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

Clinical trial design—adults

The efficacy and safety of CRYSVITA were studied in 148 adults with XLH1

Clinical Trial Design

Clinical Trial Design

Q4W, every 4 weeks; SC, subcutaneous.

    Select study endpoints (Study 3)1,2:

  • 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
  • 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
    Select study endpoints (Study 4)1,3:
  • 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

The clinical studies were designed to be representative of the most relevant adult population with XLH1-3

Disease Burden at Baseline
Study 3 (N=134,
aged 19 to 66 years)
Study 4 (N=14,
aged 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 from the studies (Study 3) discontinued due to withdrawal of consent

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 above the lower limit of normal1,2

Mean Serum Phosphorus Peak Concentrations Through Week 24 in Adults Receiving CRYSVITA Every 4 Weeks (N=134, Study 3)*

  • Q4W, every 4 weeks; SD, standard deviation.
  • *Serum phosphorus level (mg/dL) (mean ±SD). The dotted line represents the lower limit of normal (LLN, 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 gender.6

    In a study of adult patients aged 19 to 66 years (Study 3), 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 to 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

    CRYSVITA also led to decreased renal phosphate wasting1

  • At baseline, the mean (SD) ratio of renal tubular maximum reabsorption rate of phosphate to glomerular filtration rate (TmP/GFR) was 1.68 (0.40) and 1.60 (0.37) mg/dL in the CRYSVITA and placebo groups, respectively
  • At Week 22 (midpoint of a dose interval), mean (SD) TmP/GFR was 2.73 (0.75) and 1.69 (0.37) mg/dL in the CRYSVITA and placebo groups, respectively
  • At Week 24 (end of a dose interval), mean (SD) TmP/GFR was 2.21 (0.48) and 1.73 (0.42) mg/dL in the CRYSVITA and placebo groups, respectively

Proportion of Patients Achieving Mean Serum Phosphorus Levels Above the Lower Limit of Normal (LLN)* Through Week 24 (N=134, Study 3):

  • 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 gender.
  • P-value is from Cochran-Mantel-Haenszel (CMH) testing for association between achieving the primary endpoint and treatment group, adjusting for randomization stratification.

Help improve chronic hypophosphatemia and redefine XLH management with CRYSVITA

CRYSVITA led to the healing osteomalacia-related fractures
CRYSVITA led to the healing osteomalacia-related fractures

Active fractures and pseudofractures

CRYSVITA led to the healing of osteomalacia-related fractures1

In a study of adult patients with XLH aged 19 to 66 years (Study 3), 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

Location of Fractures/pseudofractures

In Study 3, fractures were predominantly located in the femur, tibia/fibula, and metatarsals
In Study 3, fractures were predominantly located in the femur, tibia/fibula, and metatarsals

CRYSVITA led to a higher rate of complete total fracture healing compared to placebo1

Comparison of Complete Total Fracture Healing at Week 24 (N=134, Study 3)

Comparison of Complete Total Fracture Healing at Week 24 (N=134, Study 3)

    At baseline, total number of active fractures/pseudofractures were1:
  • CRYSVITA = 65
  • Placebo = 91
    At Week 24, total number of healed active fractures/pseudofractures were1:
  • CRYSVITA = 28 (43%)
  • Placebo = 7 (8%)

At Week 24, a total of 6 new fractures or pseudofractures appeared in patients in the CRYSVITA group, compared to 8 new incidences in patients in the placebo group.

Radiographic example of pseudofracture healing

An example of a pseudofracture healing in a patient with XLH (female, 38 years old, Study 3) who received CRYSVITA every 4 weeks2:

Baseline

A X-ray example of an adult patient's thigh at baseline, before taking CRYSVITA, showed an active pseudofracture

Week 24

A X-ray example of an adult patient's thigh at Week 24, after taking CRYSVITA every 4 weeks, showed a healed pseudofracture

Individual results may vary.

Help heal fractures with CRYSVITA

CRYSVITA led to the healing of osteomalacia as assessed by bone histomorphometry
CRYSVITA led to the healing of osteomalacia as assessed by bone histomorphometry

Osteomalacia

CRYSVITA led to the healing of osteomalacia as assessed by bone histomorphometry1

In a study of adult patients with XLH aged 25 to 52 years (Study 4), histological and histomorphometric assessments of iliac bone crest (biopsies) were examined for changes related to the healing of osteomalacia.1

Bone Histomorphometric Results at Week 48 (N=14, Study 4)

Osteoid Volume/
Bone Volume, %
(in 10 out of 14 patients)

Osteoid Thickness, μm
(in 11 out of 14 patients)

Mineralization Lag Time, days
(in 6 out of 14 patients)

    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 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 17.2 (12.4) 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 594 (675) days, compared with a reference range of 15 to 50 days in healthy postmenopausal women

    At Week 24, CRYSVITA led to the healing of 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

References
  1. CRYSVITA (burosumab-twza) US Prescribing Information; April 2018.

  2. Data on file. 303 CSR. Ultragenyx Pharmaceutical Inc.; 2018.

  3. Data on file. 304 CSR. Ultragenyx Pharmaceutical Inc.; 2018.

  4. Ott S. Histomorphometric measurements of bone turnover, mineralization, and volume. Clin J Am Soc Nephrol. 2008;3(suppl 3):S151-S156.

  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. BLA Clinical Overview. Ultragenyx Pharmaceutical Inc.; 2018.