Illustration of mother measuring daughter after treatment with CRYSVITA®

CLINICAL EFFICACY

When compared with conventional therapy, CRYSVITA® (burosumab-twza) normalized serum phosphorus, helped heal rickets, and increased growth in pediatric patients with XLH

  • Clinical Trials Design
  • Serum Phosphorus
  • Alkaline Phosphatase
  • Rickets
  • Growth

Clinical trials design

CRYSVITA was tested in a clinical trial program of 126 children with XLH1

A Phase 3 study (Study 1) compared CRYSVITA every 2 weeks with conventional therapy (oral phosphate and active vitamin D) in children with XLH.

Select endpoints1,2:
  • Primary endpoint:
    Healing of rickets at Week 40, as assessed by Radiographic Global Impression of Change (RGI-C) scores, comparing CRYSVITA with conventional therapy (oral phosphate and active vitamin D)
  • Secondary endpoints:
    • Change from baseline, comparing CRYSVITA with conventional therapy in:
      • Lower extremity skeletal abnormalities, as assessed by the RGI-C long leg score
      • Severity of rickets, as measured by total Thacher Rickets Severity Score (RSS)
      • Standing height z-score
      • Serum phosphorus levels
      • Alkaline phosphatase (ALP) activity

Safety: Number of subjects with adverse events (AEs), serious adverse events (SAEs), and AEs leading to discontinuation

Phase 2 and Phase 3 Clinical treatment overview of CRYSVITA®
CRYSVITA was tested in 3 clinical trials of children with XLH ages 1 to 12 years
FOOTNOTES

SC, subcutaneous.
*The dose could be titrated up to 1.2 mg/kg based on serum phosphorus measurements.
Patients received a mean oral phosphate dose of approximately 41 mg/kg/day (range 18 to 110 mg/kg/day) at Week 40 and approximately 46 mg/kg/day (range 18 mg/kg/day to 166 mg/kg/day) at Week 64. They also received either a mean oral calcitriol dose of 26 ng/kg/day at Week 40 and 27 ng/kg/day at Week 64 or a therapeutically equivalent amount of alfacalcidol.
Initial doses of SC CRYSVITA were 0.1, 0.2, or 0.3 mg/kg Q2W or 0.2, 0.4, or 0.6 mg/kg Q4W.6

No pediatric patients discontinued CRYSVITA treatment

during the clinical studies.1

Phase 2 studies (Studies 2 and 3)

Select endpoints included change from baseline in serum phosphorus, rickets (as assessed by RSS and RGI-C), lower extremity skeletal abnormalities, standing height z-score, and safety.1,3,4

In all studies

In pediatric patients with XLH, oral phosphate and active vitamin D analogs were discontinued for at least 7 days prior to study enrollment as part of the washout period.1,3,4

The clinical studies were designed to be representative of the relevant pediatric population with XLH.1,5

Disease Burden at Baseline
Study 1
(N=61, ages 1 to 12 years)
Study 2
(N=52, ages 5 to 12 years)
Study 3
(N=13, ages 1 to 4 years)
Mean age (years) 6.3 8.5 2.9
Male, n (%) 27 (44%) 24 (46%) 9 (69%)
Mean serum phosphorus (mg/dL) 2.4 2.4 2.5
Radiographic evidence of rickets (%) 100% 94% 100%
Prior therapy (oral phosphate and active vitamin D analogs) (%) 100% 96% 92%
Mean duration of prior therapy (years) 4 6.9 1.4

Serum Phosphorus RESULTS IN CHILDREN

CRYSVITA increased and sustained serum phosphorus levels within the normal range, compared with conventional therapy or on its own1

Mean Serum Phosphorus Levels in Children Receiving CRYSVITA
Every 2 Weeks or Receiving Conventional Therapy1,2,*

Study 1: Mean serum phosphorus levels in children receiving CRYSVITA® or conventional therapy graph
In Study 1, CRYSVITA increased and sustained serum phosphorus levels, compared with conventional therapy
FOOTNOTES

SD, standard deviation.
*Serum phosphorus level (mg/dL) (mean ±SD). The dotted line represents the lower limit of normal (LLN, 3.2 mg/dL).

