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Efficacy in adults

Actor portrayal

person

Clinical studies showed that CRYSVITA1:

  • Increased and maintained serum phosphorus levels1
  • Healed fractures and osteomalacia1

Study design

Study 41,2

CRYSVITA was studied in a randomized, double-blind, placebo-controlled phase 3 study in 134 adult patients with XLH. Patients were randomized to receive CRYSVITA 1 mg/kg every 4 weeks (n=68) or placebo (n=66) for 24 weeks, followed by a 24-week open-label period during which all patients received CRYSVITA.

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

Study 51,3

CRYSVITA was studied in a 48-week, open-label, single-arm study in 14 adult patients with XLH. Patients received CRYSVITA 1 mg/kg every 4 weeks.

Primary endpoint
  • Percent change from baseline to week 48 in osteoid volume to bone volume as 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.1-3

Disease burden at baseline1-3

person

CHANGE IN SERUM PHOSPHORUS LEVELS*

More patients on CRYSVITA increased and maintained serum phosphorus levels over 24 weeks1,2

Element of phosphorus within a pie graph representing a 94% increase in phosphorus levels with CRYSVITA 94%

CRYSVITA

(95% CI: 85.8, 97.7)

P<0.0001†
Element of phosphorus within a pie graph representing a 8% increase in phosphorus levels with placebo 8%

Placebo

(95% CI: 3.3, 16.5)

*The primary efficacy endpoint was the proportion of patients achieving a mean serum phosphorus concentration above the LLN of 2.5 mg/dL (0.81 mmol/L) averaged across the midpoints of dosing intervals.2

†P-value is from Cochran-Mantel-Haenszel (CMH) testing for association between achieving the primary endpoint and treatment group, adjusting for randomization stratification.1

Through week 24, 94% (64 out of 68) of patients achieved mean serum phosphorus levels above the lower limit of normal (LLN)‡ of 2.5 mg/dL (0.81 mmol/L), compared with 8% (5 out of 66) of patients receiving placebo. Serum phosphorus was maintained with continued CRYSVITA treatment through week 48.1,2

‡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.1,4,5

CI=confidence interval.

CRYSVITA increased serum phosphorus levels within the normal range1,2

Mean serum phosphorus levels in adults receiving CRYSVITA every 4 weeks or receiving placebo§

Line graph of mean serum phosphorus levels in both periods of Study 4; CRYSVITA increased serum phosphorus levels within the normal range within 2 weeks; patients switching from placebo to CRYSVITA during the open-label treatment period also increased serum phosphorus levels within the normal range

§ 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) mg/dL 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 post-dose) were 3.2 (0.53) mg/dL and 2.1 (0.30) mg/dL for the CRYSVITA and placebo groups, respectively.1,4,5

SD=standard deviation.

In Study 4, there was a significant increase from baseline through week 24 in mean serum phosphorus levels with CRYSVITA compared with placebo. CRYSVITA-treated patients maintained mean serum phosphorus levels within the normal range through week 48.1

OSTEOMALACIA HEALING

CRYSVITA improved the healing of osteomalacia1,3

Bone mineralization as assessed by histomorphometry‖

3 bar graphs showing bone mineralization as assessed by histomophometry; one showing 57% reduction in osteoid volume to bone volume in 10 out of 14 patients; one showing 33% reduction in osteoid thickness in 11 out of 14 patients; one showing 74% reduction in mineralization lag time in 6 out of 14 patients

‖ Normal osteoid volume to 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.6

SD=standard deviation.

