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Efficacy

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Two phase 2 studies showed that CRYSVITA:

  • Increased and maintained serum phosphorus levels1,2
  • Helped heal osteomalacia1

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

Study designs

Study 61,3

CRYSVITA was studied in a 144-week, single-arm, open-label, phase 2 study in 14 adult patients with TIO aged 33-68 years (median 59.5 years). Patients received CRYSVITA every 4 weeks at a weight-based starting dose of 0.3 mg/kg that was titrated to achieve a fasting serum phosphorus level of 2.5 to 4.0 mg/dL. The mean dose was 0.83 mg/kg at week 20, 0.87 mg/kg at week 48, 0.77 mg/kg at week 96, and 0.71 mg/kg at week 144.

No patients discontinued the study due to adverse events.

Select endpoints:

  • Coprimary endpoints1,2:
    • Proportion of patients 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 cycles1,2
  • Safety: Number of subjects with adverse events (AEs) and serious adverse events (SAEs)1,3

Study 7

CRYSVITA was studied in a single-arm, open-label, phase 2 study of 13 adult patients with TIO aged 41-73 years (median 58.0 years). Patients received CRYSVITA every 4 weeks at a weight-based starting dose of 0.3 mg/kg that was titrated to achieve a fasting serum phosphorus level of 2.5 to 4.0 mg/dL. The mean (SD) dose was 0.91 (0.59) mg/kg at week 48 and 0.96 (0.70) mg/kg at week 88.1,4

No patients discontinued the study due to treatment-emergent adverse events (TEAEs).2,4

Select endpoints:

  • Primary endpoint: Change in serum phosphate at each timepoint4
  • Secondary endpoints1,4:
    • Percent change from baseline to week 48 in additional histomorphometric parameters, including:
      • O.Th
      • OV/BV
      • MLt
    • Change from baseline over time in ratio of renal tubular maximum phosphorus reabsorption rate to glomerular filtration rate
  • Safety: Number of subjects with TEAEs4

In both studies of adult patients with TIO, oral phosphate and active vitamin D analogs were discontinued 2 weeks prior to study enrollment, and were not allowed in the study.1

At baseline, patients with TIO experienced substantial disease burden

In Study 6:

  • 90% of patients with known tumor location underwent attempted surgical resection2
  • 45% of patients required assistance with walking2
  • Time from symptom onset to diagnosis was 4.5 years on average2

In Study 7:

  • 53.8% of patients had previously undergone surgery for their disease4
  • The average duration of disease was 10 years4

Disease burden at baseline2,5

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 assessments1,3:

  • Mean (SD) OV/BV ratio was 21.2% (19.9), compared with a reference range of 0.3% to 3.1% in healthy postmenopausal women
  • Mean (SD) 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 (SD) MLt was 667 (414) days, compared with a reference range of 15 to 50 days in healthy postmenopausal women

STUDIES 6 AND 7

CRYSVITA increased and sustained mean serum phosphorus levels near or above the lower limit of normal1,3

Mean serum phosphorus levels in adults receiving CRYSVITA every 4 weeks*

Line graph showing mean serum phosphorus levels within the normal range in patients with TIO receiving CRYSVITA every 4 weeks

*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 (SD) serum phosphorus levels across midpoints of dose intervals (2 weeks post-dose) through week 24 were 2.64 (0.76) mg/dL with CRYSVITA.

LLN=lower limit of normal; SD=standard deviation.

In Study 6, across midpoints of dose intervals through week 24*:

  • 50% (n=7) of patients achieved a mean serum phosphorus level above the LLN1,2
  • There was an increase in mean (SD) serum phosphorus levels from 1.60 (0.47) mg/dL at baseline to 2.64 (0.76) mg/dL1

In Study 7, across midpoints of dose intervals through week 24*:

  • 69% (n=9) of patients achieved mean serum phosphorus levels above the LLN1
  • There was an increase in mean (SD) serum phosphorus levels from 1.62 (0.49) mg/dL at baseline to 2.63 (0.87) mg/dL1

STUDY 6

CRYSVITA helped heal osteomalacia1,3,6

Improved bone mineralization with CRYSVITA every 4 weeks, as assessed by bone histomorphometry†

3 bar graphs showing bone mineralization as assessed by histomophometry; one showing 34% reduction in osteoid volume to bone volume in 9 out of 14 patients; one showing 36% reduction in osteoid thickness in 9 out of 14 patients; one showing 50% reduction in mineralization lag time in 3 out of 14 patients

†The upper limits of normal were defined as 3.05% for osteoid volume to bone volume, 8.9 μm for osteoid thickness, and mineralization lag time as 28.6 days.6

SD=standard deviation; ULN=upper limit of normal.

