CRYSVITA® (burosumab-twza) normalized serum phosphorus, healed rickets, and increased growth in pediatric patients with XLH

Clinical trial design—children

The efficacy and safety of CRYSVITA were established in 65 children with XLH1

Clinical Trial Design

Clinical Trial Design

  • SC, subcutaneous.
  • *Initial doses of CRYSVITA were 0.1, 0.2, or 0.3 mg/kg Q2W or 0.2, 0.4, or 0.6 mg/kg Q4W.

    Select study endpoints (Study 1)1,6:

  • Primary endpoint: Change from baseline at Week 40 in severity of rickets as measured by total Thacher Rickets Severity Score (RSS)
  • Secondary endpoints:
    • Change from baseline at Week 40 in:
      • Radiographic appearance of rickets and bowing as measured by Radiographic Global Impression of Change (RGI-C) scores
      • Standing height z-score
  • Safety: Number of subjects with adverse events (AEs), serious adverse events (SAEs), and AEs leading to discontinuation

    Select study endpoints (Study 2)1,3:

  • Primary endpoint: Change from baseline at Week 40 in serum phosphorus levels
  • Secondary endpoints:
    • Change from baseline at Week 40 in:
      • Rickets as assessed by the RGI-C global score and RSS
      • Lower extremity skeletal abnormalities as determined by the RGI-C lower limb deformity score
  • Safety: Number of subjects with AEs, SAEs, and AEs leading to discontinuation

In both 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.3,6

The clinical studies were designed to be representative of the most relevant pediatric population with XLH1,2

Disease Burden at Baseline
Study 1
(N=52, aged 5 to 12 years)
Study 2
(N=13, aged 1 to 4 years)
Mean age (years) 8.5 2.9
Male n (%) 24 (46%) 9 (59%)
Mean serum phosphorus (mg/dL) 2.4 2.5
Radiographic evidence of rickets (%) 94% 100%
Prior therapy (oral phosphate and active vitamin D analogs) (%) 96% 100%
Mean duration of prior therapy (years) 7 1.4

No pediatric patients discontinued from either of 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 led to increased and sustained serum phosphorus levels within normal range1

Mean Serum Phosphorus Levels Through Week 64 in Children Aged 5 to 12 Years Who Received CRYSVITA Every 2 Weeks (N=26, Study 1)*

Mean Serum Phosphorus Levels Through Week 64 in Children Aged 5 to 12 Years Who Received CRYSVITA Every 2 Weeks (N=26, Study 1)*

  • Q2W, every 2 weeks; 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 mg/dL to 6.1 mg/dL. Note that the normal levels of phosphorus differ based on age and gender.2

    In a study of pediatric patients aged 5 to 12 years (Study 1), when given CRYSVITA every 2 weeks1:

  • 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

    CRYSVITA also led to decreased renal phosphate wasting1

  • In pediatric patients aged 5 to 12 years, the mean ratio of renal tubular maximum reabsorption rate of phosphate to glomerular filtration rate (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

Mean Serum Phosphorus Levels Through Week 40 in Children Aged 1 to 4 Years Who Received CRYSVITA Every 2 Weeks (N=13, Study 2)*

Mean Serum Phosphorus Levels Through Week 40 in Children Aged 1 to 4 Years Who Received CRYSVITA Every 2 Weeks (N=13, Study 2)*

  • Q2W, every 2 weeks; 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 mg/dL to 6.1 mg/dL. Note that the normal levels of serum phosphorus differ based on age and gender.2

    In a study of pediatric patients aged 1 to 4 years (Study 2), when given CRYSVITA every 2 weeks1:

  • 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

Help improve chronic hypophosphatemia and redefine XLH management 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 led to the healing of rickets and correction of lower limb deformities1

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

CRYSVITA led to improvements in rickets severity 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 RSS Scores at Week 40 and Week 64 in Children Aged 5 to 12 Years Who Received CRYSVITA Every 2 Weeks (N=26, Study 1)

Mean Total RSS Scores at Week 40 in Children Aged 1 to 4 Years
Who Received CRYSVITA Every 2 Weeks (N=13, Study 2)

  • CI, confidence interval; LS, least squares.
  • *Derived from LS mean change from baseline in total score with 95% CI at Week 40, -1.1 (-1.28, -0.85).
  • †Derived from LS mean change from baseline in total score with 95% CI at Week 64, -1.0 (-1.20, -0.79).
  • ‡Derived from LS mean change from baseline in total score with 95% CI at Week 40, -1.7 (-2.03, -1.44).
  • The estimates of the LS mean change are from the generalized estimation equation (GEE) model, accounting for baseline RSS, visits, and regimen and its interaction for Study 1 and from the ANCOVA model, accounting for age and baseline RSS for Study 2.

