Crysvita ® ( burosumab-twza - PowerPoint Presentation

1. Crysvita® (burosumab-twza):A Summary of Clinical Trial DataMRCP-KRN23-00318 5/18

2. Crysvita Overview

3. Indications and UsageCrysvita is a fibroblast growth factor 23 (FGF23) blocking antibody indicated for the treatment of X-linked hypophosphatemia (XLH) in adult and pediatric patients 1 year of age and olderFGF23 = fibroblast growth factor 23; XLH = X-linked hypophosphatemia.CRYSVITA [package insert]. Novato, CA: Ultragenyx Pharmaceutical Inc.; April 2018.

4. Excess FGF23 in XLH leads to renal phosphate wasting and chronic hypophosphatemia1,2FGF23 = fibroblast growth factor 23; NaPi-2a = sodium-dependent phosphate transport protein 2a; NaPi-2c = sodium-dependent phosphate transport protein 2c; PHEX = phosphate-regulating endopeptidase homolog X-linked; XLH = X-linked hypophosphatemia.1. Razzaque MS. Nat Rev Endocrinol. 2009;5(11):611-619. 2. Martin A et al. Physiol Rev. 2012;92(1):131-155.4Defective mineralizationand delayed ossification1-⍺ hydroxylase/ 1,25(OH)2DAbnormal low phosphorusPHEX mutationPhosphate absorptionNaPi-2a/NaPi-2cPhosphate excretionBone cell producesFGF23AdultPediatric

5. CRYSVITA® (burosumab-twza) is designed to bind and inhibit excess FGF23 and restore phosphate homeostasisFGF23 = fibroblast growth factor 23; NaPi-2a = sodium-dependent phosphate transport protein 2a; NaPi-2c = sodium-dependent phosphate transport protein 2c; PHEX = phosphate-regulating endopeptidase homolog X-linked.Whyte M et al. Presented at: American Society of Bone Mineral Research 2017 Annual Meeting; September 11, 2017; Denver, CO.Improved skeletal mineralization expected1-⍺ hydroxylase/ 1,25(OH)2DNormalize serum phosphorusPHEX mutationPhosphate absorptionNaPi-2a/NaPi-2cPhosphate excretionBone cell producesFGF23CRYSVITA inhibits serum FGF235

6. Dosage and AdministrationCrysvita is administered by subcutaneous injection and should be administered by a healthcare provider.Discontinue oral phosphate and active vitamin D analogs 1 week prior to initiation of treatment. Fasting serum phosphorus concentration should be below the reference range for age prior to initiation of treatment.CRYSVITA [package insert]. Novato, CA: Ultragenyx Pharmaceutical Inc.; April 2018.

7. Recommended Dosing for Pediatric Patients (1 to <18 years of age)The recommended starting dose regimen is 0.8 mg/kg of body weight, rounded to the nearest 10 mg, administered every two weeks Minimum starting dose: 10 mg Maximum starting dose: 90 mgAfter initiation of treatment with Crysvita, measure fasting serum phosphorus every 4 weeks for the first 3 months of treatment, and thereafter as appropriate.If serum phosphorus is above the lower limit of the reference range for age and below 5 mg/dL, continue treatment with the same dose.Follow dose adjustment schedule on the following slides to maintain serum phosphorus within the reference range for age.CRYSVITA [package insert]. Novato, CA: Ultragenyx Pharmaceutical Inc.; April 2018.

8. Dose Adjustment for Pediatric Patients (1 to <18 years of age)Reassess fasting serum phosphorus level 4 weeks after dose adjustmentDo not adjust Crysvita more frequently than every 4 weeksDose increase: If serum phosphorus is below the reference range for age, the dose may be increased stepwise up to ≈2 mg/kg administered every 2 weeks (maximum dose of 90 mg) according to the dosing schedule shown in Table 1Table 1: Pediatric Dose Schedule for Stepwise Dose IncreaseBody Weight, kgDose, mgFirst Dose Increase, mgSecond Dose Increase, mg10-1410 15 20 15-18102030 19-312030 40 32-433040 60 44-5640 608057-6850 70 9069-8060 90 90 81-9370909094-105809090≥106909090CRYSVITA [package insert]. Novato, CA: Ultragenyx Pharmaceutical Inc.; April 2018.