In Study 6 (N=14, ages 33 to 68 years), histological and histomorphometric assessments of iliac bone crest (biopsies) were examined for osteomalacia healing.1,3‡ CRYSVITA improved healing at week 48, with reductions in osteoid volume to bone volume (OV/BV), osteoid thickness (O.Th), and mineralization lag time (MLt).

In the 9 patients who presented with osteomalacia, the mean (SD) score decreased in OV/BV from 21.2% (19.9) at baseline to 13.9% (16.7), a 34% reduction. O.Th declined from a mean (SD) of 18.9 (11.9) µm to 12.1 (10.1) µm, a 36% reduction. MLt declined in 3 patients from a mean (SD) of 667 (414) days to 331 (396) days, a reduction of 50%.

‡Paired bone biopsies were performed in 11 of the 14 patients.

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Osteomalacia and bone histomorphometry overview

Mineralization of the bone matrix (osteoid) is a critical step during bone formation. During this process, minerals are deposited to allow the “hardening” of the matrix into bone, hence the term mineralization.3,9

In Study 6, histological assessments of the iliac bone crest were used to determine the histomorphometric features of bone associated with osteomalacia.3,9

Bone matrix (normal)10,11

Rectangular cross-section of normal bone
Rectangular cross-section of normal bone with osteoid labeled
Rectangular cross-section of normal bone with osteoid and new bone labeled
Rectangular cross section of normal bone with osteoid, new bone, and old bone labeled

Normal bone12

Micrographic image of normal bone; mineralized bone shown in green; unmineralized osteoid shown in orange or red
Mineralized bone is shown in green and unmineralized osteoid is shown in orange or red.

Normal femur

X-ray image of a normal femur

In a normal bone:

  • Osteoid volume to bone volume (OV/BV) ratio indicates the relative proportion of unmineralized bone matrix (osteoid) relative to mineralized bone13
  • Osteoid thickness (O.Th) is a measurement of the width of mineralized bone matrix (osteoid)13
  • Mineralization lag time (MLt) is the average interval of time between osteoid formation and osteoid mineralization13

Bone matrix (osteomalacia)10,11

Rectangular cross-section of a bone with osteomalacia
Rectangular cross-section of a bone with osteomalacia with increased osteoid (volume and thickness) labeled
Rectangular cross-section of a bone with osteomalacia with increased osteoid (volume and thickness) and less new bone labeled
Rectangular cross-section of a bone with osteomalacia with increased osteoid (volume and thickness), less new bone, and old bone labeled

TIO (tumor-induced osteomalacia)12

Micrographic image of a bone with osteomalacia; mineralized bone shown in green; unmineralized osteoid shown in orange or red
Mineralized bone is shown in green and unmineralized osteoid is shown in orange or red.

Pseudofracture

X-ray image of a femur with pseudofracture

Osteomalacia is characterized by the following histomorphometric features4,14,15:

  • Increased osteoid volume to bone volume
  • Increased osteoid thickness
  • Prolonged mineralization lag time
  • Together, these indicate a greater presence of osteoid relative to mineralized bone, indicative of defective mineralization

STUDY 7

Study 7 also showed improvements in bone mineralization in patients treated with CRYSVITA1,4

At week 48 in 3 patients with paired bone biopsies, CRYSVITA healed osteomalacia, as demonstrated by bone histomorphometric assessments of osteomalacia, with a 34% reduction in OV/BV and a 16% reduction in O.Th.

X-ray image of femur and knee bones representing how CRYSVITA healed bone abnormalities

STUDY 6

Radiographic evaluation of osteomalacia

CRYSVITA helped heal bone abnormalities as demonstrated by 99mtechnetium-labelled whole body bone scans. Scans were performed at baseline and subsequent timepoints during the study on all 14 patients. At baseline, 99mtechnetium-labelled bone scans detected 249 bone abnormalities across all patients in Study 6.1

CRYSVITA decreased areas of tracer uptake on bone scans from week 48 through week 144, suggesting healing of bone abnormalities.1

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.1,7

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Indication

CRYSVITA® (burosumab-twza) is a fibroblast growth factor 23 (FGF23) blocking antibody indicated for the treatment of FGF23-related hypophosphatemia in tumor-induced osteomalacia (TIO) associated with phosphaturic mesenchymal tumors that cannot be curatively resected or localized in adult and pediatric patients 2 years of age and older.

