CRYSVITA® (burosumab-twza) normalized serum phosphorus and helped heal rickets and increase growth when compared with conventional therapy, or on its own, in pediatric patients with XLH

CRYSIVTA safety and efficacy were evaluated in children and adults

Clinical trials design—children

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

CRYSVITA was tested in 3 clinical trials of children with XLH ages 1 to 12 years
CRYSVITA was tested in 3 clinical trials of children with XLH ages 1 to 12 years
  • 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

A Phase 3 study compared CRYSVITA every 2 weeks with conventional therapy (oral phosphate and active vitamin D) for pediatric patients with XLH

    Phase 3 study (Study 1) select endpoints1,7:

  • 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 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.1,3,6

In all studies of 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.1,3,6

The clinical studies were designed to be representative of the relevant pediatric population with XLH.1,2

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% 100%
Mean duration of prior therapy (years) 4 7 1.4

No pediatric patients discontinued CRYSVITA treatment during the clinical studies1

CRYSVITA led to increased and sustained serum phosphorus levels within normal range
CRYSVITA led to increased and sustained serum phosphorus levels within normal range

Serum phosphorus

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 Therapy1,7,*

In Study 1, CRYSVITA increased and sustained serum phosphorus levels, compared with conventional therapy

Mean Serum Phosphorus Levels in Children Receiving CRYSVITA Every 2 Weeks or Receiving Conventional Therapy1,7,*

In Study 1, CRYSVITA increased and sustained serum phosphorus levels, compared with conventional therapy
  • Conventional therapy, oral phosphate and active vitamin D; 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 gender, 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

    Phase 3 study (Study 1, N=61, ages 1 to 12 years):

  • Mean ratio of tubular maximum reabsorption rate of phosphate to glomerular filtration rate (TmP/GFR) increased with CRYSVITA (n=29) from a mean (SD) of 2.2 (0.37) mg/dL at baseline to 3.4 (0.67) mg/dL and 3.3 (0.65) mg/dL at Weeks 40 and 64, respectively. With conventional therapy (n=32), mean (SD) TmP/GFR decreased from 2.0 (0.33) mg/dL at baseline to 1.8 (0.35) mg/dL and 1.9 (0.49) mg/dL at Weeks 40 and 64, respectively
  • Phase 2 study (Study 2, N=52, ages 5 to 12 years):

  • TmP/GFR increased from a mean (SD) of 2.2 (0.49) mg/dL at baseline to 3.3 (0.60) and 3.4 (0.53) mg/dL at Weeks 40 and 64, respectively
  • *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

CRYSVITA led to reductions in total serum alkaline phosphatase activity
CRYSVITA led to reductions in total serum alkaline phosphatase activity

Alkaline phosphatase

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 Therapy1,7,*

In Study 1, CRYSVITA reduced total ALP, compared with conventional therapy
In Study 1, CRYSVITA reduced total ALP, compared with conventional therapy
  • 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.7 The 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 42 to 108 U/L.9
  • Note that ranges may vary by age, gender, 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

CRYSVITA led to the healing of rickets and correction of lower limb deformities
CRYSVITA led to the healing of rickets and correction of lower limb deformities

Rickets

CRYSVITA resulted in greater improvement in rickets healing, compared with conventional therapy or on its own1

In all pediatric studies of patients with XLH aged 1 to 12 years, rickets was assessed using 2 radiographic scoring methods, RSS and RGI-C.4,5

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.1,4

  • 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 (RSS)*

In Study 1, CRYSVITA reduced RSS, compared with conventional therapy
In Study 1, CRYSVITA reduced RSS, compared with conventional therapy
  • 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 RSS.1

    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.1,5,6

  • 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 (RGI-C)*

In Study 1, CRYSVITA led to superior healing of rickets, compared with conventional therapy, as assessed by RGI-C

Mean Radiographic Global Impression of Change (RGI-C)*

In Study 1, CRYSVITA led to superior healing of rickets, compared with conventional therapy, as assessed by RGI-C
  • 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 647

Wrists

With CRYSVITA

Baseline

Week 40

Week 64

Example radiographs of wrists show substantial healing of rickets with CRYSVITA

With conventional therapy

Baseline

Week 40

Week 64

Example radiographs of wrists from patient on conventional therapy

Individual results may vary.

Knees

With CRYSVITA

Baseline

Week 40

Week 64

Example radiographs of knees show substantial healing of rickets with CRYSVITA

With conventional therapy

Baseline

Week 40

Week 64

Example radiographs of knees from patient on conventional therapy

Individual results may vary.

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

Mean Radiographic Global Impression of Change (RGI-C)1,7,*

In Study 1, CRYSVITA showed superior improvement in lower extremity skeletal abnormalities, compared with conventional therapy
In Study 1, CRYSVITA showed superior improvement in lower extremity skeletal abnormalities, compared with conventional therapy
  • 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 by RGI-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 (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

CRYSVITA Every 2 Weeks Helped Correct
Lower Extremity Skeletal Abnormalities7

Legs

With CRYSVITA

Baseline

Week 40

Week 64

Example radiographs show improvement of lower extremity skeletal abnormality of patient on CRYSVITA

With conventional therapy

Baseline

Week 40

Week 64

Example radiographs of lower limbs from patient on conventional therapy

Individual results may vary.

Help heal rickets and improve lower extremity skeletal abnormalities with CRYSVITA

CRYSVITA led to increased growth
CRYSVITA led to increased growth

Growth

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 gender-adjusted stature from the CDC.1,7

Height Z-scores With CRYSVITA Every 2 Weeks or With Conventional Therapy1,7,*

In Study 1, CRYSVITA improved growth, compared with conventional therapy

Height Z-scores With CRYSVITA Every 2 Weeks or With Conventional Therapy1,7,*

In Study 1, CRYSVITA improved growth, compared with conventional therapy
  • 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; September 2019.

  2. Data on file. BLA Clinical Overview. Ultragenyx Pharmaceutical Inc.; 2018.

  3. Data on file. 205 CSR. Ultragenyx Pharmaceutical Inc.; 2018.

  4. 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 [published online ahead of print February 14, 2019]. Bone. doi:10.1016/j.bone.2019.02.010.

  5. 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.

  6. Data on file. 201 CSR. Ultragenyx Pharmaceutical Inc.; 2018.

  7. Data on file. 301 CSR. Ultragenyx Pharmaceutical Inc.; 2019.

  8. 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.

  9. University of Rochester Medical Center website. Alkaline phosphatase. Health Encyclopedia. https://www.urmc.rochester.edu/encyclopedia/content.aspx?contenttypeid=167&contentid=alkaline_phosphatase. Accessed September 27, 2019.