9. Dose Adjustments for Pediatric Patients (1 to <18 years of age) (cont’d)Dose decrease:If serum phosphorus is above 5 mg/dL, withhold the next dose and reassess the serum phosphorus level within 4 weeksThe patient must have serum phosphorus below the reference range for age to reinitiate CrysvitaOnce serum phosphorus is below the reference range for age, treatment may be restarted according to Table 2Reassess serum phosphorus level 4 weeks after dose adjustment Table 2: Pediatric Dose Schedule for Reinitiation of TherapyPrevious Dose, mgReinitiation Dose, mg10 515 10 20 1030 10 40 20 50 20 60 30 70 30 80 40 90 40 If the level remains below the reference range for age after the re-initiation dose, the dose can be adjusted according to Table 1 (see the previous slide)CRYSVITA [package insert]. Novato, CA: Ultragenyx Pharmaceutical Inc.; April 2018.

10. Recommended Dosing and Dose Adjustments for Adult Patients (≥18 years of age)The recommended dose regimen in adults is 1 mg/kg body weight, rounded to the nearest 10 mg up to a maximum dose of 90 mg, administered every four weeks.After initiation of treatment with Crysvita, assess fasting serum phosphorus on a monthly basis, measured 2 weeks post-dose, for the first 3 months of treatment, and thereafter as appropriate. If serum phosphorus is within the normal range, continue with the same dose Dose decrease Reassess serum phosphorus level 2 weeks after dose adjustmentDo not adjust Crysvita more frequently than every 4 weeksTable 3: Adult Dose Schedule for Reinitiation of TherapyDose, mgDecreased Dose, mg40 20 50 20 60 30 7030 ≥8040 CRYSVITA [package insert]. Novato, CA: Ultragenyx Pharmaceutical Inc.; April 2018.If serum phosphorus is above the normal range, withhold the next dose and reassess the serum phosphorus level after 4 weeks. The patient must have serum phosphorus below the normal range to be able to reinitiate Crysvita. Once serum phosphorus is below the normal range, treatment may be restarted at approximately half the initial starting dose up to a maximum dose of 40 mg every 4 weeks according to the dose schedule shown in Table 3. Reassess serum phosphorus 2 weeks after any change in dose

11. Supplied/Storage and Handling Crysvita injection for subcutaneous administration is supplied as a sterile, preservative-free, clear to slightly opalescent and colorless to pale brown-yellow solution.  The product is available as one single-dose vial per carton in the following strengths: 10 mg/mL (NDC# 69794-102-01) 20 mg/mL (NDC# 69794-203-01) 30 mg/mL (NDC# 69794-304-01) Crysvita vials must be stored in the original carton until the time of use under refrigerated conditions at 36°F to 46°F (2°C to 8°C). Keep Crysvita vial in the original carton to protect from light until time of use. Do not freeze or shake Crysvita. Do not use Crysvita beyond the expiration date stamped on the carton. Crysvita vials are single-dose only. Discard any unused product. CRYSVITA [package insert]. Novato, CA: Ultragenyx Pharmaceutical Inc.; April 2018.

12. Important Safety InformationCONTRAINDICATIONSDo not use Crysvita with oral phosphate and active vitamin D analogs.Do not initiate Crysvita treatment if serum phosphorus is within or above the normal range for age.Crysvita is contraindicated in patients with severe renal impairment or end stage renal disease because these conditions are associated with abnormal mineral metabolism.CRYSVITA [package insert]. Novato, CA: Ultragenyx Pharmaceutical Inc.; April 2018.

13. Important Safety Information (cont’d)WARNINGS AND PRECAUTIONSHypersensitivityHypersensitivity reactions (e.g. rash, urticaria) have been reported in patients with Crysvita. Discontinue Crysvita if serious hypersensitivity reactions occur and initiate appropriate medical treatment.Hyperphosphatemia and Risk of NephrocalcinosisIncreases in serum phosphorus to above the upper limit of normal may be associated with an increased risk of nephrocalcinosis. For patients already taking Crysvita, dose interruption and/or dose reduction may be required based on a patient’s serum phosphorus levels.Injection Site ReactionsAdministration of Crysvita may result in local injection site reactions. Discontinue Crysvita if severe injection site reactions occur and administer appropriate medical treatment.CRYSVITA [package insert]. Novato, CA: Ultragenyx Pharmaceutical Inc.; April 2018.