Normal levels of serum phosphorus range from 3.2 to 6.1 mg/dL. Note that the normal levels of serum phosphorus vary by age and sex, and ranges may vary by testing laboratory.7

Phase 2 studies also showed that CRYSVITA increased and sustained serum phosphorus levels within the normal range1:

Study 2 (N=52, ages 5 to 12 years):

  • Mean (SD) serum phosphorus levels increased from 2.4 (0.40) mg/dL at baseline to 3.3 (0.40) mg/dL at Week 40, corresponding to a 38% increase from baseline levels, and was maintained at 3.4 (0.45) mg/dL at Week 64

Study 3 (N=13, ages 1 to 4 years):

  • Mean (SD) serum phosphorus levels increased from 2.5 (0.28) mg/dL at baseline to 3.5 (0.49) mg/dL at Week 40, corresponding to a 40% increase from baseline levels

CRYSVITA increased and sustained renal tubular reabsorption,* compared with conventional therapy from baseline to Week 641:

TmP/GFR Mean (SD), mg/dL
Study Treatment Group Baseline Week 40 Week 64
Phase 3 (N=61,
ages 1 to 12 years)
CRYSVITA (n=29) 2.2 (0.37) 3.4 (0.67) 3.3 (0.65)
Conventional therapy (n=32) 2.0 (0.33) 1.8 (0.35) 1.9 (0.49)
Phase 2 (N=52,
ages 5 to 12 years)
CRYSVITA (n=26) 2.2 (0.49) 3.3 (0.60) 3.4 (0.53)
FOOTNOTES

SD, standard deviation; TmP/GFR, ratio of renal tubular maximum reabsorption rate of phosphate to glomerular filtration rate.
*The normal range for TmP/GFR is 2.6 to 4.4 mg/dL.7

Help improve chronic hypophosphatemia and redefine
XLH management with CRYSVITA

ALKALINE PHOSPHATASE RESULTS IN CHILDREN

CRYSVITA reduced total alkaline phosphatase (ALP) activity, compared with conventional therapy or on its own1

Mean Serum ALP Concentration in Children Receiving CRYSVITA
Every 2 Weeks or Receiving Conventional Therapy 1,2,6,*

Study 1: Mean serum ALP concentration in children receiving CRYSVITA® or conventional therapy graph
In Study 1, CRYSVITA reduced total ALP, compared with conventional therapy
FOOTNOTES

ALP, alkaline phosphatase; SE, standard error; ULN, upper limit of normal.
*The upper limit of the ALP reference range for children aged 1 to 15 years is 297 to 385 U/L.7The dotted line on the graph indicates 385 U/L. The lower limit of the ALP reference range for children aged 1 to 15 years is 50 to 142 U/L.8
Note that ranges may vary by age, sex, and testing laboratory.

Phase 2 studies also showed that CRYSVITA reduced ALP activity.1

Study 2 (N=52, ages 5 to 12 years):

  • Mean (SD) serum total alkaline phosphatase activity decreased from 462 (110) U/L at baseline to 354 (73) U/L at Week 64, a mean reduction of 23%

Study 3 (N=13, ages 1 to 4 years):

  • Mean (SD) serum total alkaline phosphatase activity decreased from 549 (194) U/L at baseline to 335 (88) U/L at Week 40, a mean reduction of 36%

Help reduce serum total alkaline phosphatase activity
with CRYSVITA

RICKETS HEALING IN CHILDREN

CRYSVITA resulted in greater improvement in rickets healing, compared with conventional therapy or on its own.1 In all pediatric studies of patients with XLH aged 1 to 12 years, rickets was assessed using 2 radiographic scoring methods, Thacher Rickets Severity Score (RSS) and Radiographic Global Impression of Change (RGI-C).7,8

CRYSVITA led to greater improvements in rickets severity, compared with conventional therapy, as assessed by RSS1

RSS is a 10-point score for radiographs of wrists and knees to assess the degree of metaphyseal fraying and cupping and the proportion of the growth plate affected.1,7

  • RSS is a predefined scale that evaluates specific abnormalities in the wrists and knees
  • A reduced RSS score indicates improvement in rickets severity

Mean Total Rickets Severity Score*

Study 1: Mean total rickets severity score comparing CRYSVITA® to conventional therapy graph
In Study 1, CRYSVITA reduced RSS, compared with conventional therapy
FOOTNOTES

CI, confidence interval; LS, least squares; SD, standard deviation.

