Coverage Policy Manual - Arkansas Blue Cross and Blue Shield

Coverage Policy Manual

Policy #:

2018024

Category:

Pharmacy

Initiated:

September 2018

Last Review:

September 2026

Burosumab-twza (e.g., Crysvita)

Description:

Burosumab is a fibroblast growth factor 23 (FGF23) blocking antibody indicated for the treatment of X-linked hypophosphatemia (XLH) and tumor-induced osteomalacia (TIO). In a placebo-controlled study involving 134 adult patients with XLH, 94% of adults receiving burosumab once a month achieved normal phosphorus concentrations compared to 8% of those receiving placebo. In pediatric studies, 94% to 100% of patients treated with burosumab every 2 weeks achieved normal phosphorus concentrations. Additionally, there was an improvement in X-ray findings associated with XLH in both children and adults receiving burosumab therapy. In 2 single-arm, phase 2 trials (n = 14 and n = 13), the mean serum phosphorus concentrations increased to above the lower limit of normal (LLN) following 24 weeks of burosumab therapy in 50% and 69% of adult patients with TIO. The use of oral phosphate and active vitamin D analogs is contraindicated during burosumab treatment; discontinue these products 1 week prior to the initiation of burosumab. Ensure serum phosphorous concentrations are below the reference range for age prior to treatment initiation; monitor serum phosphorus monthly for the first 3 months of treatment and periodically thereafter.

Policy/
Coverage:

Prior Approval is required for Burosumab-twza (e.g., Crysvita).

INITIAL AND CONTINUATION APPROVAL will be for duration of treatment course or 12 months (whichever comes first). Approval timeframes may differ for members/participants of Self-Insured plans.

Effective December 2, 2026

Meets Primary Coverage Criteria Or Is Covered For Contracts Without Primary Coverage Criteria

Burosumab-twza (e.g., Crysvita) meets member benefit certificate Primary Coverage Criteria that there be scientific evidence of effectiveness in improving health outcomes or for members with contracts without Primary Coverage Criteria, is considered Medically Necessary and is covered when member receives a “recommended” determination from criteria review in InterQual® for Burosumab-twza (e.g., Crysvita) based on diagnosis and requested product.

Click the following link to view the specific criteria in InterQual®: https://prod.ds.interqual.com/service/connect/transparency?tid=27b0a724-ca06-4b22-846b-598b8dae52fc

See Criteria below.

X-LINKED HYPOPHOSPHATEMIA

INITIAL APPROVAL:

1. Individual is 6 months of age or older; AND

2. Individual has a diagnosis of x-linked hypophosphatemia confirmed by one of the following:

a. PHEX (phosphate regulating endopeptidase homolog X-linked) pathogenic gene mutation – laboratory documentation must be provided (Imel, 2019); OR

b. serum fibroblast growth factor 23 (FGF23) level higher than upper limit of normal for the assay laboratory documentation must be provided (NCT02163577, 2019); AND

4. Individual’s fasting serum phosphorus level is below age-based normal level (see policy guidelines) – laboratory documentation must be provided (Crysvita, 2026). Burosumab cannot be initiated if the serum phosphorus is within or above the normal range for age; AND

5. One of the following:

a. Individual’s epiphyseal plate has not fused (Carpenter, 2018); OR

b. Individual’s epiphyseal plate has fused AND the individual is experiencing symptoms of XLH (e.g., bone pain, fractures, pseudofractures, limited ambulation) imaging or radiographic documentation must be provided at time of request (Insogna, 2018); AND

6. Burosumab will not be used in combination with oral phosphate or active vitamin D analogs (Crysvita, 2026); AND

7. Individual does not have severe renal impairment or end stage renal disease defined as a glomerular filtration rate less than 30mL/min (Crysvita, 2026); AND

8. Individual has characteristic biochemical findings consistent with renal phosphate wasting (e.g., low tubular maximum phosphate resorption per glomerular filtration rate (TmP/GFR), elevated fractional excretion of phosphate (FEPO4), elevated urinary phosphate excretion despite hypophosphatemia); AND

AUTHORIZATION RENEWAL:

1. Manageable or no side effects; AND

2. Individual has demonstrated a clinically meaningful response to treatment with burosumab – documentation from the medical record must be provided; AND

3. Burosumab will not be used in combination with oral phosphate or active vitamin D analogs.

HYPOPHOSPHATEMIA IN TUMOR-INDUCED OSTEOMALACIA

INITIAL APPROVAL:

1. Individual is 2 years of age or older; AND

2. Individual has been diagnosed with hypophosphatemia in tumor-induced osteomalacia; AND

3. Individual has a phosphaturic mesenchymal tumor that cannot be curatively resected or cannot be located (Crysvita, 2026); AND

4. Individual’s FGF23 level is higher than upper limit of normal for the assay (laboratory documentation must be provided) (NCT02304367, 2020); AND

5. Individual’s fasting serum phosphorus is below the normal range for age (see policy guidelines) (laboratory documentation must be provided); AND

6. Individual has characteristic biochemical findings consistent with renal phosphate wasting (e.g., low tubular maximum phosphate resorption per glomerular filtration rate (TmP/GFR), elevated fractional excretion of phosphate (FEPO4), elevated urinary phosphate excretion despite hypophosphatemia); AND

7. Burosumab will not be used in combination with oral phosphate or active Vitamin D analogs (Crysvita, 2026); AND

8. Individual does not have severe renal impairment or end stage renal disease defined as a glomerular filtration rate less than 30mL/min (Crysvita, 2026).

AUTHORIZATION RENEWAL:

1. Manageable or no side effects; AND

2. Individual has demonstrated a clinically meaningful response to treatment with burosumab – documentation from the medical record must be provided; AND

3. Burosumab will not be used in combination with oral phosphate or active vitamin D analogs.

Does Not Meet Primary Coverage Criteria Or Is Not Covered For Contracts Without Primary Coverage Criteria

Burosumab-twza (e.g., Crysvita) does not meet member benefit certificate Primary Coverage Criteria that there be scientific evidence of effectiveness in improving health outcomes and is not covered for any indication or circumstance not described above.

For contracts without Primary Coverage Criteria, Burosumab-twza (e.g., Crysvita) is considered not Medically Necessary and is not covered or is investigational for any indication or circumstance not described above. Not Medically Necessary or Investigational services are specific contract exclusions in most member benefit certificates of coverage.

Click the following link to view the specific criteria in InterQual®: https://prod.ds.interqual.com/service/connect/transparency?tid=27b0a724-ca06-4b22-846b-598b8dae52fc

POLICY GUIDELINES

Age-Based Normal Serum Phosphate Reference Intervals

Age mg/dL mmol/L

1-3 years 3.8-6.5 1.25-2.10

4-11 years 3.7-5.6 1.20-1.80

12-15 years 2.9-5.4 0.95-1.75

greater than 15 years 2.7-4.7 0.90-1.50

Please refer to a separate policy on Site of Care or Site of Service Review (policy #2018030) for pharmacologic/biologic medications.

Please refer to a separate policy on Maximum Dosage and Frequency (policy #2025031) for pharmacologic/biologic medications.