14. Important Safety Information (cont’d)ADVERSE REACTIONS Pediatric Patients The most common adverse reactions (more than 10%) in pediatric XLH patients are: headache, injection site reaction, vomiting, pyrexia, pain in extremity, vitamin D decreased, rash, toothache, myalgia, tooth abscess, and dizziness. Adult Patients The most common adverse reactions (more than 5% and in at least 2 patients more than placebo) in adult XLH patients are: back pain, headache, tooth infection, restless leg syndrome, vitamin D decreased, dizziness, constipation, blood phosphorus increased. Spinal stenosis is prevalent in adults with XLH and spinal cord compression has been reported. It is unknown if CRYSVITA therapy exacerbates spinal stenosis or spinal cord compression. CRYSVITA [package insert]. Novato, CA: Ultragenyx Pharmaceutical Inc.; April 2018.

15. Important Safety Information (cont’d)USE IN SPECIFIC POPULATIONSThere are no available data on Crysvita use in pregnant women to inform a drug-associated risk of adverse developmental outcomes. Serum phosphorus levels should be monitored throughout pregnancy. Report pregnancies to the Ultragenyx Adverse Event reporting line at 1-888-756-8657.There is no information regarding the presence of Crysvita in human milk, or the effects of Crysvita on milk production or the breastfed infant. Therefore, the developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for Crysvita and any potential adverse effects on the breastfed infant from Crysvita or from the underlying maternal condition.PATIENT COUNSELING INFORMATIONInstruct patients to contact their physician if hypersensitivity reactions, injection site reactions, and restless leg syndrome induction or worsening of symptoms occur.CRYSVITA [package insert]. Novato, CA: Ultragenyx Pharmaceutical Inc.; April 2018.

16. Crysvita Pharmacokinetics

17. PharmacokineticsThe following pharmacokinetic parameters were observed in patients with XLH administered the approved recommended starting dosage based on a 70 kg patient, unless otherwise specified.Burosumab-twza exhibited linear pharmacokinetics following SC injections within the dose range of 0.1 to 1 mg/kg (0.08 to 0.8 times the maximum approved recommended dosage based on a 70 kg patient).SC = subcutaneous; SD = standard deviation; XLH = X-linked hypophosphatemia.CRYSVITA [package insert]. Novato, CA: Ultragenyx Pharmaceutical Inc.; April 2018.PatientsSteady-state trough mean (±SD) concentration of burosumab-twzaAdult patients5.8 (±3.4) mcg/mlPediatric patients 5-12 years of age 15.8 (±9.4) mcg/mlPediatric patients 1-4 years of age 11.2 (±4.6) mcg/ml

18. Pharmacokinetics (cont’d)The effect of renal or hepatic impairment on the pharmacokinetics of burosumab-twza is unknownNo drug interaction studies have been conducted with CrysvitaPK = pharmacokinetics; Tmax = the amount of time that a drug is present at the maximum concentration in serum.AbsorptionThe burosumab-twza mean Tmax values ranged from 8 to 11 daysDistributionThe apparent volume of distribution of burosumab-twza is 8 LEliminationThe apparent clearance is 0.290 L/d. The half-life of burosumab-twza is approximately 19 daysMetabolismThe exact pathway for burosumab-twza metabolism has not been characterized. Burosumab-twza is expected to be degraded into small peptides and amino acids via catabolic pathwaysCRYSVITA [package insert]. Novato, CA: Ultragenyx Pharmaceutical Inc.; April 2018.

19. Crysvita Immunogenicity

20. ImmunogenicityPre-existing ADAs have been detected in up to 10% of patients in clinical studiesADAs were not detected in any clinical trial patients who were antibody-negative at the start of treatment However, the assay used to measure ADA is subject to interference by serum burosumab-twza, possibly resulting in an underestimation of the incidence of antibody formationDue to the limitation of the assay conditions, the potential clinical impact of antibodies to burosumab-twza is not knownADA = antidrug antibody.CRYSVITA [package insert]. Novato, CA: Ultragenyx Pharmaceutical Inc.; April 2018.