*The estimates of LS mean and 95% CI for Week 40 are from an ANCOVA model accounting for treatment group, baseline RSS, and baseline age stratification factor; the estimates for Week 64 are from a generalized estimating equation (GEE) model accounting for treatment group, visit, treatment-by-visit interaction, baseline RSS, and baseline age stratification factor.

Phase 2 studies also showed that CRYSVITA improved rickets severity, as assessed by RSS1

Study 2 (N=52, ages 5 to 12 years):

  • Mean RSS score declined from 1.9 (1.17) at baseline to 0.8 at Week 40, corresponding to a 58% reduction in RSS score after adjusting for variables in the study
  • This improvement was maintained at Week 64

Study 3 (N=13, ages 1 to 4 years):

  • Mean RSS score declined from 2.9 (1.37) at baseline to 1.2 at Week 40, corresponding to a 59% reduction in RSS score after adjusting for the variables in the study

CRYSVITA was superior to conventional therapy in rickets healing, as assessed by RGI-C1

RGI-C is a 7-point scale designed for comprehensive evaluation of skeletal health.1,4,8

  • A complement to the RSS, RGI-C scores assess changes in the severity of rickets using the disease-specific qualitative RGI-C scoring system
  • An RGI-C score of +2.0 indicates a substantial healing of rickets

Mean Radiographic Global Impression of Change*

Study 1: LS mean radiographic global impression of change score comparing CRYSVITA® to conventional therapy graph
In Study 1, CRYSVITA led to superior healing of rickets, compared with conventional therapy, as assessed by RGI-C
FOOTNOTES

LS, least squares; SE, standard error.
*RGI-C at Week 40 was the primary endpoint of the study.

A Phase 2 study also showed that CRYSVITA led to substantial healing of rickets, as assessed by RGI-C.1

Study 2 (N=52, ages 5 to 12 years):

  • At Week 40, mean RGI-C score was +1.7, indicating that healing of rickets occurred
    • 18 out of 26 patients achieved an RGI-C score of +2.0, indicating substantial healing of rickets
  • A mean RGI-C global score of +1.6 was maintained at Week 64

Study 3 (N=13, ages 1 to 4 years):

  • At Week 40, mean RGI-C score was +2.3, indicating substantial healing of rickets
    • 13 out of 13 patients achieved an RGI-C score of +2.0

Radiographic examples of healing of rickets (RGI-C +2.0)

The following is an example of a patient with XLH (male, aged 7.8 years, Study 1) who received CRYSVITA every 2 weeks for 64 weeks, compared with a patient (male, aged 7.7 years, Study 1) who continued on conventional therapy.1

Substantial Healing of Rickets (RGI-C Score of +2.0) at Week 40 Was Maintained at Week 645

Wrists

Individual results may vary.

Knees

Individual results may vary.

CRYSVITA demonstrated superior improvement in lower extremity
skeletal abnormalities, compared with conventional therapy

Mean Radiographic Global Impression of Change1,2,*

Study 1: Mean lower extremity skeletal abnormality score comparing CRYSVITA® to conventional therapy graph
FOOTNOTES

CI, confidence interval; LS, least squares; SE, standard error.

*The estimates of LS mean and 95% CI for Week 40 are from an ANCOVA model accounting for treatment group and baseline age stratification factor; the estimates for Week 64 are from a generalized estimating equation (GEE) model accounting for treatment group, visit, treatment-by-visit interaction, and baseline age stratification factor.

A Phase 2 study also showed that CRYSVITA improved lower extremity skeletal abnormalities, as assessed byRGI-C.1

Study 3 (N=13, ages 1 to 4 years):

  • At Week 40, mean (SE) change in lower limb deformity was +1.3 (0.14)

Radiographic example of lower extremity skeletal abnormality improvement

The following is an example of correction of lower extremity skeletal abnormality in a patient with XLH (female, aged 2.9 years, Study 1) who received CRYSVITA every 2 weeks for 64 weeks, compared with a patient (female, aged 2.9 years, Study 1) who continued on conventional therapy.1

CRYSVITA Every 2 Weeks Helped Correct Lower Extremity Skeletal Abnormalities5

Legs

Individual results may vary.

The THACHER Rickets Severity Score and the Radiographic Global Impression of Change Scoring Methods

The Thacher Rickets Severity Score4,7

RSS is a 10-point score for radiographs of wrists and knees to assess the degree of metaphyseal fraying and cupping and the proportion of the growth plate affected.