Effective February 11, 2026 to December 1, 2026

Meets Primary Coverage Criteria Or Is Covered For Contracts Without Primary Coverage Criteria

Initial Approval and Continuation of Therapy:

Member receives a “recommended” determination from InterQual criteria review for Burosumab-twza (e.g., Crysvita) based on diagnosis and requested product. Click the following link to view the InterQual® criteria: https://prod.ds.interqual.com/service/connect/transparency?tid=27b0a724-ca06-4b22-846b-598b8dae52fc

Does Not Meet Primary Coverage Criteria Or Is Not Covered For Contracts Without Primary Coverage Criteria

For contracts without Primary Coverage Criteria, Burosumab-twza (e.g., Crysvita) is considered not Medically Necessary and is not covered or is investigational for any indication or circumstance not described above. Not Medically Necessary or Investigational services are specific contract exclusions in most member benefit certificates of coverage.

Please refer to a separate policy on Site of Care or Site of Service Review (policy #2018030) for pharmacologic/biologic medications.

Please refer to a separate policy on Maximum Dosage and Frequency (policy #2025031) for pharmacologic/biologic medications.

Effective September 2025 to February 10, 2026

Meets Primary Coverage Criteria or Is Covered for Contracts Without Primary Coverage Criteria

Burosumab (e.g., Crysvita) meets member benefit primary coverage criteria that there be scientific evidence of effectiveness in improving health outcomes for the following indications when ALL the following criteria are met:

X-LINKED HYPOPHOSPHATEMIA

INITIAL APPROVAL:

1. Individual is 6 months of age or older; AND

2. Individual has a diagnosis of x-linked hypophosphatemia with a PHEX (phosphate regulating endopeptidase homolog X-linked) gene mutation – laboratory documentation must be provided (Imel, 2019); AND

3. Individual has a serum fibroblast growth factor 23 (FGF23) level higher than 30 pg/mL by Kainos assay- laboratory documentation must be provided (NCT02163577, 2019); AND

4. Individual’s fasting serum phosphorus level is below age-based normal level (see policy guidelines) – laboratory documentation must be provided (Crysvita, 2023). Burosumab cannot be initiated if the serum phosphorus is within or above the normal range for age; AND

5. One of the following:

a. Individual’s epiphyseal plate has not fused (Carpenter, 2018); OR

b. Individual’s epiphyseal plate has fused AND the individual is experiencing symptoms of XLH (e.g., bone pain, fractures, pseudofractures, limited ambulation); OR

c. Imaging or radiographic documentation must be provided at time of request (Insogna, 2018); AND

6. Will not be used in combination with oral phosphate or active vitamin D analogs (Crysvita, 2023); AND

7. Individual does not have severe renal impairment or end stage renal disease defined as a glomerular filtration rate less than 30mL/min (Crysvita, 2023); AND

8. Individual has evidence of reduced renal tubular phosphate reabsorption of phosphate corrected for glomerular filtration rate (TmP/GFR).

CONTINUATION OF THERAPY:

1. Individual has previously met all initial approval criteria; AND

2. Individual has demonstrated a clinically meaningful response to treatment with burosumab – documentation from the medical record must be provided; AND

3. Will not be used in combination with oral phosphate or active vitamin D analogs.

HYPOPHOSPHATEMIA IN TUMOR-INDUCED OSTEOMALACIA

INITIAL APPROVAL:

1. Individual is 2 years of age or older; AND

2. Individual has been diagnosed with hypophosphatemia in tumor-induced osteomalacia; AND

3. Individual has a phosphaturic mesenchymal tumor that cannot be curatively resected or cannot be located (Crysvita, 2023); AND

4. Individual’s FGF23 level is equal or greater than 100pg/mL (laboratory documentation must be provided) (NCT02304367, 2020); AND

5. Individual’s fasting serum phosphorus is below the normal range for age (see policy guidelines) (laboratory documentation must be provided); AND

6. Individual’s ratio of renal tubular maximum reabsorption rate of phosphate to glomerular filtration rate (TmP/GFR) is less than 2.5mg/dL (NCT02304367, 2020); AND

7. Will not be used in combination with oral phosphate or active Vitamin D analogs (Crysvita, 2023); AND

8. Individual does not have severe renal impairment or end stage renal disease defined as a glomerular filtration rate less than 30mL/min (Crysvita, 2023).

CONTINUATION OF THERAPY:

1. Individual has previously met all initial approval criteria; AND

2. Individual has demonstrated a clinically meaningful response to treatment with burosumab –documentation from the medical record must be provided; AND

3. Will not be used in combination with oral phosphate or active vitamin D analogs.

Does Not Meet Primary Coverage Criteria Or Is Not Covered For Contracts Without Primary Coverage Criteria

Burosumab (e.g., Crysvita), for any indication or circumstance not described above, does not meet member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness in improving health outcomes.

For members with contracts without primary coverage criteria, burosumab (e.g., Crysvita), for any indication or circumstance not described above, is considered investigational. Investigational services are specific contract exclusions in most member benefit certificates of coverage.

POLICY GUIDELINES

Age-Based Normal Serum Phosphate Reference Intervals

Age mg/dL mmol/L

1-3 years 3.8-6.5 1.25-2.10

4-11 years 3.7-5.6 1.20-1.80

12-15 years 2.9-5.4 0.95-1.75

greater than 15 years 2.7-4.7 0.90-1.50

DOSAGE AND ADMINISTRATION

For FDA labeled indications, Burosumab (e.g., Crysvita) must be dosed in accordance with the indication specific recommended dose per FDA label unless otherwise specified below.

Pediatric XLH (6 months and older):

For individuals who weigh less than 10 kg, starting dose regimen is 1 mg/kg of body weight rounded to the nearest 1 mg, administered every two weeks.
For individuals who weigh 10 kg and greater, starting dose regimen is 0.8 mg/kg of body weight rounded to the nearest 10 mg, administered every two weeks. The minimum starting dose is 10 mg up to a maximum dose of 90 mg.
Dose may be increased up to approximately 2 mg/kg (maximum 90 mg), administered every two weeks to achieve normal serum phosphorus.

Adult XLH:

Dose regimen is 1 mg/kg body weight rounded to the nearest 10 mg up to a maximum dose of 90 mg administered every four weeks.

Pediatric TIO (2 years and older):

Starting dose is 0.4 mg/kg of body weight rounded to the nearest 10 mg every 2 weeks. Dose may be increased up to 2 mg/kg not to exceed 180 mg, administered every two weeks.

Adult TIO:

Starting dose is 0.5 mg/kg every four weeks. Dose may be increased up to 2 mg mg/kg not to exceed 180 mg, administered every two weeks.

Burosumab-twza is available as 10 mg/mL, 20 mg/mL, or 30 mg/mL in a single-dose vial.

Burosumab-twza should be administered as a subcutaneous injection by a healthcare professional.

Please refer to a separate policy on Site of Care or Site of Service Review (policy #2018030) for pharmacologic/biologic medications.