21. Crysvita Clinical Studies in Pediatric XLH

22. Study 1: OverviewRandomized, open-label phase 2 study in prepubescent XLH patients aged 5-12 years (N=52)Compared treatment with Crysvita administered Q2W vs Q4W0164064WeeksClinicaltrials.gov identifier: NCT02163577All 52 patients completed ≥64 weeks on study; no patient discontinued Burosumab-twza dose was adjusted to target a fasting serum phosphorous concentration of 3.5 to 5.0 mg/dL based on the fasting phosphorus level the day of dosing26 of 52 patients received Crysvita Q2W up a maximum dose of 2 mg/kg. The average dose was 0.73 (range 0.3, 1.5) at week 16, 0.98 mg/kg (range: 0.4, 2.0) at week 40 and 1.04 mg/kg (range: 0.4, 2.0) at week 60The remaining 26 patients received Crysvita Q4W Oral phosphate and active vitamin D analogs were discontinued prior to study enrollmentTitration periodTreatment period48 weeks(N=26)Group Receiving Crysvita Q2WGroup Receiving Crysvita Q4WTitration periodTreatment period48 weeks(N=26)Q2W = every 2 weeks; Q4W = every 4 weeks.CRYSVITA [package insert]. Novato, CA: Ultragenyx Pharmaceutical Inc.; April 2018.

23. Study 1: primary and select secondary endpoints1,2 Primary endpointChange from baseline at week 40 in severity of rickets as measured by RSS total scoreSelect safety endpointTreatment emergent AEs leading to discontinuation Select secondary endpointsChange from baseline at week 40 in severity of rickets as measured by RSS knee and wrist scoresChange from baseline at week 40 in the radiographic appearance of rickets and bowing as measured by RGI-C scoresChange from baseline at week 40 in standing height Z-score growthAE = adverse event; RGI-C = Radiographic Global Impression of Change; RSS = Rickets Severity Score; SAE = serious adverse event.1. ClinicalTrials.gov; NCT02163577. Accessed April 18, 2018; 2. Ultragenyx Pharmaceutical, data on file.

24. Study 1: Baseline CharacteristicsPatient CharacteristicsAll Patients(N=52)Age, y, mean8.5Male46%Use of prior oral phosphate/ active vitamin D analogs 96%Duration of prior oral phosphate/ active vitamin D analogs, y, mean (SD)7 (2.4)Radiographic evidence of rickets at baseline94%Serum phosphorus levels at baseline, mean (SD) 2.38 (0.40) RSS total score at baseline, mean (SD)1.9 (1.17) SD = standard deviation; RSS = Rickets Severity Score.1. CRYSVITA [package insert]. Novato, CA; 2. Ultragenyx Pharmaceutical Inc.; April 2018.

25. Study 1: Results—Serum PhosphorusThe ratio of TmP/GFR increased from a mean (SD) of 2.2 (0.49) at baseline to 3.3 (0.60) and 3.4 (0.53) mg/dL at weeks 40 and 64, respectively2 Serum Phosphorus Levels (Mean ± SD) Over Time in Children Aged 5-12 Years Receiving Crysvita Q2W (N=26)1,2Mean ±SE. Gray box indicates normal range.Q2W = every 2 weeks; TmP/GFR = renal tubular maximum reabsorption rate of phosphate to glomerular filtration rate; SD = standard deviation.1. Whyte M, et al. Presented at: American Society of Bone Mineral Research (ASBMR) 2017 Annual Meeting; September 11, 2017 Denver, CO; 2. CRYSVITA [package insert]. Novato, CA: Ultragenyx Pharmaceutical Inc.; April 2018. Lower limit of normal(3.2 mg/dL)1WeeksSerum Phosphorus,mg/dL

26. Study 1: Results—Radiographic Evaluation of RicketsAt week 40, 18 of 26 patients achieved a RGI-C global score of ≥ +2.0, indicating substantial healing of rickets These findings were maintained at week 64Mean +Mean +LS Mean Change From Baseline in RSS Total Scorea (reduction indicates improvement) with 95% CI in Children Aged 5-12 Years Receiving Crysvita Q2W (N=26)aThe estimates of LS means and 95% CI (confidence interval) are from the generalized estimation equation model accounting for baseline RSS, visits and regimen and its interaction. RSS = Rickets Severity Score; Q2W = every 2 weeks; RGI-C = Radiographic Global Impression of Change; LS = least squares; CI = confidence interval.CRYSVITA [package insert]. Novato, CA: Ultragenyx Pharmaceutical Inc.; April 2018.LS Mean RGI-C Global Scorea (Positive Indicates Healing) with 95% CI in Children Aged 5-12 Years Receiving Crysvita Q2W (N=26)Baseline mean (SD) RSS total score was 1.9 (1.17)LS Mean change from baseline