  • Total points progress in half-point increments from 0-10: wrists (0-4) plus knees (0-6)
  • RSS is assigned by an independent expert blinded to dose and patient
  • Higher scores indicate a more severe state of rickets, and a reduction in RSS indicates an improvement in severity

An Example of RSS Scores From Knee X-rays9


Example of RSS scores from knee X-rays

RSS=1.0
RSS=2.0

The Radiographic Global Impression of Change

RGI-C is a 7-point scale (-3=severe worsening; 0=no change; +3=near/complete healing) designed for comprehensive evaluation of skeletal health1,4,8

  • A complement to the RSS, RGI-C scores assess changes in the severity of rickets using the disease-specific qualitative RGI-C scoring system
  • RGI-C scores are assigned by 3 independent experts blinded to dose and patient
  • An RGI-C score of +2.0 indicates substantial healing of rickets

RGI-C Scoring Scale

Radiographic global impression of change scoring scale

Help heal rickets and improve lower skeletal
abnormalities with CRYSVITA

GROWTH IN CHILDREN

CRYSVITA improved growth, compared with conventional therapy or on its own1

In a study of pediatric patients with XLH aged 1 to 12 years (Study 1), standing height z-score was used as a measurement for growth. The “stature-for-age” z-score was determined based on a percentile basis using the Centers for Disease Control/National Center for Health Statistics (CDC/NCHS) Clinical Growth Charts.

Standing height was used to calculate the stature-for-age z-score based on standardized age- and sex-adjusted stature from the CDC.1,2

Height Z-scores With CRYSVITA Every 2 Weeks or With Conventional Therapy1,2,*

Study 1: Height z-score with CRYSVITA® or with conventional therapy graph
FOOTNOTES

CI, confidence interval; GEE, generalized estimating equation; LS, least squares; SE, standard error.

*The estimates of LS mean, SE, and 95% CI are from a GEE model, which included change from baseline for recumbent length/standing height z-score as the dependent variable, treatment group, visit, interaction between treatment group by visit, and baseline RSS stratification as factors; and age and baseline recumbent length/standing height z-score as continuous covariates, with exchangeable covariance structure.

CRYSVITA treatment increased standing mean (SD) height z-score from -2.32 (1.17) at baseline to -2.11 (1.11) at Week 64 (LS mean change [SE] of +0.17 [0.07]), while for conventional therapy it increased from -2.05 (0.87) at baseline to -2.03 (0.83) at Week 64 (LS mean [SE] change of +0.02 [0.04]).

A Phase 2 study also showed that CRYSVITA improved growth1

  • Standing height z-score increased from -1.72 (1.03) at baseline to -1.54 (1.13) at Week 64 (LS mean change of +0.19 [95% CI: 0.09 to 0.29])

Help increase growth with CRYSVITA

References
  1. CRYSVITA (burosumab-twza) US Prescribing Information; June 2020.
  2. Imel EA, Glorieux FH, Whyte MP, et al. Burosumab versus conventional therapy in children with X-linked hypophosphataemia: a randomised, active-controlled, open-label, phase 3 trial. Lancet. 2019;309(10189):2416-2427.
  3. Whyte MP, Carpenter TO, Gottesman GS, et al. Efficacy and safety of burosumab in children aged 1-4 years with X-linked hypophosphataemia: a multicentre, open-label, phase 2 trial. Lancet Diabetes Endocrinol. 2019;7(3):189-199.
  4. Carpenter TO, Whyte MP, Imel EA, et al. Burosumab therapy in children with X-linked hypophosphatemia. N Engl J Med. 2018;378(21):1987-1998.
  5. Data on file. BLA Clinical Overview. Ultragenyx Pharmaceutical Inc.; 2018.
  6. Mayo Clinic Laboratories. Pediatric test catalog: Alkaline Phosphatase, Serum. Accessed December 20, 2021. https://pediatric.testcatalog.org/show/ALP
  7. Thacher TD, Pettifor JM, Tebben PJ, et al. Rickets severity predicts clinical outcomes in children with X-linked hypophosphatemia: utility of the radiographic Rickets Severity Score. Bone. 2019;122:76-81. doi:10.1016/j.bone.2019.02.010
  8. Whyte MP, Fujita KP, Moseley S, Thompson DD, McAlister WH. Validation of a novel scoring system for changes in skeletal manifestations of hypophosphatasia in newborns, infants, and children: the Radiographic Global Impression of Change scale. J Bone Miner Res. 2018;33(5):868-874. doi:10.1002/jbmr.3377
  9. Data on file. 201 CSR. Ultragenyx Pharmaceutical Inc.; 2018.