Effective September 2024 to August 2025

Meets Primary Coverage Criteria or Is Covered for Contracts Without Primary Coverage Criteria

X-LINKED HYPOPHOSPHATEMIA

INITIAL APPROVAL STANDARD REVIEW for up to 6 months:

1. Individual is 6 months of age or older; AND

2. Individual has a diagnosis of x-linked hypophosphatemia with a PHEX (phosphate regulating endopeptidase homolog X-linked) gene mutation – laboratory documentation must be provided (Imel, 2019); AND

3. Individual has a serum fibroblast growth factor 23 (FGF23) level higher than 30 pg/mL by Kainos assay- laboratory documentation must be provided (NCT02163577, 2019); AND

4. Individual’s fasting serum phosphorus level is below age-based normal level (see policy guidelines) – laboratory documentation must be provided (Crysvita, 2023). Burosumab cannot be initiated if the serum phosphorus is within or above the normal range for age; AND

5. One of the following:

a. The individual’s epiphyseal plate has not fused (Carpenter, 2018); OR

b. The individual’s epiphyseal plate has fused AND the individual is experiencing symptoms of XLH (e.g., bone pain, fractures, pseudofractures, limited ambulation); OR

c. Imaging or radiographic documentation must be provided at time of request (Insogna, 2018); AND

6. Will not be used in combination with oral phosphate or active vitamin D analogs (Crysvita, 2023); AND

7. Individual does not have severe renal impairment or end stage renal disease defined as a glomerular filtration rate less than 30mL/min (Crysvita, 2023); AND

8. Individual has evidence of reduced renal tubular phosphate reabsorption of phosphate corrected for glomerular filtration rate (TmP/GFR); AND

9. Must be dosed in accordance with the FDA label.

CONTINUED APPROVAL for up to 1 year:

1. Individual has previously met all initial approval criteria; AND

2. The individual has demonstrated a clinically meaningful response to treatment with burosumab – documentation from the medical record must be provided; AND

3. Will not be used in combination with oral phosphate or active vitamin D analogs; AND

4. Must be dosed in accordance with the FDA label.

HYPOPHOSPHATEMIA IN TUMOR-INDUCED OSTEOMALACIA

INITIAL APPROVAL STANDARD REVIEW for up to 6 months:

1. Individual is 2 years of age or older; AND

2. Individual has been diagnosed with hyposphatemia in tumor-induced osteomalacia; AND

3. Individual has a phosphaturic mesenchymal tumor that cannot be curatively resected or cannot be located (Crysvita, 2023); AND

4. Individual’s FGF23 level is equal or greater than 100pg/mL (laboratory documentation must be provided) (NCT02304367, 2020); AND

5. Individual’s fasting serum phosphorus is below the normal range for age (see policy guidelines) (laboratory documentation must be provided); AND

6. Individual’s ratio of renal tubular maximum reabsorption rate of phosphate to glomerular filtration rate (TmP/GFR) is less than 2.5mg/dL (NCT02304367, 2020); AND

7. Will not be used in combination with oral phosphate or active Vitamin D analogs (Crysvita, 2023); AND

8. Individual does not have severe renal impairment or end stage renal disease defined as a glomerular filtration rate less than 30mL/min (Crysvita, 2023); AND

9. Must be dosed in accordance with the FDA label.

CONTINUED APPROVAL for up to 1 year:

1. Individual has previously met all initial approval criteria; AND

2. The individual has demonstrated a clinically meaningful response to treatment with burosumab –documentation from the medical record must be provided; AND

3. Will not be used in combination with oral phosphate or active vitamin D analogs; AND

4. Must be dosed in accordance with the FDA label.

Policy Guidelines

Age-Based Normal Serum Phosphate Reference Intervals

Age mg/dL mmol/L

1-3 years 3.8-6.5 1.25-2.10

4-11 years 3.7-5.6 1.20-1.80

12-15 years 2.9-5.4 0.95-1.75

>15 years 2.7-4.7 0.90-1.50

Dosage and Administration

Dosing per FDA Guidelines

Pediatric XLH (6 months and older):

For individuals who weigh less than 10 kg, starting dose regimen is 1 mg/kg of body weight rounded to the nearest 1 mg, administered every two weeks.
For individuals who weigh 10 kg and greater, starting dose regimen is 0.8 mg/kg of body weight rounded to the nearest 10 mg, administered every two weeks. The minimum starting dose is 10 mg up to a maximum dose of 90 mg.
Dose may be increased up to approximately 2 mg/kg (maximum 90 mg), administered every two weeks to achieve normal serum phosphorus.

Adult XLH:

Dose regimen is 1 mg/kg body weight rounded to the nearest 10 mg up to a maximum dose of 90 mg administered every four weeks.

Pediatric TIO (2 years and older):

Starting dose is 0.4 mg/kg of body weight rounded to the nearest 10 mg every 2 weeks. Dose may be increased up to 2 mg/kg not to exceed 180 mg, administered every two weeks.

Adult TIO:

Starting dose is 0.5 mg/kg every four weeks. Dose may be increased up to 2 mg mg/kg not to exceed 180 mg, administered every two weeks.

Burosumab-twza is available as 10 mg/mL, 20 mg/mL, or 30 mg/mL in a single-dose vial.

Burosumab-twza should be administered as a subcutaneous injection by a healthcare professional.

Please refer to a separate policy on Site of Care or Site of Service Review (policy #2018030) for pharmacologic/biologic medications.

Does Not Meet Primary Coverage Criteria Or Is Investigational For Contracts Without Primary Coverage Criteria

Effective November 2023 to August 2024

INITIAL APPROVAL STANDARD REVIEW for up to 6 months:

Meets Primary Coverage Criteria Or Is Covered For Contracts Without Primary Coverage Criteria

Burosumab-twza meets member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness in improving health outcomes for:

A. The treatment of X-linked hypophosphatemia (XLH) in adult and pediatric individuals 6 months of age and older when ALL of the following requirements are met:

1. PHEX (phosphate regulating endopeptidase homolog X-linked) gene mutation – (laboratory documentation must be provided) (Imel, 2019) and

2. Serum fibroblast growth factor 23 (FGF23) level > 30 pg/mL by Kainos assay (NCT02163577, 2019) (laboratory documentation must be provided); and

3. *Individual’s fasting serum phosphorus level is below age-based normal level (see below) – (laboratory documentation must be provided) (FDA, 2020). Burosumab cannot be initiated if the serum phosphorus is within or above the normal range for age;

AND

4. One of the following:

a. The individual’s epiphyseal plate has not fused (Carpenter, 2018) or

b. The individual’s epiphyseal plate has fused AND the individual is experiencing symptoms of XLH (e.g., bone pain, fractures, pseudofractures, limited ambulation). or

c. Imaging or radiographic documentation must be provided at time of request (Insogna, 2018),

AND

5. Use will not be in combination with oral phosphate or active vitamin D analogs (FDA, 2020) and

6. The individual does not have severe renal impairment or end stage renal disease defined as a glomerular filtration rate < 30mL/min (FDA, 2020); and

7. Evidence of reduced renal tubular phosphate reabsorption of phosphate corrected for glomerular filtration rate (TmP/GFR); and

8. Must be dosed in accordance with the FDA label.

B. The treatment of FGF23-related hypophosphatemia in tumor-induced osteomalacia (TIO) in adult and pediatric individuals 2 years of age and older when ALL the following requirements are met:

1. Individual has a phosphaturic mesenchymal tumor cannot be curatively resected or cannot be located (FDA, 2020); and

2. Individual’s FGF23 level ≥ 100pg/mL (laboratory documentation must be provided) (NCT02304367, 2020); and

3. *Individual’s fasting serum phosphorus is below the normal range for age (NCT02304367, 2020) (laboratory documentation must be provided); and

4. Individual’s ratio of renal tubular maximum reabsorption rate of phosphate to glomerular filtration rate (TmP/GFR) < 2.5mg/dL (NCT02304367, 2020); and

5. Use will not be in combination with oral phosphate or active Vitamin D analogs (FDA, 2020); and

6. Individual does not have severe renal impairment or end stage renal disease defined as a glomerular filtration rate < 30mL/min (FDA, 2020); and

7. Must be dosed in accordance with the FDA label.

*Age-Based Normal Serum Phosphate Reference Intervals

Age              mg/dL          mmol/L.