    In a study of pediatric patients aged 5 to 12 years (Study 1), when given CRYSVITA every 2 weeks1:

  • 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

    In a study of pediatric patients aged 1 to 4 years (Study 2), when given CRYSVITA every 2 weeks1:

  • 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 led to the healing of rickets 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

Global RGI-C Scores at Week 40 in Children Aged 1 to 12 Years Who Received CRYSVITA Every 2 Weeks (N=26, Study 1 and N=13, Study 2)1

Global RGI-C Scores at Week 40 in Children Aged 1 to 12 Years Who Received CRYSVITA Every 2 Weeks (N=26, Study 1 and N=13, Study 2)1

In a study of pediatric patients aged 5 to 12 years (Study 1), when given CRYSVITA every 2 weeks1:

  • 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. These scores were also maintained through Week 64
  • A mean RGI-C global score of +1.6 was maintained through Week 64

In a study of pediatric patients aged 1 to 4 years (Study 2), when given CRYSVITA every 2 weeks1:

  • 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
  • Using standing long leg radiographs, mean (SE) lower limb was +1.3 (0.14)

Radiographic examples of healing of rickets (RGI-C ≥+2.00)

An example of a patient with XLH (female, 4 years old, Study 2) who received CRYSVITA every 2 weeks for 40 weeks3,4:

Wrists

Baseline

An X-ray of a child's wrists at baseline, before taking CRYSVITA, showed widened growth plates and irregular metaphyseal margins

Week 40

An X-ray of a child's wrists at Week 40, after taking CRYSVITA every 2 weeks, showed healing of growth plates

Individual results may vary.

Knees

Baseline

An X-ray of a child's knees at baseline, before taking CRYSVITA, showed partial lucency and visible smooth margins of metaphyses

Week 40

An X-ray of a child's knees at Week 40, after taking CRYSVITA every 2 weeks, showed healing of growth plates

Individual results may vary.

An example of correction of lower limb deformity in a patient with XLH (female, 4 years old, Study 2) who received CRYSVITA every 2 weeks for 40 weeks3,4:

Legs

Baseline

A long standing X-ray of a child's legs at baseline, before taking CRYSVITA, showed lower limb deformity

Week 40

A long standing X-ray of a child's legs at Week 40, after taking CRYSVITA every 2 weeks, showed correction of lower limb deformity

Individual results may vary.

Help heal rickets and correct lower limb deformities 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 led to reductions in serum total alkaline phosphatase activity1

Serum ALP Activity at Week 64 in Children Aged 5 to 12 Years Who Received CRYSVITA Every 2 Weeks (N=26, Study 1)1,*

Serum ALP Activity at Week 40
in Children Aged 1 to 4 Years Who Received CRYSVITA Every 2 Weeks (N=13, Study 2)1,†

  • *The upper limit of the normal ranges for the ages of the children in Study 1 was approximately 297 to 385 U/L, depending on the sex and age of the child.
  • †The upper limit of the normal ranges for the ages of the children in Study 2 was approximately 297 to 345 U/L, depending on the sex and age of the child.

    In a study of pediatric patients aged 5 to 12 years (Study 1), when given CRYSVITA every 2 weeks1:

  • Mean alkaline phosphatase activity decreased from 462 (110) U/L at baseline to 354 (73) U/L at Week 64, a reduction of 23% (P < 0.0001)

    In a study of pediatric patients aged 1 to 4 years (Study 2), when given CRYSVITA every 2 weeks1:

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

Help reduce serum total alkaline phosphatase activity with CRYSVITA

CRYSVITA led to increased growth
CRYSVITA led to increased growth

Growth

CRYSVITA led to increased growth1

In a study of pediatric patients with XLH aged 5 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.1,6

Change From Baseline in Standing Height Z-score Through Week 64 (N=26, Study 1)

Change From Baseline in Standing Height Z-score Through Week 64 (N=26, Study 1)

    In a study of pediatric patients aged 5 to 12 years (Study 1), when given CRYSVITA every 2 weeks1:

  • 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; April 2018.

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

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

  4. Thacher TD, Fischer PR, Pettifor JM, Lawson JO, Manaster BJ, Reading JC. Radiographic scoring method for the assessment of the severity of nutritional rickets. J Trop Pediatr. 2000;46(3):132-139.

  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.