CRYSVITA® CLINICAL EFFICACY

CLINICAL EFFICACY

CRYSVITA® (burosumab-twza) normalized serum phosphorus and helped heal osteomalacia-related fractures and osteomalacia in adults with XLH

  • Clinical Trials Design
  • Serum Phosphorus
  • Osteomalacia
  • Fractures
  • Patient-reported Outcomes

Clinical trials design

CRYSVITA was tested in a clinical trial program of 148 adults with XLH1

Note that in the Prescribing Information, the Phase 3 study (N=134, ages 19 to 66 years) is identified as Study 4, and the Phase 3 study (N=14, ages 25 to 52 years) is identified as Study 5.

Phase 3 (Study 4) select endpoints1,2:

  • Primary endpoint: Proportion of subjects achieving mean serum phosphorus levels above the lower limit of normal at the midpoint of dosing interval, averaged across dose cycles from baseline to Week 24
  • Secondary endpoint: Change from baseline to Week 24 in patient-reported joint stiffness, as assessed by the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC)
  • Exploratory endpoint: Resolution of pre-existing active pseudofractures and/or fractures at postbaseline visits, as defined by skeletal survey
  • Safety: Number of subjects with adverse events (AEs), serious adverse events (SAEs), and AEs leading to discontinuation
Phase 3 clinical overview of adult patient studies with CRYSVITA®
CRYSVITA was tested in 2 clinical trials of adults ages 19 to 66 years
FOOTNOTES

SC, subcutaneous.

Phase 3 (Study 5) select endpoints1,3:

  • Primary endpoint:
    • Percent change from baseline to Week 48 in:
      • Osteoid volume/bone volume (OV/BV)
      • Determined by iliac crest biopsies
  • Secondary endpoints:
    • Percent change from baseline in additional histomorphometric parameters, including:
      • Osteoid thickness
      • Mineralization lag time
  • Safety: Number of subjects with AEs, SAEs, and AEs leading to discontinuation

In both studies of adult patients with XLH, oral phosphate and active vitamin D analogs were not allowed.1

Learn more about osteomalacia

The clinical studies were designed to be representative of the relevant adult population with XLH1-4

Overall Disease Burden at Baseline
Study 4 (N=134,
ages 19 to 66 years)
Study 5 (N=14,
ages 25 to 52 years)
Mean age (years) 40 40
Male, n (%) 47 (35%) 6 (43%)
Mean serum phosphorus (mg/dL) 1.98 (0.31) 2.24 (0.40)
Prior therapy (oral phosphate and active vitamin D analogs) (%) 90% 86%
Symptoms of osteomalacia 100% had skeletal pain associated with osteomalacia/XLH

52% had active fractures/
pseudofractures, located predominantly in femurs, tibia/fibula, and metatarsals of feet
43% had evidence of prior fractures, 36% had evidence of prior pseudofractures

One patient in the CRYSVITA group (Study 4) withdrew during the 24-week double-blind period, and 7 patients withdrew during the subsequent 24-week open-label period of the double-blind, placebo-controlled study

Osteomalacia and bone histomorphometry

Mineralization of the bone matrix (osteoid) is a critical step during bone formation. During this process, minerals are deposited to allow the “hardening” of the matrix into bone, hence the term mineralization.5

 

In Study 5 (N=14, ages 25 to 52 years), histological assessments of the iliac bone crest were used to determine the histomorphometric features of bone associated with osteomalacia.1,5

Normal bone


Normal bone illustration

Normal bone illustration

Normal bone

Normal femur


Microscope view of normal bone development

X-ray of normal femur

Mineralized bone is shown in green and unmineralized osteoid is shown in orange or red.