1-3 yrs          3.8-6.5          1.25-2.10

4-11 yrs        3.7-5.6          1.20-1.80

12-15 yrs      2.9-5.4          0.95-1.75

>15 yrs         2.7-4.7          0.90-1.50

CONTINUED APPROVAL for up to 1 year:

Authorization/reauthorization has been previously approved by Arkansas Blue Cross Blue Shield for treatment of x-linked hypophosphatemia (XLH), OR for the treatment of FGF23-related hypophosphatemia in TIO and the individual has previously met all indication-specific criteria; AND
The individual has demonstrated a clinically meaningful response to treatment with burosumab –documentation from the medical record must be provided; AND
Use will not be in combination with oral phosphate or active vitamin D analogs.

Dosing and Administration

Dosing per FDA Guidelines

Pediatric XLH (6 months and older):

For individuals who weigh less than 10 kg, starting dose regimen is 1 mg/kg of body weight rounded to the nearest 1 mg, administered every two weeks.
For individuals who weigh 10 kg and greater, starting dose regimen is 0.8 mg/kg of body weight rounded to the nearest 10 mg, administered every two weeks. The minimum starting dose is 10 mg up to a maximum dose of 90 mg.
Dose may be increased up to approximately 2 mg/kg (maximum 90 mg), administered every two weeks to achieve normal serum phosphorus.

Adult XLH:

Dose regimen is 1 mg/kg body weight rounded to the nearest 10 mg up to a maximum dose of 90 mg administered every four weeks.

Pediatric TIO (2 years and older):

Starting dose is 0.4 mg/kg of body weight rounded to the nearest 10 mg every 2 weeks. Dose may be increased up to 2 mg/kg not to exceed 180 mg, administered every two weeks.

Adult TIO:

Starting dose is 0.5 mg/kg every four weeks. Dose may be increased up to 2 mg mg/kg not to exceed 180 mg, administered every two weeks.

Burosumab-twza is available as 10 mg/mL, 20 mg/mL, or 30 mg/mL in a single-dose vial.

Burosumab-twza should be administered as a subcutaneous injection by a healthcare professional.

Please refer to a separate policy on Site of Care or Site of Service Review (policy #2018030) for pharmacologic/biologic medications.

Does Not Meet Primary Coverage Criteria Or Is Investigational For Contracts Without Primary Coverage Criteria

Burosumab-twza for any indication or circumstance not described above does not meet member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness in improving health outcomes

Effective January 1, 2022 - October 31, 2023

INITIAL APPROVAL STANDARD REVIEW for up to 6 months:

Meets Primary Coverage Criteria Or Is Covered For Contracts Without Primary Coverage Criteria

Burosumab-twza meets member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness in improving health outcomes for:

A. The treatment of X-linked hypophosphatemia (XLH) in adult and pediatric individuals 6 months of age and older when ALL of the following requirements are met:

PHEX (phosphate regulating endopeptidase homolog X-linked) gene mutation – (laboratory documentation must be provided) (Imel, 2019) AND
Serum fibroblast growth factor 23 (FGF23) level > 30 pg/mL by Kainos assay (NCT02163577, 2019) (laboratory documentation must be provided)
Individual’s fasting serum phosphorus level is below age-based normal level (see below) – (laboratory documentation must be provided) (FDA, 2020). Burosumab cannot be initiated if the serum phosphorus is within or above the normal range for age.

Age-Based Normal Serum Phosphate Reference Intervals

Age           mg/dL         mmol/L.

1-3 yrs       3.8-6.5        1.25-2.10

4-11 yrs      3.7-5.6        1.20-1.80

12-15 yrs     2.9-5.4        0.95-1.75

>15 yrs        2.7-4.7        0.90-1.50

4. One of the following:

a. The individual’s epiphyseal plate has not fused (Carpenter, 2018) OR

b. The individual’s epiphyseal plate has fused AND the individual is experiencing symptoms of XLH (e.g., bone pain, fractures, pseudofractures, limited ambulation).

c. Imaging or radiographic documentation must be provided at time of request (Insogna, 2018), AND

5. Use will not be in combination with oral phosphate or active vitamin D analogs (FDA, 2020) AND

6. The individual does not have severe renal impairment or end stage renal disease defined as a glomerular filtration rate < 30mL/min (FDA, 2020) AND

7. Evidence of reduced renal tubular phosphate reabsorption of phosphate corrected for glomerular filtration rate (TmP/GFR) AND

8. Must be dosed in accordance with the FDA label.

B. The treatment of FGF23-related hypophosphatemia in tumor-induced osteomalacia (TIO) in adult and pediatric individuals 2 years of age and older when ALL of the following requirements are met:

Individual has a phosphaturic mesenchymal tumor cannot be curatively resected or cannot be located (FDA, 2020) AND
Individual’s FGF23 level ≥ 100pg/mL (laboratory documentation must be provided) (NCT02304367, 2020) AND
Individual’s fasting serum phosphorus is below the normal range for age (NCT02304367, 2020) (laboratory documentation must be provided) AND
Individual’s ratio of renal tubular maximum reabsorption rate of phosphate to glomerular filtration rate (TmP/GFR) < 2.5mg/dL (NCT02304367, 2020) AND
Use will not be in combination with oral phosphate or active Vitamin D analogs (FDA, 2020) AND
Individual does not have severe renal impairment or end stage renal disease defined as a glomerular filtration rate < 30mL/min (FDA, 2020) AND
Must be dosed in accordance with the FDA label.

CONTINUED APPROVAL for up to 1 year:

Authorization/reauthorization has been previously approved by Arkansas Blue Cross Blue Shield for treatment of x-linked hypophosphatemia (XLH), OR the individual has previously met all indication-specific criteria.

2. The individual has demonstrated a clinically meaningful response to treatment with burosumab –documentation from the medical record must be provided.

3. Use will not be in combination with oral phosphate or active vitamin D analogs.

Dosing and Administration

Dosing per FDA Guidelines

For subcutaneous use only

Pediatric XLH (6 months and older):

For individuals who weigh less than 10 kg, starting dose regimen is 1 mg/kg of body weight rounded to the nearest 1 mg, administered every two weeks.
For individuals who weigh 10 kg and greater, starting dose regimen is 0.8 mg/kg of body weight rounded to the nearest 10 mg, administered every two weeks. The minimum starting dose is 10 mg up to a maximum dose of 90 mg.

Dose may be increased up to approximately 2 mg/kg (maximum 90 mg), administered every two weeks to achieve normal serum phosphorus.

Adult XLH:

Dose regimen is 1 mg/kg body weight rounded to the nearest 10 mg up to a maximum dose of 90 mg administered every four weeks.

