CRYSVITA® (burosumab-twza) increased and sustained serum phosphorus and healed osteomalacia in adults with TIO1

Clinical trials design

CRYSVITA was tested in a clinical trial program of 27 adults with TIO1

Clinical trial design—CRYSVITA® for TIO

All patients discontinued oral phosphate and active vitamin D analogs 2 weeks prior to study enrollment.

Clinical trial design—CRYSVITA® for TIO

All patients discontinued oral phosphate and active vitamin D analogs 2 weeks prior to study enrollment.

SC, subcutaneous.

    Phase 2 (Study 6) select endpoints1,2:

  • Coprimary endpoints:
    • Proportion of subjects achieving mean serum phosphorus levels above the lower limit of normal at the midpoint of the dosing interval, averaged across dose cycles from baseline to Week 24
    • Percent change from baseline to Week 48 of osteomalacia-associated bone measurements in:
      • Osteoid thickness (O.Th)
      • Osteoid volume/bone volume (OV/BV)
      • Mineralization lag time (MLt)
  • Secondary endpoint: Percent change from baseline to Week 24 of serum phosphorus levels at the midpoint of the dosing interval, averaged across dose cycles
  • Safety: Number of subjects with adverse events (AEs), serious adverse events (SAEs), and AEs leading to discontinuation

    Phase 2 (Study 7) select endpoints1,2:

  • Primary endpoint: Change from baseline to Week 24 in serum phosphorus levels
  • Secondary endpoints:
    • Percent change from baseline to Week 48 in additional histomorphometric parameters, including:
      • Osteoid thickness
      • Osteoid volume/bone volume
      • Mineralization lag time
    • Change from baseline to Week 48 in ratio of renal tubular maximum phosphate reabsorption rate to glomerular filtration rate
  • Safety: Number of subjects with AEs, SAEs, and AEs leading to discontinuation

In both studies of adult patients with TIO, oral phosphate and active vitamin D analogs were not allowed.1,2

At baseline, patients with TIO experienced substantial disease burden1,2

    In Study 6:

  • 90% (9/10) of patients with known tumor location underwent attempted surgical resection
  • 45% (5/11) of patients required assistance with walking
  • On average, the time from symptom onset to diagnosis was 4.5 years
Baseline Characteristics
  Study 6 (N=14,
ages 33 to 68 years)
Study 7 (N=13,
ages 41 to 73 years)
Median age (years) 59.5 58.0
Male, n (%) 8 (57%) 6 (46%)
Mean serum
phosphorus,
(mg/dL) (SD)
1.60 (0.47) 1.62 (0.49)
Prior therapy (oral
phosphate and/or
active vitamin D analogs) (%)
100% 100%

One patient in each study withdrew due to neoplasm progression

CRYSVITA® increased and sustained serum phosphorus
CRYSVITA® increased and sustained serum phosphorus

Serum phosphorus

CRYSVITA increased and sustained
serum phosphorus
1,2

Mean Serum Phosphorus Levels in Adults Receiving CRYSVITA Every 4 Weeks1,2,*

Mean serum phosphorus levels—Adults receiving CRYSVITA®
Mean serum phosphorus levels—Adults receiving CRYSVITA®
  • LLN, lower limit of normal; SD, standard deviation.
  • *Serum phosphorus level (mg/dL) (mean ±SD). The dotted horizontal line represents the 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, and ranges may vary by testing laboratory. At baseline, mean (SD) serum phosphorus levels were 1.60 (0.47) mg/dL. Mean serum phosphorus levels across midpoints of dose intervals (2 weeks post-dose) through Week 24 were 2.64 (0.76) mg/dL with CRYSVITA.

    In the Phase 2 studies, when given CRYSVITA every 4 weeks1:

  • Mean (SD) serum phosphorus levels increased from 1.60 (0.47) mg/dL at baseline to 2.64 (0.76) mg/dL at Week 24 in Study 6 (N=14, ages 33 to 68 years)
  • Mean (SD) serum phosphorus levels increased from 1.62 (0.49) mg/dL at baseline to 2.63 (0.87) mg/dL at Week 24 in Study 7 (N=13, ages 41 to 73 years)

In the Phase 2 studies (N=27, ages 33 to 73 years), CRYSVITA increased and sustained renal tubular reabsorption1,2,†

TMP/GFR MEAN (SD), mg/dL
Phase 2 Study Baseline Week 24 Week 48 Week 72 Week 144
Study 6 (N=14) 1.12 (0.54) 2.12 (0.64) 2.11 (0.37) 2.18 (0.67)
Study 7 (N=13) 1.15 (0.43) 2.30 (0.71) 2.30 (0.48) 2.29 (0.50)

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.2
Note that ranges may vary by age, sex, and testing laboratory.