In a normal bone:

  • Osteoid volume to bone volume (OV/BV)
    ratio indicates the relative proportion of unmineralized bone matrix (osteoid) relative to actual mineralized bone

  • Osteoid thickness (O.Th)
    is a measurement of unmineralized bone matrix (osteoid)
  • Mineralization lag time (MLt) is the rate of osteoid formation relative to bone mineralization

Osteomalacia


Osteomalacia bone illustration

Osteomalacia bone illustration

XLH (osteomalacia)

Pseudofracture


Microscope view of osteomalacia bone development

X-ray of pseudofractures due to osteomalacia

Mineralized bone is shown in green and unmineralized osteoid is shown in orange or red.

Osteomalacia is characterized by the following histomorphometric features:
  • Increased osteoid volume/bone volume
  • Increased osteoid thickness
  • Prolonged mineralization lag time
  • Together, these indicate a greater presence of osteoid relative to mineralized bone, indicative of defective mineralization

SERUM PHOSPHORUS RESULTS IN ADULTS

CRYSVITA increased and sustained serum phosphorus levels above the lower limit of normal1,2

MEAN SERUM PHOSPHORUS LEVELS IN ADULTS RECEIVING CRYSVITA EVERY 4 WEEKS OR RECEIVING PLACEBO

Study 4: Mean serum phosphorus levels in adults receiving CRYSVITA® or placebo graph
In Study 4, CRYSVITA increased and sustained serum phosphorus levels, compared with placebo
FOOTNOTES

SD, standard deviation.
*Serum phosphorus level (mg/dL) (mean ±SD). The dotted line represents the lower limit of normal (LLN, 2.5 mg/dL). Normal levels of serum phosphorus range from 2.5 to 4.5 mg/dL. Note that the normal levels of serum phosphorus vary by age and sex. At baseline mean (SD), serum phosphorus levels were 2.0 (0.30) and 1.9 (0.32) mg/dL for the CRYSVITA and placebo groups, respectively. Mean serum phosphorus levels across midpoints of dose intervals (2 weeks postdose) were 3.2 (0.53) and 2.1 (0.30) mg/dL for the CRYSVITA and placebo groups, respectively.

In Study 4 (N=134, ages 19 to 66 years), when given CRYSVITA or placebo every 4 weeks1:

  • Mean (SD) serum phosphorus levels across midpoints of dose intervals (2 weeks postdose) increased from 2.0 (0.30) mg/dL at baseline to 3.2 (0.53) mg/dL in the CRYSVITA group compared with 1.9 (0.32) mg/dL at baseline to 2.1 (0.30) mg/dL in the placebo group
  • Mean (SD) serum phosphorus levels across the ends of dose intervals were 2.7 (0.45) mg/dL and 2.0 (0.30) mg/dL in the CRYSVITA and placebo groups, respectively
  • During the open-label treatment period, serum phosphorus was maintained with continued CRYSVITA therapy with no evidence of loss of effect through Week 48

In Study 4 (N=134, ages 19 to 66 years), CRYSVITA also led to decreased renal phosphate wasting.1,3,6*

TmP/GFR MEAN (SD), mg/dL
Treatment Group Baseline Week 22 (dose
interval midpoint)
Week 24 (end of
dose interval)
Week 48
CRYSVITA to
CRYSVITA (n=68)
1.68
(0.40)
2.73 (0.75) 2.21 (0.48) 2.22 (0.52)
Placebo to
CRYSVITA (n=66)
1.60 (0.37) 1.69 (0.37) 1.73 (0.42) 2.2 (0.59)
FOOTNOTES

*The normal range for TmP/GFR is 2.6 to 4.4 mg/dL.2

A significantly higher proportion of patients achieved normalized serum phosphorus with CRYSVITA, compared with placebo1

Proportion of Patients Achieving Mean Serum Phosphorus Levels
Above the Lower Limit of Normal (LLN)* Through Week 24 (N=134, Study 4)

Infographic of proportion of patients achieving mean serum phosphorus levels with CRYSVITA® vs placebo

FOOTNOTES

CI, confidence interval.
*LLN is 2.5 mg/dL. The range of normal levels of serum phosphorus is 2.5 mg/dL to 4.5 mg/dL. Note that the range of normal levels of phosphorus differ based on age and sex.
†P-value is from Cochran-Mantel-Haenszel (CMH) testing for association between achieving the primary endpoint and treatment group, adjusting for randomization stratification.