Pediatric TIO (2 years and older):

Starting dose is 0.4 mg/kg of body weight rounded to the nearest 10 mg every 2 weeks. Dose may be increased up to 2 mg/kg not to exceed 180 mg, administered every two weeks.

Adult TIO:

Starting dose is 0.5 mg/kg every four weeks. Dose may be increased up to 2 mg mg/kg not to exceed 180 mg, administered every two weeks.

Burosumab-twza is available as 10 mg/mL, 20 mg/mL, or 30 mg/mL in a single-dose vial.

Please refer to a separate policy on Site of Care or Site of Service Review (policy #2018030) for pharmacologic/biologic medications.

Does Not Meet Primary Coverage Criteria Or Is Investigational For Contracts Without Primary Coverage Criteria

Effective October 2020 to December 31, 2021

Meets Primary Coverage Criteria Or Is Covered For Contracts Without Primary Coverage Criteria

Initiation of Burosumab-twza (Cryvista®) meets member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness for:

The treatment of X-linked hypophosphatemia (XLH) in adult and pediatric patients 6 months of age and older when ALL of the following requirements are met:

a. PHEX (phosphate regulating endopeptidase homolog X-linked) gene mutation –( laboratory documentation must be provided) AND

b. Serum fibroblast growth factor 23 (FGF23) level > 30 pg/mL by Kainos assay (laboratory documentation must be provided)

c. Member’s fasting serum phosphorus level is below age-based normal level (see below) –(laboratory documentation must be provided). Burosumab cannot be initiated if the serum phosphorus is within or above the normal range for age.

Age-Based Normal Serum Phosphate Reference Intervals

Age           mg/dL         mmol/L.

1-3 yrs       3.8-6.5        1.25-2.10

4-11 yrs     3.7-5.6        1.20-1.80

12-15 yrs   2.9-5.4        0.95-1.75

>15 yrs     2.7-4.7        0.90-1.50

d. One of the following:

1. The patient’s epiphyseal plate has not fused OR

2.   The patient's epiphyseal plate has fused AND the patient is experiencing symptoms of XLH (e.g. bone pain, fractures, pseudofractures, limited ambulation).

        3. Imaging or radiographic documentation must be provided at time of request, AND

e. Use will not be in combination with oral phosphate or active vitamin D analogs AND

f.   The patient does not have severe renal impairment or end stage renal disease defined as a glomerular filtration rate < 30mL/min AND

g. Evidence of reduced renal tubular phosphate reabsorption of phosphate corrected for glomerular filtration rate (TmP/GFR).

2. The treatment of FGF23-related hypophosphatemia in tumor-induced osteomalacia (TIO) in adult and pediatric patients 2 years of age and older when ALL of the following requirements are met:

a. Member has a phosphaturic mesenchymal tumor cannot be curatively resected or cannot be located AND

b. Member’s FGF23 level ≥ 100pg/mL (laboratory documentation must be provided) (NCT02304367, 2020) AND

c. Member’s fasting serum phosphorus is below the normal range for age (laboratory documentation must be provided) AND

d. Member’s ratio of renal tubular maximum reabsorption rate of phosphate to glomerular filtration rate (TmP/GFR) < 2.5mg/dL (NCT02304367, 2020) AND

e. Use will not be in combination with oral phosphate or active Vitamin D analogs AND

f. Member does not have severe renal impairment or end stage renal disease defined as a glomerular filtration rate < 30mL/min

Dosing and Administration

For subcutaneous use only

Pediatric XLH (6 months and older):

o For patients who weigh less than 10 kg, starting dose regimen is 1 mg/kg of body weight rounded to the nearest 1 mg, administered every two weeks

o For patients who weigh 10 kg and greater, starting dose regimen is 0.8 mg/kg of body weight rounded to the nearest 10 mg, administered every two weeks. The minimum starting dose is 10 mg up to a maximum dose of 90 mg.

Dose may be increased up to approximately 2 mg/kg (maximum 90 mg), administered every two weeks to achieve normal serum phosphorus.

Adult XLH: Dose regimen is 1 mg/kg body weight rounded to the nearest 10 mg up to a maximum dose of 90 mg administered every four weeks.
Pediatric TIO (2 years and older): Starting dose is 0.4 mg/kg of body weight rounded to the nearest 10 mg every 2 weeks. Dose may be increased up to 2 mg/kg not to exceed 180 mg, administered every two weeks.
Adult TIO: Starting dose is 0.5 mg/kg every four weeks. Dose may be increased up to 2 mg mg/kg not to exceed 180 mg, administered every two weeks.

Please refer to a separate policy on Site of Care or Site of Service Review (policy #2018030) for pharmacologic/biologic medications.

Approval duration: 6 months

Continuation of burosumab-twza (Crysvita®) meets primary coverage criteria when ALL of the following criteria are met:

Authorization/reauthorization has been previously approved by Arkansas Blue Cross Blue Shield for treatment of x-linked hypophosphatemia (XLH), OR the member has previously met all indication-specific criteria.

2. The patient has demonstrated a clinically meaningful response to treatment with burosumab –documentation from the medical record must be provided.

3. Use will not be in combination with oral phosphate or active vitamin D analogs

Please refer to a separate policy on Site of Care or Site of Service Review (policy #2018030) for pharmacologic/biologic medications.

Approval duration: 6 months

Does Not Meet Primary Coverage Criteria Or Is Investigational For Contracts Without Primary Coverage Criteria

Burosumab-twza (Cryvista®) does not meet member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness for any other indication than those listed above as meeting primary coverage criteria.

For members with contracts without primary coverage criteria, Burosumab-twza (Cryvista®) is considered investigational. Investigational services are specific contract exclusions in most member benefit certificates of coverage.

Effective September 2018 to September 2020

Meets Primary Coverage Criteria Or Is Covered For Contracts Without Primary Coverage Criteria

Burosumab-twza (Cryvista®) meets member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness.

Initiation of burosumab-twza (Crysvita®) meets primary coverage criteria when ALL of the following requirements are met:

Member is diagnosed with x-linked hypophosphatemia (XLH) > 1 year of age with diagnosis supported by the following:

a. PHEX (phosphate regulating endopeptidase homolog X-linked) gene mutation –( laboratory documentation must be provided) AND

b. Serum fibroblast growth factor 23 (FGF23) level > 30 pg/mL by Kainos assay (laboratory documentation must be provided)

2. Member’s fasting serum phosphorus level is below age-based normal level (see below) –(laboratory documentation must be provided). Burosumab cannot be initiated if the serum phosphorus is within or above the normal range for age.

Age-Based Normal Serum Phosphate Reference Intervals

Age         mg/dL      mmol/L.

1-3 yrs      3.8-6.5    1.25-2.10

4-11 yrs    3.7-5.6    1.20-1.80

12-15 yrs   2.9-5.4    0.95-1.75

>15 yrs     2.7-4.7    0.90-1.50

3. One of the following:

a. The patient’s epiphyseal plate has not fused OR

b. The patients epiphyseal plate has fused AND the patient is experiencing symptoms of XLH (e.g. bone pain, fractures, pseudofractures, limited ambulation).

c. Imaging or radiographic documentation must be provided at time of request, AND

4. Use will not be in combination with oral phosphate or active vitamin D analogs AND

5. The patient does not have severe renal impairment or end stage renal disease defined as a glomerular filtration rate < 30mL/min AND

6. Evidence of reduced renal tubular phosphate reabsorption of phosphate corrected for glomerular filtration rate (TmP/GFR).