In Study 5, histological and histomorphometric assessments of iliac bone crest (biopsies) were examined for signs of osteomalacia healing. CRYSVITA improved healing at week 48, with significant reductions in osteoid volume to bone volume (OV/BV), osteoid thickness (O.Th), and mineralization lag time (MLt).1,3

In 10 patients, the mean (SD) score decreased in OV/BV from 26% (12.4) at baseline to 11% (6.5), a 57% reduction. O.Th declined in 11 patients from a mean (SD) of 17 (4.1) μm to 12 (3.1) μm, a 33% reduction. In 6 patients, MLt was reduced from a mean (SD) of 594 (675) days to 156 (77) days, a 74% decrease.1,3

FRACTURE HEALING

CRYSVITA helped heal osteomalacia-related fractures/pseudofractures1,2,7

Switching to CRYSVITA from placebo led to a higher rate of fracture healing

Line graph showing how switching to CRYSVITA from placebo led to a higher rate of fracture healing; 43% of patients demonstrated complete healing with CRYSVITA vs 8% of patients on placebo during the double-blind treatment period; 63% of patients demonstrated complete healing with CRYSVITA vs 35% of patients on placebo during the open-label treatment period

Total fractures were both active fractures and pseudofractures. At baseline, the total number of active fractures/pseudofractures were 65 with CRYSVITA and 91 with placebo. 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 1 cortex. These fractures were predominantly located in femurs, tibia/fibula, and metatarsals of the feet. Healing is defined as complete or partial healing.1,7

At week 24, 43% of baseline fractures/pseudofractures were healed in the CRYSVITA arm. During the open-label treatment period, patients who continued receiving CRYSVITA showed a higher rate of fracture healing with 63% of fractures/pseudofractures healed at week 48.1,2,7

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.1

Radiographic examples of demonstrated osteomalacia-related pseudofracture healing2

X-ray of a femur bone showing a pseudofracture at baseline
X-ray of a femur bone showing a healed pseudofracture at week 24 with CRYSVITA

Individual results may vary.

PATIENT-REPORTED OUTCOMES

CRYSVITA was shown to improve XLH-related joint stiffness; no significant differences were noted in pain and physical function1,2

Study 4 evaluated patient-reported XLH-related symptoms (pain, joint stiffness, and physical function). CRYSVITA was shown to improve patient-reported joint stiffness compared with placebo; no significant differences were noted in patient-reported pain intensity or physical function score at 24 weeks. Patient-reported joint stiffness was assessed using the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC).1,2

CRYSVITA improved XLH-related joint stiffness from baseline to week 241:
  • 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 reflect less severe symptoms)

WOMAC stiffness#

Line graph showing -7.9 change in joint stiffness as evaluated by the WOMAC scale with CRYSVITA and +0.3 change with placebo; with negative numbers representing improvement

Mean (SD) baseline stiffness scores were 61.4 (20.77) and 64.7 (20.25) in the placebo and CRYSVITA groups, respectively.7

#The estimates of LS means at week 24 are from the generalized estimating equation (GEE) model.2

LS=least squares; SE=standard error; WOMAC=Western Ontario and McMaster Universities Osteoarthritis Index.

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Indication

CRYSVITA® (burosumab-twza) is a fibroblast growth factor 23 (FGF23) blocking antibody indicated for the treatment of X-linked hypophosphatemia (XLH) in adult and pediatric patients 6 months of age and older.

Indication

CRYSVITA® (burosumab-twza) is a fibroblast growth factor 23 (FGF23) blocking antibody indicated for the treatment of X-linked hypophosphatemia (XLH) in adult and pediatric patients 6 months 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.

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

Pediatric Patients

  • Adverse reactions reported in 10% or more of CRYSVITA-treated pediatric XLH patients across three studies are: pyrexia (55%, 44%, and 62%), injection site reaction (52%, 67%, and 23%), cough (52%), vomiting (41%, 48%, and 46%), pain in extremity (38%, 46%, and 23%), headache (34% and 73%), tooth abscess (34%, 15%, and 23%), dental caries (31%), diarrhea (24%), vitamin D decreased (24%, 37%, and 15%), toothache (23% and 15%), constipation (17%), myalgia (17%), rash (14% and 27%), dizziness (15%), and nausea (10%).
  • Postmarketing experience reported in CRYSVITA-treated pediatric XLH patients: blood phosphorus increased.