27. Study 1: Results—Serum ALP ActivitySerum Total ALP Activity (Mean ± SD) in Children Aged 5-12 Years Receiving Crysvita Q2W (N=26)ALP = alkaline phosphatase; SD = standard deviation; Q2W = every 2 weeks.CRYSVITA [package insert]. Novato, CA: Ultragenyx Pharmaceutical Inc.; April 2018.-23%p < 0.0001

28. Study 1: Results—Standing Height Z-ScoreStanding Height Z-Score at Baseline and Week 64(Mean ± SD) in Children Aged 5-12 Years Receiving Crysvita Q2W (N=26)SD = standard deviation; Q2W = every 2 weeks.CRYSVITA [package insert]. Novato, CA: Ultragenyx Pharmaceutical Inc.; April 2018.

29. Study 2: OverviewOpen-label, phase 2 study in pediatric patients aged 1-4 years (N=13)Patients received Crysvita at a dose of 0.8 mg/kg Q2W with titration up to 1.2 mg/kg based on serum phosphorus measurementsAll patients completed ≥40 weeks on study; no patients discontinuedOral phosphate and active vitamin D analogs were discontinued prior to study enrollment01640WeeksGroup Receiving Crysvita Q2WTitration periodTreatment period40 weeks(N=13)Clinicaltrials.gov identifier: NCT02750618Q2W = every 2 weeks.CRYSVITA [package insert]. Novato, CA: Ultragenyx Pharmaceutical Inc.; April 2018.

30. Study 2: primary and select secondary endpoints Primary endpointChange from baseline at week 40 in serum phosphorusSelect safety endpointNumber of participants with AEs, SAEs, and AEs leading to discontinuation Select secondary endpointsChange from baseline in rickets at week 40 as assessed by the RGI-C global score and RSS Change from baseline in lower extremity skeletal abnormalities at week 40 as determined by the RGI-C lower limb deformity scoreChange from baseline over time in serum ALPAE = adverse event; ALP = alkaline phosphatase; RGI-C = Radiographic Global Impression of Change; RSS = Rickets Severity Score; SAE = serious adverse event.ClinicalTrials.gov; : NCT02750618. Accessed April 18, 2018

31. Study 2: Baseline CharacteristicsPatient CharacteristicsAll Patients(N=13)Age, y, mean2.9Male69%Use of prior oral phosphate/active vitamin D analogs 100%Duration of prior oral phosphate/ active vitamin D analogs, y, mean (SD)16.9 (13.9)Radiographic evidence of rickets at baseline100%Serum phosphorus levels (mg/dL) at baseline, mean (SD) 2.51 (0.28) RSS total score at baseline, mean (SD)2.9 (1.37) SD = standard deviation; RSS = Rickets Severity Score.CRYSVITA [package insert]. Novato, CA: Ultragenyx Pharmaceutical Inc.; April 2018.

32. Study 2 Results: Serum Phosphorus and Serum aLP activitySerum Phosphorus Levels (Mean ± SD) in Children Aged 1-4 Years Receiving Crysvita Q2W (N=13)1Serum Phosphorus, mg/dLALP Activity (Mean ± SD) in Children Aged 1-4 Years Receiving Crysvita Q2W (N=13)1ALP (U/L)BaselineWeek 401. CRYSVITA [package insert]. Novato, CA: Ultragenyx Pharmaceutical Inc.; April 2018; 2. Imel et al. ASBMR 2017. Poster MO 0695.Lower limit of normal(3.2 mg/dL)2SD = standard deviation; Q2W = every 2 weeks; ALP = alkaline phosphatase.-36%