Dosing and Administration

Dose does not exceed any of the following:

Age 1 to 17 years: 0.8 mg/kg (rounded to the nearest 10 mg) up to 90 mg every two weeks

b. Age 18 years and older: 1 mg/kg (rounded to the nearest 10 mg) up to 90 mg every four weeks

Please refer to a separate policy on Site of Care or Site of Service Review (policy #2018030) for pharmacologic/biologic medications.

Approval duration: 6 months

Continuation of burosumab-twza (Crysvita®) meets primary coverage criteria when ALL of the following criteria are met:

Authorization/reauthorization has been previously approved by Arkansas Blue Cross Blue Shield for treatment of x-linked hypophosphatemia (XLH), OR the member has previously met all indication-specific criteria.

2. The patient has demonstrated a clinically meaningful response to treatment with burosumab –documentation from the medical record must be provided.

3. Use will not be in combination with oral phosphate or active vitamin D analogs

Dosing and Administration

Dose does not exceed any of the following:

Age 1 to 17 years: 2 mg/kg (rounded to the nearest 10 mg) up to 90 mg every two weeks

b. Age 18 years and older: 1 mg/kg (rounded to the nearest 10 mg) up to 90 mg every four weeks

Please refer to a separate policy on Site of Care or Site of Service Review (policy #2018030) for pharmacologic/biologic medications.

Approval duration: 6 months

Does Not Meet Primary Coverage Criteria Or Is Investigational For Contracts Without Primary Coverage Criteria

For members with contracts without primary coverage criteria, Burosumab-twza (Cryvista) is considered investigational. Investigational services are specific contract exclusions in most member benefit certificates of coverage.

Rationale:

X-linked hypophosphatemia (XLH) is an inherited disorder characterized by low phosphate levels due to phosphate wasting, which leads to weakened bones. XLH has a wide phenotypic range, with some children becoming symptomatic early in life and others who have no symptoms except isolated hypophosphatemia. XLH frequently becomes evident within the first two years of life with the onset of weight-bearing. Common laboratory findings include low phosphate when corrected for GFR, normal PTH, and normal calcium levels. Diagnosis can be confirmed through genetic testing or through laboratory findings of low phosphate and high FGF23.

The safety and efficacy of burosumab in pediatric patients was evaluated in an open-label, randomized phase 2 study in which 52 participants were enrolled to either burosumab every 2 weeks or burosumab every 4 weeks. The primary outcome was change in baseline at week 40 in severity of rickets as measured by the Rickets Severity Score (RSS). Secondary measures included radiographic appearance of rickets and bowing, change in Z-score from baseline, and growth up to week 40. Inclusion criteria included patients age 5-12 with open growth plates, Tanner stage of ≤2, diagnosis confirmed by either genetic testing or FGF23 levels >30pg/mL, serum phosphorous <2.8mg/dL, normal creatinine, and radiographic evidence of disease. Exclusions included concomitant use of Vitamin D, oral phosphate, corticosteroids, growth hormone, or bisphosphonates for more than 6 months, hypo- or hypercalcemia, HIV, Hepatitis C, or other immunodeficiency, or use of other monoclonal antibody. Patients had a mean increase in phosphorous levels from 2.4 at baseline to 3.3 at week 40. The RSS decreased from 1.9 to 0.8 at week 40. These findings were maintained at week 64.

In X-linked hypophosphatemia (XLH), inherited loss-of-function mutations in the PHEX gene cause excess circulating levels of fibroblast growth factor 23 (FGF23), leading to lifelong renal phosphate wasting and hypophosphatemia. Adults with XLH present with chronic musculoskeletal pain and stiffness, short stature, lower limb deformities, fractures, and pseudofractures due to osteomalacia, accelerated osteoarthritis, dental abscesses, and enthesopathy. Burosumab, a fully human monoclonal antibody, binds and inhibits FGF23 to correct hypophosphatemia. This report summarizes results from a double-blind, placebo-controlled, phase 3 trial of burosumab in symptomatic adults with XLH. Participants with hypophosphatemia and pain were assigned 1:1 to burosumab 1 mg/kg (n = 68) or placebo (n = 66) subcutaneously every 4 weeks (Q4W) and were comparable at baseline. Across midpoints of dosing intervals, 94.1% of burosumab-treated participants attained mean serum phosphate concentration above the lower limit of normal compared with 7.6% of those receiving placebo (p < 0.001). Burosumab significantly reduced the Western Ontario and the McMaster Universities Osteoarthritis Index (WOMAC) stiffness subscale compared with placebo (least squares [LS] mean ± standard error [SE] difference, -8.1 ± 3.24; p = 0.012). Reductions in WOMAC physical function subscale (-4.9 ± 2.48; p = 0.048) and Brief Pain Inventory worst pain (-0.5 ± 0.28; p = 0.092) did not achieve statistical significance after Hochberg multiplicity adjustment. At week 24, 43.1% (burosumab) and 7.7% (placebo) of baseline active fractures were fully healed; the odds of healed fracture in the burosumab group was 16.8-fold greater than that in the placebo group (p < 0.001). Biochemical markers of bone formation and resorption increased significantly from baseline with burosumab treatment compared with placebo. The safety profile of burosumab was similar to placebo. There were no treatment-related serious adverse events or meaningful changes from baseline in serum or urine calcium, intact parathyroid hormone, or nephrocalcinosis. These data support the conclusion that burosumab is a novel therapeutic addressing an important medical need in adults with XLH.

2019 Update

A literature search conducted through September 2019 did not reveal any new information that would prompt a change in the coverage statement.

2020 Update

In an open-label, phase 2 trial at three hospitals in the USA, children (aged 1-4 years) with X-linked hypophosphataemia received burosumab (0·8 mg/kg) via subcutaneous injection every 2 weeks for 64 weeks. The dose was increased to 1·2 mg/kg if two consecutive pre-dose serum phosphorus concentrations were below 1·03 mmol/L (3·2 mg/dL), serum phosphorus had increased by less than 0·16 mmol/L (<0·5 mg/dL) from baseline, and a dose of burosumab had not been missed. Participants could continue to receive burosumab for up to an additional 96 weeks during the extension period. Key inclusion criteria were age 1-4 years at the time of informed consent; fasting serum phosphorus concentration of less than 0·97 mmol/L (3·0 mg/dL); serum creatinine 8·8-35·4 μmol/L (0·1-0·4 mg/dL); radiographic evidence of rickets (at least five participants were required to have a Thacher Rickets Severity Score of ≥1·5 at the knee); and a confirmed PHEX mutation or a variant of unknown significance in the patient or direct relative also affected with X-linked hypophosphataemia. Conventional therapy was stopped upon enrolment. The coprimary endpoints were safety and change from baseline to week 40 in fasting serum phosphorus concentrations. Changes in rickets severity from baseline to weeks 40 and 64 (assessed radiographically using Thacher Rickets Severity Score and an adaptation of the Radiographic Global Impression of Change), and recumbent length or standing height, were key secondary outcomes.