Serum phosphorus was maintained with continued CRYSVITA treatment through Week 481

Help improve chronic hypophosphatemia and redefine XLH management
with CRYSVITA

OSTEOMALACIA HEALING IN ADULTS

CRYSVITA demonstrated healing of osteomalacia, as assessed by bone histomorphometry1

In Study 5 (N=14, ages 25 to 52 years), histological and histomorphometric assessments of iliac bone crest (biopsies) were examined for changes related to the healing of osteomalacia.1

Improved Bone Mineralization With CRYSVITA Every 4 Weeks
After 48 Weeks of Treatment, as Assessed by Histomorphometry1,3,*

Phase 3
(N=14, ages 25 to 52 years)

Osteoid Volume/
Bone Volume
(in 10 out of 14 patients)
Osteoid volume to bone volume  reduction with CRYSVITA® graph

Osteoid Thickness
(in 11 out of 14 patients)
Osteoid thickness reduction with CRYSVITA® graphic

Mineralization Lag Time
(in 6 out of 14 patients)
Mineralization lag time reduction with CRYSVITA® graphic

FOOTNOTES

SD, standard deviation.
*Normal osteoid volume/bone volume was defined as 0.30% to 3.10%; osteoid thickness as 5.5 to 12 μm; and mineralization lag time as 15 to 50 days.

At baseline, histomorphometric assessments of osteomalacia were determined by a comparison using reference measurements3,5:

  • In 10 out of 14 patients, mean osteoid volume to bone volume (OV/BV) ratio was a mean (SD) score of 26% (12.4), compared with a reference range of 0.3% to 3.1% in healthy postmenopausal women
  • In 11 out of 14 patients, mean Osteoid thickness (O.Th) was a mean (SD) of 17 (4.1) μm, compared with the reference range of 5.5 to 12 μm
  • Mineralization lag time (MLt) was measurable at baseline for 6 subjects. For these 6 subjects, mean MLt was a mean (SD) of 594 (675) days, compared with a reference range of 15 to 50 days in healthy postmenopausal women

At Week 48, CRYSVITA healed osteomalacia, as demonstrated by bone histomorphometric assessments of osteomalacia, such as1

  • 57% reduction in osteoid volume/bone volume
  • 33% reduction in osteoid thickness
  • 74% reduction in mineralization lag time

Help heal osteomalacia with CRYSVITA

ACTIVE FRACTURE AND PSEUDOFRACTURE HEALING IN ADULTS

CRYSVITA healed osteomalacia-related fractures1

In Study 4 (N=134, ages 19 to 66 years), osteomalacia-related active fractures were defined as atraumatic lucencies extending across both bone cortices, and pseudofractures were defined as atraumatic lucencies extending across 1 cortex. The total number of fractures was defined as fractures and pseudofractures combined.1

Predominant Location of Fractures/Pseudofractures

Illustration of predominant locations of fractures and pseudofractures
In Study 4, fractures were predominantly located in the femur, tibia/fibula, and metatarsals

CRYSVITA led to a higher rate of complete total fracture healing, including in patients who switched from placebo1

Switching to CRYSVITA Every 4 Weeks From Placebo
Led to a Higher Rate of Fracture Healing1,2,*

Phase 3 results of improved fracture healing with CRYSVITA® compared to placebo graph
In Study 4, CRYSVITA led to greater total fracture and pseudofracture healing, compared with placebo
FOOTNOTES

*Total fractures are osteomalacia-related fractures that were defined as atraumatic lucencies extending across both bone cortices, and pseudofractures that were defined as atraumatic lucencies extending across one cortex. These fractures were predominantly located in femurs, tibia/fibula, and metatarsals of the feet. Total fractures were both active fractures and pseudofractures. Healing is defined as complete or partial healing.

At baseline, the total number of active fractures/pseudofracture were1:

  • CRYSVITA=65
  • Placebo=91

At Week 24, the total number of healed active fractures/pseudofractures were1:

  • CRYSVITA=28 (43%)
  • Placebo=7 (8%)

At Week 24, 68 patients receiving CRYSVITA had a total of 6 new fractures or pseudofractures, compared with 8 new abnormalities in 66 patients receiving placebo.