Adult Patients

  • Adverse reactions reported in more than 5% of CRYSVITA-treated adult XLH patients and in at least 2 patients more than placebo in one study are: back pain (15%), headache (13%), tooth infection (13%), restless legs syndrome (12%), vitamin D decreased (12%), dizziness (10%), constipation (9%), muscle spasms (7%), and blood phosphorus increased (6%).
  • Spinal stenosis is prevalent in adults with XLH, and spinal cord compression has been reported. It is unknown if CRYSVITA therapy exacerbates spinal stenosis or spinal cord compression.

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 at 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 X-linked hypophosphatemia (XLH) in adult and pediatric patients 6 months 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.

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

Pediatric Patients

  • Adverse reactions reported in 10% or more of CRYSVITA-treated pediatric XLH patients across three studies are: pyrexia (55%, 44%, and 62%), injection site reaction (52%, 67%, and 23%), cough (52%), vomiting (41%, 48%, and 46%), pain in extremity (38%, 46%, and 23%), headache (34% and 73%), tooth abscess (34%, 15%, and 23%), dental caries (31%), diarrhea (24%), vitamin D decreased (24%, 37%, and 15%), toothache (23% and 15%), constipation (17%), myalgia (17%), rash (14% and 27%), dizziness (15%), and nausea (10%).
  • Postmarketing experience reported in CRYSVITA-treated pediatric XLH patients: blood phosphorus increased.

Adult Patients

  • Adverse reactions reported in more than 5% of CRYSVITA-treated adult XLH patients and in at least 2 patients more than placebo in one study are: back pain (15%), headache (13%), tooth infection (13%), restless legs syndrome (12%), vitamin D decreased (12%), dizziness (10%), constipation (9%), muscle spasms (7%), and blood phosphorus increased (6%).
  • Spinal stenosis is prevalent in adults with XLH, and spinal cord compression has been reported. It is unknown if CRYSVITA therapy exacerbates spinal stenosis or spinal cord compression.

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 at 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. Insogna KL, Briot K, Imel EA, et al. A randomized, double-blind, placebo-controlled, phase 3 trial evaluating the efficacy of burosumab, an anti-FGF23 antibody, in adults with X-linked hypophosphatemia: week 24 primary analysis. J Bone Miner Res. 2018;33(8):1383-1393. doi:10.1002/jbmr.3475 3. Insogna KL, Rauch F, Kamenický P, et al. Burosumab improved histomorphometric measures of osteomalacia in adults with X-linked hypophosphatemia: a phase 3, single-arm, international trial. J Bone Miner Res. 2019;34(12):2183-2191. doi:10.1002/jbmr.3843 4. Ruppe MD. X-linked hypophosphatemia. In: Adam MP, Everman DB, Mirzaa GM, et al., eds. GeneReviews®. Seattle (WA): University of Washington, Seattle; February 9, 2012. Updated April 13, 2017. https://www.ncbi.nlm.nih.gov/books/NBK83985/ 5. Onufrak SJ, Bellasi A, Cardarelli F, et al. Investigation of gender heterogeneity in the associations of serum phosphorus with incident coronary artery disease and all-cause mortality. Am J Epidemiol. 2008;169(1):67-77. doi:10.1093/aje/kwn285 6. Data on file. 304 CSR. Ultragenyx Pharmaceutical Inc.; 2018. 7. Data on file. 303 CSR. Ultragenyx Pharmaceutical Inc.; 2018. 8. Ott SM. Histomorphometric measurements of bone turnover, mineralization, and volume. Clin J Am Soc Nephrol. 2008;3(suppl 3):S151-S156. doi:10.2215/CJN.04301206 9. 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 10. Osteoid. Science Direct. Accessed February 28, 2023. www.sciencedirect.com/topics/biochemistry-genetics-and-molecular-biology/osteoid 11. Cohen A, Drake MT. Clinical manifestations, diagnosis, and treatment of osteomalacia. UpToDate. Updated November 19, 2021. Accessed February 28, 2023. https://www.uptodate.com/contents/clinical-manifestations-diagnosis-and-treatment-of-osteomalacia 12. 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