Between May 16, 2016, and June 10, 2016, 3 children with X-linked hypophosphataemia were enrolled. All 13 children completed 64 weeks of treatment and were included in the efficacy and safety analysis; none exceeded 70 weeks of treatment at the time of analysis. Serum phosphorus least squares mean increase from baseline to week 40 of treatment was 0·31 mmol/L (SE 0·04; 95% CI 0·24-0·39; 0·96 mg/dL [SE 0·12]; p<0·0001). All patients had at least one adverse event. 14 treatment-related adverse events, mostly injection site reactions, occurred in five children. One serious adverse event considered unrelated to treatment (tooth abscess) occurred in a child with a history of tooth abscess. All other adverse events were mild to moderate, except a severe food allergy considered unrelated to treatment. No instances of nephrocalcinosis or noteworthy changes in the results of a standard safety chemistry panel emerged. Total Thacher Rickets Severity Score decreased by a least squares mean of -1·7 (SE 0·1; p<0·0001) from baseline to week 40 and by -2·0 (SE 0·1; p<0·0001) by week 64. The Radiographic Global Impression of Change score also indicated significant improvement, with a least squares mean score of +2·3 (SE 0·1) at week 40 and +2·2 (0·1) at week 64 (both p<0·0001). Mean length or standing height Z score was maintained from baseline to week 64.

Burosumab had a favorable safety profile, increased serum phosphorus, and improved rickets and prevented early declines in growth in children aged 1-4 years with X-linked hypophosphataemia. These findings could substantially alter the treatment of young children with X-linked hypophosphataemia. (Whyte MP, Carpenter TO, Gottesman GS, et al., 2019)

In a randomized, active-controlled, open-label, phase 3 trial at 16 clinical sites, children with X-linked hypophosphataemia aged 1–12 years were enrolled. Key eligibility criteria were a total Thacher rickets severity score of at least 2·0, fasting serum phosphorus lower than 0·97 mmol/L (3·0 mg/dL), confirmed PHEX (phosphate-regulating endopeptidase homolog, X-linked) mutation or variant of unknown significance in the patient or a family member with appropriate X-linked dominant inheritance, and receipt of conventional therapy for at least 6 consecutive months for children younger than 3 years or at least 12 consecutive months for children older than 3 years. Eligible patients were randomly assigned (1:1) to receive either subcutaneous burosumab starting at 0·8 mg/kg every 2 weeks (burosumab group) or conventional therapy prescribed by investigators (conventional therapy group). Both interventions lasted 64 weeks. The primary endpoint was change in rickets severity at week 40, assessed by the Radiographic Global Impression of Change global score. All patients who received at least one dose of treatment were included in the primary and safety analyses.

Recruitment took place between Aug 3, 2016, and May 8, 2017. Of 122 patients assessed, 61 were enrolled. Of these, 32 (18 girls, 14 boys) were randomly assigned to continue receiving conventional therapy and 29 (16 girls, 13 boys) to receive burosumab. For the primary endpoint at week 40, patients in the burosumab group had significantly greater improvement in Radiographic Global Impression of Change global score than did patients in the conventional therapy group (least squares mean +1·9 [SE 0·1] with burosumab vs +0·8 [0·1] with conventional therapy; difference 1·1, 95% CI 0·8–1·5; p<0·0001). Treatment-emergent adverse events considered possibly, probably, or definitely related to treatment by the investigator occurred more frequently with burosumab (17 [59%] of 29 patients in the burosumab group vs seven [22%] of 32 patients in the conventional therapy group). Three serious adverse events occurred in each group, all considered unrelated to treatment and resolved.

Significantly greater clinical improvements were shown in rickets severity, growth, and biochemistries among children with X-linked hypophosphataemia treated with burosumab compared with those continuing conventional therapy. (Imel EA, Glorieux FH, Whyte MP, et. al., 2019).

In a single-arm open-label study, 14 adult patients enrolled with a confirmed diagnosis of FHF23-related hypophosphatemia produced by an underlying tumor that was not amendable to surgical excision or could not be located. In this study burosumab-twza increased mean serum phosphorus level from 1.60 mg/dL at baseline to 2.64 mg/dL average across the midpoint of dose intervals through week 24 with 50% of patients achieving a mean serum phosphorus level above the LLN averaged across the midpoint of dose intervals through week 24. Increase in the mean serum phosphorus concentrations was sustained near or above the LLN through week 144. The ratio of renal tubular max reabsorbsorption rate of phosphate to GFR increased in these patients from a mean of 1.12 mg/dL abt baseline to 2.12 mg/dL at week 48 and remained stable through week 144. Osteomalacia was present at baseline in 9 out of 11 patients with paired bone biopsies, and healing was assessed after 48 weeks of treatment. In these 9 patients with osteomalacia at baseline, OV/BV decreased from a mean score of 21.2% at baseline to 13.9%, a change of -34%. O.Th declined from a mean of 18.9 micrometers to 12.1 micrometers, a change of -36%. MLt declined in 3 patients from a mean of 667 days to 331 days, a change of -50%. (Clinicaltrials.gov., 2020)

In a single-arm open-label study with 13 adults with a confirmed diagnosis of TIO who received burosumab-twza. Burosumab-twza increased mean serum phosphorus levels from 1.62 mg/dL at baseline to 2.63 mg/dL averaged across the midpoint of dose intervals through week 24 with 69% of patients achieving a mean serum phosphorus level above the LLN averaged across the midpoint on dose interval through week 24. Mean serum phosphorus concentrations were sustained above LLN through week 88. The renal phosphate reabsorptive capacity, as assessed by TmP/GFR, increased from a mean of 1.15 mg/dL at baseline to 2.30 mg/dL at week 48. Osteomalacia was present at baseline in all 3 patients with paired bone biopsies, and healing was assessed after 48 weeks of treatment. In these 3 patients, OV/BV decreased from a mean score of 14.0% at baseline to 9.2%, a change of -34%. O.Th declined from a mean of 16.0 micrometers to 13.5 micrometers, a change of -16%. (Clinicaltrials.gov., 2020)

2021 Update

Annual policy review completed with a literature search using the MEDLINE database through September 2021. No new literature was identified that would prompt a change in the coverage statement.

2022 Update

In X-linked hypophosphatemia (XLH), excess fibroblast growth factor-23 causes hypophosphatemia and low calcitriol, leading to musculoskeletal disease with clinical consequences. XLH treatment options include conventional oral phosphate with active vitamin D, or monotherapy with burosumab, a monoclonal antibody approved to treat children and adults with XLH. We have previously reported outcomes up to 64 weeks, and here we report safety and efficacy follow-up results up to 160 weeks from an open-label, multicenter, randomized, dose-finding trial of burosumab for 5- to 12-year-old children with XLH.

After 1 week of conventional therapy washout, patients were randomized 1:1 to burosumab every 2 weeks (Q2W) or every 4 weeks (Q4W) for 64 weeks, with dosing titrated based on fasting serum phosphorus levels between baseline and week 16. From week 66 to week 160, all patients received Q2W burosumab.

Twenty-six children were randomized initially into each Q2W and Q4W group and all completed treatment to week 160. In 41 children with open distal femoral and proximal tibial growth plates (from both treatment groups), total Rickets Severity Score significantly decreased by 0.9 ± 0.1 (least squares mean ± SE; P < 0.0001) from baseline to week 160. Fasting serum phosphorus increases were sustained by burosumab therapy throughout the study, with an overall population mean (SD) of 3.35 (0.39) mg/dL, within the pediatric normal range (3.2-6.1 mg/dL) at week 160 (mean change from baseline P < 0.0001). Most adverse events were mild to moderate in severity.

