
Clinical trials design—adults
CRYSVITA was tested in a clinical trial program of 148 adults with XLH1

SC, subcutaneous.
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.
- 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 (Study 4) select endpoints1,2:
- Primary endpoint:
- Percent change from baseline to Week 48 in:
- Osteoid volume/bone volume (OV/BV)
- Determined by iliac crest biopsies
- Percent change from baseline to Week 48 in:
- Secondary endpoints:
- Percent change from baseline in additional histomorphometric parameters, including:
- Osteoid thickness
- Mineralization lag time
- Percent change from baseline in additional histomorphometric parameters, including:
- Safety: Number of subjects with AEs, SAEs, and AEs leading to discontinuation
Phase 3 (Study 5) select endpoints1,3:
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 relevant adult population with XLH1-3
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
Serum phosphorus
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*

- 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 wasting1,*
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) |
- *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)

- 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
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/Volume
(in 10 out of 14 patients)

Osteoid Thickness
(in 11 out of 14 patients)

Mineralization Lag Time
(in 6 out of 14 patients)

- 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.
- 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 baseline, histomorphometric assessments of osteomalacia were determined by a comparison using reference measurements3,5:
- 57% reduction in osteoid volume/bone volume
- 33% reduction in osteoid thickness
- 74% reduction in mineralization lag time
At Week 48, CRYSVITA healed osteomalacia, as demonstrated by bone histomorphometric assessments of osteomalacia, such as1:
Help heal osteomalacia with CRYSVITA
Active fractures and pseudofractures
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
Location of Fractures/Pseudofractures

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 Healing1,7,*

- *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.
- CRYSVITA=65
- Placebo=91
- CRYSVITA=28 (43%)
- Placebo=7 (8%)
- CRYSVITA to CRYSVITA=41 (63%)
- Placebo to CRYSVITA=32 (35%)
At baseline, the total number of active fractures/pseudofractures were1:
At Week 24, the total number of healed active fractures/pseudofractures were1:
At Week 48, the total number of healed active fractures/pseudofractures were1:
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 Pseudofractures Healed at Weeks 24 and 48

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:
Pseudofractures at Baseline

Healed Pseudofractures 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, 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 joint 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 phsyical 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
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CRYSVITA (burosumab-twza) US Prescribing Information; June 2020.
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Data on file. 303 CSR. Ultragenyx Pharmaceutical Inc.; 2018.
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Data on file. 304 CSR. Ultragenyx Pharmaceutical Inc.; 2018.
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Ott S. Histomorphometric measurements of bone turnover, mineralization, and volume. Clin J Am Soc Nephrol. 2008;3(suppl 3):S151-S156.
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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.
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Data on file. BLA Clinical Overview. Ultragenyx Pharmaceutical Inc.; 2018.