33. Study 2: Results—Radiographic Evaluation of Rickets+MeanAll 13 patients achieved a RGI-C global score ≥ +2.0, indicating substantial healing of ricketsThe mean (SE) lower limb deformity as assessed by RGI-C, using standing long leg radiographs, was +1.3 (0.14)LS Mean RGI-C Global Scorea (Positive Indicates Healing) with 95% CI in Children Aged 1-4 Years Receiving Crysvita Q2W (N=13)LS Mean Change From Baseline in RSS Total Scorea (reduction indicates improvement) with 95% CI in Children Aged 1-4 Years Receiving Crysvita Q2W (N=13)aThe estimates of LS means and 95% CI (confidence interval) are from the generalized estimation equation model accounting for baseline RSS,visits and regimen and from ANCOVA model accounting for age and baseline RSS.RSS = Rickets Severity Score; SE = standard error; Q2W = every 2 weeks; RGI-C = Radiographic Global Impression of Change; SD = Standard deviation.CRYSVITA [package insert]. Novato, CA: Ultragenyx Pharmaceutical Inc.; April 2018.LS Mean change from baselineLS Mean RGI-C Global Score

34. ARStudy 1(N=52)n (%)Study 2(N=13)n (%)Overall (N=65)n (%)Headache38 (73)1 (8)39 (60)Injection site reactiona35 (67)3 (23)38 (59)Vomiting25 (48)6 (46)31 (48) Pyrexia23 (44)8 (62)31 (48)Pain in extremity24 (46)3 (23)27 (42)Vitamin D decreasedb19 (37)2 (15)21 (32)Rashc14 (27)1 (8)15 (23)Toothache12 (23)2 (15)14 (22)Myalgia9 (17)1 (8)10 (15)Tooth abscess8 (15)3 (23)11 (17)Dizzinessd8 (15)0 (0)8 (12)Adverse Reactions in Pediatric Patients with XLHThe data described here reflect exposure to Crysvita in 65 pediatric XLH patients, which included:52 exposed for ≥64 weeks (study 1) 13 exposed for ≥40 weeks (study 2)Overall, pediatric XLH patients have been exposed to Crysvita for a mean duration of 108 weeks (minimum, 40.9 weeks; maximum, 150.0 weeks)ARs Reported in >10% of Pediatric Patients Receiving Crysvita in Studies 1 and 2aInjection site reaction includes injection site reaction, injection site erythema, injection site pruritus, injection site swelling, injection site pain, injection site rash, injection site bruising, injection site discoloration, injection site discomfort, injection site hematoma, injection site hemorrhage, injection site induration, injection site macule, and injection site urticaria. bVitamin D decreased includes vitamin D deficiency, blood 25-hydroxycholecalciferol decreased, and vitamin D decreased. cRash includes rash, rash pruritic, rash maculopapular, and rash pustular. dDizziness includes dizziness and dizziness exertional.XLH = X-linked hypophosphatemia; AR = adverse reaction.CRYSVITA [package insert]. Novato, CA: Ultragenyx Pharmaceutical Inc.; April 2018.

35. Adverse Reactions in Pediatric Patients with XLH (cont’d)Hypersensitivity reactionsThe most frequent potential hypersensitivity events were rash (22%), injection site rash (6%), and urticaria (5%)Hyperphosphatemia There were no events of hyperphosphatemia reportedInjection site reactionsApproximately 58% of pediatric patients had a local reaction (eg, injection site urticaria, erythema, rash, swelling, bruising, pain, pruritus, hematoma) at the site of Crysvita injectionInjection site reactions were generally mild in severity, occurred within 1 day of injection, lasted approximately 1-3 days, required no treatment, and resolved in almost all instancesCRYSVITA [package insert]. Novato, CA: Ultragenyx Pharmaceutical Inc.; April 2018.

36. Crysvita Clinical Studies in Adult XLH

37. Study 3: OverviewRandomized, 24-week, double-blind, placebo-controlled study in adult XLH patients (N=134)Crysvita was administered at a dose of 1 mg/kg every 4 weeksOne patient in the Crysvita group discontinued treatmentOral phosphate and active vitamin D analogs were not allowed during the studyClinicaltrials.gov identifier: NCT02526160Patient Characteristic All Patients (N=134)Age, y, mean (range) 40 (19-66)Male35%Treatment period24 weeks(N=68)Treatment period(N=134)Placebo24 weeks(N=66)Week02448Placebo-Controlled Treatment PeriodTreatment Continuation Period24-Week Double-Blind Period24-Week Open-Label PeriodXLH = X-linked hypophosphatemia.CRYSVITA [package insert]. Novato, CA: Ultragenyx Pharmaceutical Inc.; April 2018.Treatment period(N=134)