CRYSVITA led to active fracture and pseudofracture healing through Week 48

Proportion of Active Fractures
Healed at Weeks 24 and 48
Proportion of active fractures healed with CRYSVITA® graph

Proportion of Active Pseudofractures
Healed at Weeks 24 and 48
Proportion of active pseudofractures healed with CRYSVITA® graph

During the open-label treatment period, patients who continued receiving CRYSVITA showed continued healing of active fractures (n=8, 57%) and active pseudofractures (n=33, 65%). In the placebo to CRYSVITA group, fracture healing was observed at Week 48 for active fractures (n=6, 46%) and active pseudofractures (n=26, 33%).

Healing of osteomalacia, as evaluated by radiographs of pseudofractures

The following is an example of a pseudofracture healing in a patient with XLH (female, aged 38 years, Study 4) who received CRYSVITA every 4 weeks2:

Pseudofracture at Baseline
healed with CRYSVITA® graph

Healed Pseudofractures at Week 24 With CRYSVITA
X-ray of healed pseudofracture at week 24 with CRYSVITA®

Individual results may vary.

Help heal fractures with CRYSVITA

Patient-reported outcomes

CRYSVITA was shown to improve patient-reported joint stiffness, compared with placebo; no significant differences were noted in pain and physical function1

In Study 4 (N=134, ages 19 to 66 years), patient-reported joint stiffness was assessed using the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC).

WOMAC Stiffness1,2,*

LS mean change from baseline of WOMAC stiffness comparing CRYSVITA® and placebo
CRYSIVTA improved joint stiffness by Week 24, compared with placebo
FOOTNOTES

LS, least squares; SE, standard error; WOMAC, Western Ontario and McMaster Universities Osteoarthritis Index.
Mean (SD) baseline stiffness scores were 61.4 (20.77) and 64.7 (20.25) in the placebo and CRYSVITA groups, respectively.
*The estimates of LS means at Week 24 are from the generalized estimating equation (GEE) model.

CRYSVITA improved stiffness from baseline to Week 24:

  • The CRYSVITA arm showed a mean improvement from baseline (-7.9), compared with the placebo arm (+0.3), in the stiffness severity score (range 0 to 100; lower scores are reflective of symptom improvement)

Other XLH-related patient-reported symptoms, including pain and physical function, were assessed in Study 4. At 24 weeks, no significant difference between CRYSVITA and placebo was demonstrated in patient-reported pain intensity or physical function score.

Help improve XLH-related joint stiffness with CRYSVITA

References
  1. CRYSVITA (burosumab-twza) US Prescribing Information; June 2020.
  2. Insogna KL, Briot K, Imel EA, et al. A randomized, double-blind, placebo-controlled, phase 3 trial evaluating the efficacy of burosumab, an anti-FGF23 antibody, in adults with X-linked hypophosphatemia: week 24 primary analysis. J Bone Miner Res. 2018;33(8):1383-1393.
  3. Insogna KL, Rauch F, Kamenický P, et al. Burosumab improved histomorphometric measures of osteomalacia in adults with X-linked hypophosphatemia: a phase 3, single-arm, international trial. J Bone Miner Res. 2019;34(12):2183-2191.
  4. Data on file. 304 CSR. Ultragenyx Pharmaceutical Inc.; 2018.
  5. Recker RR, Kimmel DB, Parfitt AM, et al. Static and tetracycline-based bone histomorphometric data from 34 normal postmenopausal females. J Bone Miner Res. 1988;3(2)133-144.
  6. Data on file. 303 CSR. Ultragenyx Pharmaceutical Inc.; 2018.
Phase 2 and Phase 3 Clinical treatment overview of CRYSVITA®
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X-ray of left wrist of patient receiving CRYSVITA® at baseline
X-ray of left wrist of patient receiving CRYSVITA® at week 64
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X-ray of left wrist of patient on conventional therapy at baseline
X-ray of left wrist of patient on conventional therapy at week 64
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X-ray of right knee of patient receiving CRYSVITA® at baseline
X-ray of right knee of patient receiving CRYSVITA® at week 64
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X-ray of right knee of patient on conventional therapy at baseline
X-ray of right knee of patient on conventional therapy at week 64
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X-ray of lower extremity skeletal abnormalities of patient receiving CRYSVITA® at baseline
X-ray of lower extremity skeletal abnormalities of patient receiving CRYSVITA® at week 64
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X-ray of lower extremity skeletal abnormalities of patient on conventional therapy at baseline
X-ray of lower extremity skeletal abnormalities of patient on conventional therapy at week 64
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X-ray examples of RSS of 1.0 and RSS of 2.0
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