiation visit was removed.

(continued) e. As previously communicated by memorandum (13 December 2016), updates were made to indicate that the scope of the genitourinary exam should have been noninvasive and as per age-appropriate standard of care, at the investigator’s discretion based on clinical judgement. f. ECG was changed from an ectopic mineralization assessment to a general safety assessment. ECG was performed to evaluate for changes associated with left ventricular hypertrophy. Ectopic mineralization was not expected to affect ECG parameters and ECG was inadvertently listed in that section in the original protocol. g. Updates were made such that concomitant medications and therapies were reviewed between site visits by telephone call from the study site every 2 weeks and recorded in the subject’s CRF. Inclusion of telephone calls provided a mechanism to track use of concomitant medications and therapies at a consistent frequency during the Extension Period. 7. Statistical Analysis and Data Monitoring Committee: The statistical models for efficacy analysis were updated to incorporate Baseline adjustment and repeated measures at multiple time points. A newly added section described the timing of planned analyses for the study and more precisely defined the end of the study. Updates were made to stipulate that the Data Monitoring Committee was to review safety data through the Treatment Period (Week 64); long-term safety during the Extension Period was to be reviewed by the Ultragenyx SSRT on an ongoing basis. 8. Investigators and Study Administrative Structure: As previously communicated by memorandum (30 September 2016), updates were made to include language describing the Coordinating Investigator for the study. The Coordinating Investigator is Erik Imel, MD, Indiana University School of Medicine.

(continued) 9. Reporting and Follow-up of Adverse Events: Language was revised to reflect the revised study design and safety follow-up procedures. The reporting periods of AEs were defined as those from the time the subjects signs informed consent through “the final protocol-defined safety follow-up telephone call or safety visit”. Previously, these were defined as those through “12 weeks (approximately 5 times the elimination half-life) following the last dose of study drug.” 10. Nomenclature: Clarification was made in the Schedules of Events to change the explanation of anti-burosumab antibodies from human anti-human antibodies (HAHA) to the more correct and specific term, anti-drug antibodies (ADA).