Indication

CRYSVITA® (burosumab-twza) is a fibroblast growth factor 23 (FGF23) blocking antibody indicated for the treatment of FGF23-related hypophosphatemia in tumor-induced osteomalacia (TIO) associated with phosphaturic mesenchymal tumors that cannot be curatively resected or localized in adult and pediatric patients 2 years of age and older.

Important Safety Information

CONTRAINDICATIONS

CRYSVITA is contraindicated:

  • In concomitant use with oral phosphate and/or active vitamin D analogs (e.g., calcitriol, paricalcitol, doxercalciferol, calcifediol) due to the risk of hyperphosphatemia.
  • When serum phosphorus is within or above the normal range for age.
  • In patients with severe renal impairment or end stage renal disease because these conditions are associated with abnormal mineral metabolism.

WARNINGS AND PRECAUTIONS

Hypersensitivity

  • Hypersensitivity reactions (e.g., rash, urticaria) have been reported in patients with CRYSVITA. Discontinue CRYSVITA if serious hypersensitivity reactions occur and initiate appropriate medical treatment.

Hyperphosphatemia and Risk of Nephrocalcinosis

  • Increases in serum phosphorus to above the upper limit of normal may be associated with an increased risk of nephrocalcinosis. For patients already taking CRYSVITA, dose interruption and/or dose reduction may be required based on a patient’s serum phosphorus levels.
  • Patients who undergo treatment of the underlying tumor should have dosing interrupted and adjusted to prevent hyperphosphatemia.

Injection Site Reactions

  • Administration of CRYSVITA may result in local injection site reactions. Discontinue CRYSVITA if severe injection site reactions occur and administer appropriate medical treatment.

ADVERSE REACTIONS

Adult Patients

  • Adverse reactions reported in more than 10% of CRYSVITA-treated adult TIO patients in two studies are: tooth abscess (19%), muscle spasms (19%), dizziness (15%), constipation (15%), injection site reaction (15%), rash (15%), and headache (11%).

USE IN SPECIFIC POPULATIONS

  • There are no available data on CRYSVITA use in pregnant women to inform a drug-associated risk of adverse developmental outcomes. Serum phosphorus levels should be monitored throughout pregnancy. Report pregnancies to the Kyowa Kirin, Inc. Adverse Event reporting line 1-844-768-3544.
  • There is no information regarding the presence of CRYSVITA in human milk or the effects of CRYSVITA on milk production or the breastfed infant. Therefore, the developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for CRYSVITA and any potential adverse effects on the breastfed infant from CRYSVITA or from the underlying maternal condition.

PATIENT COUNSELING INFORMATION

  • Advise patients not to use any oral phosphate and/or active vitamin D analog products.
  • Instruct patients to contact their physician if hypersensitivity reactions, injection site reactions, and restless legs syndrome induction or worsening of symptoms occur.

You may report side effects to the FDA at (800) FDA-1088 or www.fda.gov/medwatch. You may also report side effects to Kyowa Kirin, Inc. at 1-844-768-3544.

For important risk and use information, please see the full Prescribing Information for CRYSVITA.

Indication

CRYSVITA® (burosumab-twza) is a fibroblast growth factor 23 (FGF23) blocking antibody indicated for the treatment of FGF23-related hypophosphatemia in tumor-induced osteomalacia (TIO) associated with phosphaturic mesenchymal tumors that cannot be curatively resected or localized in adult and pediatric patients 2 years of age and older.

Important Safety Information

CONTRAINDICATIONS

CRYSVITA is contraindicated:

  • In concomitant use with oral phosphate and/or active vitamin D analogs (e.g., calcitriol, paricalcitol, doxercalciferol, calcifediol) due to the risk of hyperphosphatemia.
  • When serum phosphorus is within or above the normal range for age.
  • In patients with severe renal impairment or end stage renal disease because these conditions are associated with abnormal mineral metabolism.

WARNINGS AND PRECAUTIONS

Hypersensitivity

  • Hypersensitivity reactions (e.g., rash, urticaria) have been reported in patients with CRYSVITA. Discontinue CRYSVITA if serious hypersensitivity reactions occur and initiate appropriate medical treatment.

Hyperphosphatemia and Risk of Nephrocalcinosis

  • Increases in serum phosphorus to above the upper limit of normal may be associated with an increased risk of nephrocalcinosis. For patients already taking CRYSVITA, dose interruption and/or dose reduction may be required based on a patient’s serum phosphorus levels.
  • Patients who undergo treatment of the underlying tumor should have dosing interrupted and adjusted to prevent hyperphosphatemia.