38. Study 3: primary and select exploratory efficacy endpoints1,2Primary endpointProportion of subjects achieving mean serum phosphorus levels above the lower limit of normal at the midpoint of the dose interval, as averaged across dose cycles between baseline and week 24Select safety endpointIncidence, frequency, and severity of AEs and SAEs Select exploratory efficacy endpointResolution of pre-existing active pseudofractures and/or fractures at postbaseline visits as defined by skeletal surveyAE = adverse event; SAE = serious adverse event.1. ClinicalTrials.gov; NCT02526160. Accessed April 18, 2018; 2. Ultragenyx Pharmaceutical, data on file.

39. Study 3: Results—Increase in Serum Phosphorus8%(N=5)94% (N=64)P<0.0001At baseline, mean (SD) serum phosphorus was 1.9 (0.32) and 2.0 (0.30) mg/dL in the placebo and Crysvita groups respectivelyTmP/GFR = renal tubular maximum reabsorption rate of phosphate to glomerular filtration rate; SD = standard deviation.CRYSVITA [package insert]. Novato, CA: Ultragenyx Pharmaceutical Inc.; April 2018.TmP/GFR Ratios (Mean ± SD) After 24 Weeks of Treatment With Crysvita (N=68) or Placebo (N=66)Proportion of Patients Achieving Mean Serum Phosphorus > LLN Across Midpoints ofDose Intervals Through Week 24 with 95% CIN=66N=68CrysvitaCrysvita

40. Proportion of Healed Fractures After 24 Weeks of Treatment With Crysvita or PlaceboStudy 3: Results—Radiographic Evaluation of OsteomalciaAt baseline, 52% of patients had either active (unhealed) fractures (12%) or active pseudofractures (47%)The active fractures and pseudofractures were located predominantly in the femur, tibia/fibula, and metatarsals of the feetAt week 24, fractures healed completely in 43% of patients treated with Crysvita, compared with 8% of patients receiving placebo0/1321/517/9128/657/147/78Osteomalacia-related fractures are defined as atraumatic lucencies extending across both bone cortices and pseudofractures are defined as atraumatic lucencies extending across one cortexCRYSVITA [package insert]. Novato, CA: Ultragenyx Pharmaceutical Inc.; April 2018.Crysvita

41. Study 4: OverviewOpen-label, single-arm study in adult XLH patients (N=14)Objective: to evaluate the effects of Crysvita on osteomalacia in adults with XLHDuring active treatment, 1.0 mg/kg of body weight, rounded to the nearest 10 mg, was administered Q4WOral phosphate and active vitamin D analogs were not allowed during the studyClinicaltrials.gov identifier: NCT02537431048Treatment period48 weeks(N=14)WeeksBone BiopsyBone BiopsyPatient Characteristics All Patients (N=14)Age, y, mean (range) 40 (25-52)Male, n (%)6 (43)XLH = X-linked hypophosphatemia; Q4W = every 4 weeks.CRYSVITA [package insert]. Novato, CA: Ultragenyx Pharmaceutical Inc.; April 2018.

42. Study 4: primary and select secondary endpoints1,2 Primary endpointPercent change from baseline in osteoid volume/bone volume (OV/BV) at week 48 based on analysis of iliac crest bone biopsiesSelect safety endpointIncidence, frequency, and severity of AEs and SAEs Select secondary endpointsPercent change from baseline in additional histomorphometric parameters, including osteoid thickness, osteoid surface/bone surface, and mineralization lag timeAE = adverse event; SAE = serious adverse event.1. ClinicalTrials.gov; NCT02526160. Accessed April 18, 2018; 2. Ultragenyx Pharmaceutical, data on file.

43. Study 4: Results—Bone HistomorphometryDecrease in Osteoid Thickness (Mean ± SD) at Week 48 in Patients Treated With Crysvita (N=11)Decrease in OV/BV (Mean ± SD) at Week 48 in Patients Treated With Crysvita (N=10)Decrease in MLT (Mean ± SD) at Week 48 in Patients Treated With Crysvita (N=6)Improvement of osteomalacia was determined by histologic and histomorphometric evaluation of iliac crest bone biopsies-57%-33%-74%OV = osteoid volume; BV = bone volume; MLT = mineralization lag time.CRYSVITA [package insert]. Novato, CA: Ultragenyx Pharmaceutical Inc.; April 2018.