In children with XLH, burosumab administration for 160 weeks improved phosphate homeostasis and rickets and was well-tolerated. Long-term safety was consistent with the reported safety profile of burosumab. (Linglart A, Imel EA, Whyte MP, et.al., 2022).

2023 Update

Annual policy review completed with a literature search using the MEDLINE database through September 2023. No new literature was identified that would prompt a change in the coverage statement.

2024 Update

Annual policy review completed with a literature search using the MEDLINE database through August 2024. No new literature was identified that would prompt a change in the coverage statement.

2025 Update

Burosumab is indicated for treatment of a rare bone disease, X-linked hypophosphatemia (XLH). The aim of this analysis was to evaluate the relationship between a treatment response biomarker and patient-reported outcomes (PROs). Longitudinal data for PROs were obtained from adults with XLH from a phase III study. Individual rich time profiles of the biomarker, serum phosphate were simulated using a prior population pharmacokinetic-pharmacodynamic model to calculate serum phosphate exposure metrics for each 28-day treatment cycle, which were then merged with PROs data. Item response theory parameters were first estimated to map a latent variable, that is, disability score, relative to baseline. Next, the relationships between serum phosphate exposures and ψ were modeled using a nonlinear mixed-effect (NLME) modeling approach. A combined item response theory-NLME model with average serum phosphate as a predictor of ψ described PROs data well. The model estimates suggested 28%, 31%, and 25% reduction in Western Ontario and McMaster Universities Osteoarthritis Index, brief pain inventory, and brief fatigue inventory scores, respectively, with every unit increase in average serum phosphate from the lower limit of normal (2.5 mg/dL). Additionally, a time effect of ~ 0.08% improvements each week was estimated. The analysis suggested that burosumab treatment-induced improvements in serum phosphate levels are associated with improvements in PROs in adults with X-linked hypophosphatemia. The analyses confirmed the importance of prolonged serum phosphate level correction in adult patients with XLH. These results can be useful to guide the design of further studies and to design treatment optimization strategies. (Mehta, 2024)

September 2026 Update

Kainos assay is no longer commercially available in the United States. The proposed update removes reliance on specialized diagnostic testing that is no longer routinely available in the United States and permits diagnosis of XLH or FGF23-mediated hypophosphatemia through currently accepted clinical, genetic, biochemical, and specialist-supported diagnostic methods. The revision maintains objective evidence of hypophosphatemia and renal phosphate wasting while reducing unnecessary barriers to medically necessary treatment with Crysvita.

CPT/HCPCS:

References:

X-linked hypophosphatemia. Genetic and Rare Diseases Information Center. Available at: https://rarediseases.info.nih.gov/diseases/12943/x-linked-hypophosphatemia. Accessed August 20, 2018

Clinicaltrials.gov(2019) Study of KRN23, a Recombinant Fully Human Monoclonal Antibody Against FGF23, in Pediatric Subjects With X-linked Hypophosphatemia (XLH). NCT02163577. Available at: https://clinicaltrials.gov/ct2/show/NCT02163577?term=burosumab&rank=

Clinicaltrials.gov(2020) A Phase 2 Open-Label Trial to Assess the Efficacy and Safety of KRN23 in Patients With Tumor-Induced Osteomalacia or Epidermal Nevus Syndrome. NCT02722798. Available at: https://clinicaltrials.gov/ct2/show/NCT02722798?term=NCT02722798&draw=2&rank=1

Clinicaltrials.gov(2020) A Phase 2 Open-Label Trial to Assess the Efficacy and Safety of KRN23 in Patients With Tumor-Induced Osteomalacia or Epidermal Nevus Syndrome. NCT02722798. Available at: https://clinicaltrials.gov/ct2/show/NCT02722798?term=NCT02722798&draw=2&rank=1

Clinicaltrials.gov.(2020) A Phase 2 Open-Label Trial to Assess the Efficacy and Safety of KRN23, an Antibody to FGF23, in Subjects With Tumor-Induced Osteomalacia (TIO) or Epidermal Nevus Syndrome (ENS)-Associated Osteomalacia. NCT02304367. Available at: https://clinicaltrials.gov/ct2/show/NCT02304367?term=NCT02304367&draw=2&rank=1

Imel EA, Glorieux FH, Whyte MP, et. al.(2019) Burosumab versus conventional therapy in children with X-linked hypophosphataemia: a randomised, active-controlled, open-label, phase 3 trial. Lancet. 2019 Jun 15;393(10189):2416-2427. doi: 10.1016/S0140-6736(19)30654-3. Epub 2019 May 16. Erratum in: Lancet. 2019 Jul 13;394(10193):120. PMID: 31104833; PMCID: PMC7179969.

Insogna KL, et al,(2018) RCT Phase 3 Trial for Efficacy of Burosumab in Adults with X-linked hypophosphatemia, J Bone Miner Res. 2018;33(8):1383.

Insogna,KL, Briot, K, Imel EA, et al.(2018) 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 Jun 26. doi: 10.1002/jbmr.3475. [Epub ahead of print]

Linglart A, Imel EA, Whyte MP, Portale AA, Högler W, Boot AM, Padidela R, Van't Hoff W, Gottesman GS, Chen A, Skrinar A, Scott Roberts M, Carpenter TO.(2022) Sustained Efficacy and Safety of Burosumab, a Monoclonal Antibody to FGF23, in Children With X-Linked Hypophosphatemia. J Clin Endocrinol Metab. 2022 Feb 17;107(3):813-824. doi: 10.1210/clinem/dgab729. PMID: 34636899; PMCID: PMC8851952.

Mehta K, Gosselin NH, Insogna K, et.al.,(2024) Item Response Theory Quantifies the Relationship Between Improvements in Serum Phosphate and Patient-Reported Outcomes in Adults With X-Linked Hypophosphatemia. Clin Pharmacol Ther. 2024 Nov;116(5):1343-1351. doi: 10.1002/cpt.3406. Epub 2024 Aug 12. PMID: 39129452.

NCCN(2026) NCCN Drugs & Biologics Compendium for Lutetium Lu 177 dotatate (e.g., Lutathera), National Comprehensive Cancer Network, Inc. 2026. All rights reserved. Accessed June 30, 2026. To view the most recent and complete version of the Compendium, go online to NCCN.org.

Package Insert(2024) Lutathera Millburn, NJ: Advanced Accelerator Applications USA, Inc.; 2024.

Study of KRN23, a Recombinant Fully Human Monoclonal Antibody Against FGF23, in Pediatric Subjects With X-linked Hypophosphatemia (XLH). ClinicalTrials.gov. Available at: https://clinicaltrials.gov/ct2/show/NCT02163577?term=burosumab&rank=

Whyte MP, Carpenter TO, Gottesman GS, et al.(2019) Efficacy and safety of burosumab in children aged 1-4 years with X-linked hypophosphataemia: a multicentre, open-label, phase 2 trial. Lancet Diabetes Endocrinol. 2019;7(3):189-199. doi:10.1016/S2213-8587(18)30338-3

Group specific policy will supersede this policy when applicable. This policy does not apply to the Wal-Mart Associates Group Health Plan participants.