Injection Site Reactions

  • Administration of CRYSVITA may result in local injection site reactions. Discontinue CRYSVITA if severe injection site reactions occur and administer appropriate medical treatment.

ADVERSE REACTIONS

Adult Patients

  • Adverse reactions reported in more than 10% of CRYSVITA-treated adult TIO patients in two studies are: tooth abscess (19%), muscle spasms (19%), dizziness (15%), constipation (15%), injection site reaction (15%), rash (15%), and headache (11%).

USE IN SPECIFIC POPULATIONS

  • There are no available data on CRYSVITA use in pregnant women to inform a drug-associated risk of adverse developmental outcomes. Serum phosphorus levels should be monitored throughout pregnancy. Report pregnancies to the Kyowa Kirin, Inc. Adverse Event reporting line 1-844-768-3544.
  • There is no information regarding the presence of CRYSVITA in human milk or the effects of CRYSVITA on milk production or the breastfed infant. Therefore, the developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for CRYSVITA and any potential adverse effects on the breastfed infant from CRYSVITA or from the underlying maternal condition.

PATIENT COUNSELING INFORMATION

  • Advise patients not to use any oral phosphate and/or active vitamin D analog products.
  • Instruct patients to contact their physician if hypersensitivity reactions, injection site reactions, and restless legs syndrome induction or worsening of symptoms occur.

You may report side effects to the FDA at (800) FDA-1088 or www.fda.gov/medwatch. You may also report side effects to Kyowa Kirin, Inc. at 1-844-768-3544.

For important risk and use information, please see the full Prescribing Information for CRYSVITA.

References:

1. CRYSVITA (burosumab-twza). US Prescribing Information. Kyowa Kirin, Inc.; March 2023. 2. Data on file. 201 CSR. Ultragenyx Pharmaceutical Inc.; 2018. 3. Jan de Beur SM, Miller PD, Weber TJ, et al. Burosumab for the treatment of tumor-induced osteomalacia. J Bone Miner Res. 2021;36(4):627-635. doi:10.1002/jbmr.4233 4. Imanishi Y, Ito N, Rhee Y, et al. Interim analysis of a phase 2 open-label trial assessing burosumab efficacy and safety in patients with tumor-induced osteomalacia. J Bone Miner Res. 2021;36(2):262-270. doi:10.1002/jbmr.4184 5. Data on file. KRN3002 CSR. Ultragenyx Pharmaceutical Inc.; 2018. 6. Jan de Beur SM, Miller PD, Weber TJ, et al. Burosumab for the treatment of tumor-induced osteomalacia. J Bone Miner Res. 2021;36(4)(suppl):1-8. doi:10.1002/jbmr.4233 7. Kane SM, Davis DD. Technetium-99m. StatPearls Publishing; 2022. 8. Brandi ML, Clunie GPR, Houillier P, et al. Challenges in the management of tumor-induced osteomalacia (TIO). Bone 2021;152:116064. doi:10.1016/j.bone.2021.116064 9. Ott SM. Histomorphometric measurements of bone turnover, mineralization, and volume. Clin J Am Soc Nephrol. 2008;3 Suppl 3(Suppl 3):S151-S156. doi:10.2215/CJN.04301206 10. Jan de Beur SM. Tumor-induced osteomalacia. JAMA. 2005;294(10):1260-1267. doi:10.1001/jama.294.10.1260 11. Balcerzak M, Hamade E, Zhang L, et al. The roles of annexins and alkaline phosphatase in mineralization process. Acta Biochim Pol. 2003;50(4):1019-1038. 12. Dahir K, Roberts MS, Krolczyk S, Simmons JH. X-linked hypophosphatemia: a new era in management. J Endocr Soc. 2020;4(12):bvaa151. doi:10.1210/jendso/bvaa151 13. Osteoid. Science Direct. Accessed February 28, 2023. www.sciencedirect.com/topics/biochemistry-genetics-and-molecular-biology/osteoid 14. Cohen A, Drake MT. Clinical manifestations, diagnosis, and treatment of osteomalacia. UpToDate. Accessed February 28, 2023. www.uptodate.com/contents/clinical-manifestations-diagnosis-and-treatment-of-osteomalacia 15. Parfitt AM, Qiu S, Rao DS. The mineralization index–a new approach to the histomorphometric appraisal of osteomalacia. Bone 2004;35(1):320-325. doi:10.1016/j.bone.2004.02.016