100% (27/27) of patients across both trials achieved increases in serum phosphorus with CRYSVITA through Week 144 in Study 6 and Week 88 in Study 71,2

50% (7/14) of patients in Study 6 and 69% (9/13) of patients in Study 7 achieved mean serum phosphorus levels above the LLN averaged across the midpoint of dose intervals through Week 24.

Serum phosphorus was maintained with continued CRYSVITA treatment through Week 144 in Study 61

Improve chronic hypophosphatemia in patients with TIO with CRYSVITA

CRYSVITA® demonstrated healing of osteomalacia
CRYSVITA® demonstrated healing of osteomalacia

Osteomalacia

CRYSVITA demonstrated healing of osteomalacia, as assessed by bone histomorphometry1

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 “hardening” of the matrix into bone, hence the term mineralization.3

Normal bone

Mineralized bone and unmineralized osteoid in normal bone

Normal femur

Normal mineralization in bone

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

Bone mineralization with CRYSVITA® for TIO
Bone mineralization with CRYSVITA® for TIO

Osteomalacia

Mineralized bone and unmineralized osteoid in patient with osteomalacia

Pseudofracture

Pseudofracture in patient with osteomalacia

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

    In 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 is characterized by the following histomorphometric features:

  • Increased OV/BV
  • Increased O.Th
  • Prolonged MLt

Together, these indicate a greater presence of osteoid relative to mineralized bone, indicative of defective mineralization.

In Study 6 (N=14, ages 33 to 68 years), histological and histomorphometric assessments of iliac bone crest (biopsies) were examined for changes related to the healing of osteomalacia.

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

Phase 2 (Study 6)
(N=14, ages 33 to 68 years)

Osteoid Volume/
Bone Volume
(in 9 of 14 patients)

Bone mineralization with CRYSVITA® for TIO

Osteoid Thickness
(in 9 of 14 patients)

Bone mineralization with CRYSVITA® for TIO

Mineralization Lag Time
(in 3 of 14 patients)

Bone mineralization with CRYSVITA® for TIO
  • SD, standard deviation. ULN, upper limit of normal.
    *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.2
    Paired bone biopsies were performed in 11 of the 14 patients.

    At baseline, histomorphometric assessments were determined in 11 out of 14 patients in Study 6 by a comparison using reference measurements. At baseline, 9 patients had osteomalacia based on histomorphometric assessments1:

  • Mean OV/BV ratio was 21.2% (19.9), compared with a reference range of 0.3% to 3.1% in healthy postmenopausal women
  • Mean O.Th was 18.9 (11.9) µm, compared with the reference range of 5.5 to 12 μm
  • MLt was measurable at baseline for 3 subjects. For these 3 subjects, mean MLt was 667 (414) days, compared with a reference range of 15 to 50 days in healthy postmenopausal women

    At Week 48 in Study 6, CRYSVITA healed osteomalacia, as demonstrated by bone histomorphometric assessments of osteomalacia, such as1:

  • 34% reduction in osteoid volume/bone volume
  • 36% reduction in osteoid thickness
  • 50% reduction in mineralization lag time

    At Week 48 in Study 7 in 3 patients with paired bone biopsies, CRYSVITA healed osteomalacia, as demonstrated by bone histomorphometric assessments of osteomalacia, such as1:

  • 34% reduction in osteoid volume/bone volume
  • 16% reduction in osteoid thickness

Radiographic evaluation of osteomalacia

99mtechnetium-labelled whole-body scans use a radioactive tracer to identify areas of unusual bone rebuilding. In patients with TIO, increased tracer uptake on bone scans is presumed to be nontraumatic fractures and pseudofractures.

    At baseline, 99mtechnetium-labelled bone scans detected 249 bone abnormalities across all patients in Study 61:

  • CRYSVITA decreased areas of tracer uptake on bone scans from Week 48 through Week 144, suggesting healing of bone abnormalities

Help heal osteomalacia with CRYSVITA

References
  1. CRYSVITA (burosumab-twza) US Prescribing Information; June 2020.

  2. Data on file. Ultragenyx Pharmaceutical Inc.

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