44. Adverse Reactions in Adult Patients with XLHThe data described here reflect exposure to Crysvita in 68 adult XLH patients, aged 20-63 years (mean age, 41 years), of whom most were white/Caucasian (81%) and female (65%)Crysvita was studied primarily in a randomized, double-blind, placebo-controlled, phase 3 study in adults with XLH (study 3: Crysvita = 68, placebo = 66), in which patients received Crysvita at a mean dose of 0.95 mg/kg (range, 0.3-1.2 mg/kg) SC every 4 weeks at Week 24.aHeadache includes headache and head discomfort. bTooth infection includes tooth abscess and tooth infection. cVitamin D decreased includes vitamin D deficiency, blood 25-hydroxycholecalciferol decreased, and vitamin D decreased. dBlood phosphorus increased includes blood phosphorus increased and hyperphosphatemia.XLH = X-linked hypophosphatemia; SC = subcutaneously; AR = adverse reaction; RLS = restless leg syndrome.CRYSVITA [package insert]. Novato, CA: Ultragenyx Pharmaceutical Inc.; April 2018.ARs Occurring in >5% of Crysvita-Treated Adult Patients and in ≥2 Patients More Than With Placebo in Study 3ARCrysvita(N=68)n (%)Placebo(N=66)n (%)Back pain10 (15)6 (9)Headachea9 (13)6 (9)Tooth infectionb9 (13)6 (9)RLS8 (12)5 (8)Vitamin D decreasedc8 (12)3 (5)Dizziness7 (10)4 (6)Constipation6 (9)0 (0)Blood phosphorus increasedd4 (6)0 (0)

45. Adverse Reactions in Adult Patients with XLH (cont’d)Hypersensitivity reactionsIn the double-blind period of study 3 in adults, ≈6% of patients in both the Crysvita and placebo treatment groups experienced a potential hypersensitivity eventThe events were mild or moderate and did not require discontinuationHyperphosphatemiaIn the double-blind period of study 3 in adults, ≈7% of patients in the Crysvita treatment group experienced hyperphosphatemia meeting the protocol-specified criteria for dose reduction, either a single serum phosphorus level >5.0 mg/dL or 2 serum phosphorus levels >4.5 mg/dL (the upper limit of normal)The hyperphosphatemia was managed with dose reduction. The dose for all patients meeting the protocol-specified criteria was reduced by 50%A single patient required a second dose reduction for continued hyperphosphatemiaInjection site reactionsIn the double-blind period of study 3 in adults, ≈12% of patients in both the Crysvita and placebo treatment groups had a local reaction at the site of the injectionInjection site reaction, erythema, rash, bruising, pain, pruritus, and hematomaInjection site reactions were generally mild in severity, occurred within 1 day of injection, lasted approximately 1-3 days, required no treatment, and resolved in almost all instancesCRYSVITA [package insert]. Novato, CA: Ultragenyx Pharmaceutical Inc.; April 2018.

46. Adverse Reactions in Adult Patients with XLH (cont’d)RLSIn the double-blind period of study 3 in adult patients, ≈12% of the Crysvita treatment group had worsening of baseline RLS or new-onset RLS of mild to moderate severityThese events did not lead to dose discontinuationNonserious RLS has also been reported in other repeat-dose adult XLH studiesIn one case, worsening baseline RLS led to drug discontinuation and subsequent resolution of the eventSpinal Stenosis Spinal stenosis is prevalent in adults with XLH and spinal cord compression has been reported.In the Crysvita phase 2 and phase 3 studies of adults with XLH (total N=176), a total of 6 patients underwent spinal surgery. Most of these cases appeared to involve progression of a pre-existing spinal stenosis. It is unknown if Crysvita therapy exacerbates spinal stenosis or spinal cord compression. RLS = restless leg syndrome; XLH = X-linked hypophosphatemia.CRYSVITA [package insert]. Novato, CA: Ultragenyx Pharmaceutical Inc.; April 2018.