Notification



Notification Issue Date:



Medical Policy Bulletin


Title:Burosumab-twza (Crysvita®)

Policy #:08.01.49a

This policy is applicable to the Company’s commercial products only. Policies that are applicable to the Company’s Medicare Advantage products are accessible via a separate Medicare Advantage policy database.


The Company makes decisions on coverage based on Policy Bulletins, benefit plan documents, and the member’s medical history and condition. Benefits may vary based on contract, and individual member benefits must be verified. The Company determines medical necessity only if the benefit exists and no contract exclusions are applicable.

When services can be administered in various settings, the Company reserves the right to reimburse only those services that are furnished in the most appropriate and cost-effective setting that is appropriate to the member’s medical needs and condition. This decision is based on the member’s current medical condition and any required monitoring or additional services that may coincide with the delivery of this service.

This Medical Policy Bulletin document describes the status of medical technology at the time the document was developed. Since that time, new technology may have emerged or new medical literature may have been published. This Medical Policy Bulletin will be reviewed regularly and be updated as scientific and medical literature becomes available. For more information on how Medical Policy Bulletins are developed, go to the About This Site section of this Medical Policy Web site.



Policy

MEDICALLY NECESSARY

INITIAL THERAPY
Burosumab-twza (Crysvita®) is considered medically necessary and, therefore, covered for individuals at least 1 year of age and older with X-linked Hypophosphatemia (XLH) when the following criteria listed below are met:
  • Diagnosis of XLH supported by ONE of the following:
    • Documented PHEX pathogenic (i.e., disease-causing) mutation in either the individual or in a directly related family member with appropriate x-linked inheritance
    • Serum fibroblast growth factor 23 FGF23 (FGF23) level > 30 pg/mL
  • Documentation of classic clinical features of disease (e.g., rickets, growth abnormalities [short stature or lower extremity bowing], bone pain, bone fractures)
  • Fasting serum phosphorus is below the normal range for age
  • Does not have renal impairment or end stage renal disease defined as a glomerular filtration rate < 30 mL/min
  • Individual has or is willing to discontinue use of oral phosphate or active vitamin D analogs within one week of treatment initiation

CONTINUATION THERAPY
Burosumab-twza (Crysvita®) is considered medically necessary and, therefore, covered during continuation therapy for individuals at least 1 year of age and older with X-linked Hypophosphatemia (XLH) when the following criteria listed below are met:
  • Normalized serum phosphate during therapy, and the absence of hyperphosphatemia
  • Documented clinical improvement in the following:
    • Adult individuals --- (e.g., improvement in bone pain, enhanced mobility, radiographic evidence of improvement in osteomalacia/ fracture healing)
    • Pediatric individuals --- (e.g., enhanced height velocity, improvement in lower extremity bowing and associated abnormalities, improved walking ability, radiographic evidence of improvements of rickets/ osteomalacia/ epiphyseal healing)

EXPERIMENTAL/INVESTIGATIONAL

All other uses of burosumab-twza (Crysvita®) are considered experimental/investigational and, therefore, not covered unless the indication is supported as an accepted off-label use, as defined in the Company medical policy on off-label coverage for prescription drugs and biologics.

REQUIRED DOCUMENTATION

The individual's medical record must reflect the medical necessity for the care provided. These medical records may include, but are not limited to: records from the professional provider's office, hospital, nursing home, home health agencies, therapies, and test reports.

The Company may conduct reviews and audits of services to our members, regardless of the participation status of the provider. All documentation is to be available to the Company upon request. Failure to produce the requested information may result in a denial for the drug.
Guidelines

BENEFIT APPLICATION

Subject to the terms and conditions of the applicable benefit contract, burosumab-twza (Crysvita®) for subcutaneous injection is covered under the medical benefits of the Company’s products when the medical necessity criteria listed in this medical policy are met.

AGE- AND GENDER-BASED NORMAL SERUM PHOSPHATE REFERENCE INTERVALS

Serum phosphorus is measured in milligrams of phosphorus per deciliter of blood (mg/dL). The Pathology and Laboratory Medicine Department of Children's Hospital of Philadelphia (CHOP) established the following normative serum phosphate reference intervals based on gender and age:

Male
Female
0D-11 Mos: 4.8-8.2 mg/dL
0D-11 Mos: 4.8-8.2 mg/dL
1-3 Yrs: 3.8-6.5 mg/dL
1-3 Yrs: 3.8-6.5 mg/dL
4-6 Yrs: 4.1-5.4 mg/dL
4-6 Yrs: 4.1-5.4 mg/dL
7-11 Yrs: 3.7-5.6 mg/dL
7-11 Yrs: 3.7-5.6 mg/dL
12-13 Yrs: 3.3-5.4 mg/dL
12-13 Yrs: 3.3-5.4 mg/dL
14-15 Yrs: 2.9-5.4 mg/dL
14-15 Yrs: 2.9-5.4 mg/dL
16-20 Yrs: 2.7-4.7 mg/dL
16-20 Yrs: 2.7-4.7 mg/dL
≥ 21 Yrs: 2.5-4.5 mg/dL
≥ 21Yrs: 2.5-4.5 mg/dL
*CHOP: Reference Range Document

DOSING REGIMEN

In pediatric individuals with XLH: Starting dose regimen is 0.8 mg/kg of body weight rounded to the nearest 10 mg, administered every 2 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 2 weeks to achieve normal serum phosphorus.

In adult individuals with XLH: Dose regimen is 1 mg/kg body weight rounded to the nearest 10 mg until a maximum dose of 90 mg administered every 4 weeks.

US FOOD AND DRUG ADMINISTRATION (FDA) STATUS

Burosumab-twza (Crysvita®) was approved by the FDA on April 17, 2018 for treatment of individuals at least one year of age and older with X-linked Hypophosphatemia when the criteria listed above are met.

Description

Burosumab-twza (Crysvita®) is a fibroblast growth factor 23 (FGF23) blocking antibody indicated for the treatment of X-linked hypophosphatemia (XLH) in adult and pediatric individuals 1 year of age and older.

XLH is associated with a mutation in the phosphate-regulating gene with homologies to endopeptidases on the X chromosome (PHEX) gene sequence. The PHEX protein regulates a second hormone called fibroblast growth factor 23 (FGF23). The disease is characterized by excess activity of FGF23, which is responsible for reducing serum levels of phosphorus and vitamin D by regulating phosphate excretion and vitamin D production by the kidney. Phosphate wasting in XLH is caused by excessive levels and activity of FGF23. KRN23 is a recombinant human IgG1 monoclonal antibody designed to bind to FGF23 and thereby inhibit the excessive biological activity of FGF23. By blocking excess FGF23 in individuals with XLH, KRN23 is intended to increase phosphate reabsorption from the kidney and increase the production of vitamin D, increasing the overall serum concentration, which enhances intestinal absorption of phosphate and calcium.

X-linked dominant disorders are caused by mutations in genes on the X chromosome, one of the two sex chromosomes in each cell. Females have two X chromosomes; a mutation in either one of the two copies of the allele in each cell is sufficient to cause the disorder. In males (who have only one X chromosome), a mutation in the only copy of the gene in each cell causes the disorder. In most cases, males experience more severe symptoms of the disorder than females. A characteristic of X-linked inheritance is that fathers cannot pass X-linked traits to their sons since the son would only inherit the Y chromosome (no male-to-male transmission).

PEER-REVIEWED LITERATURE
Summary

In April 2018, based on results from the following studies, burosumab-twza (Crysvita®) was approved by the US Food and Drug Administration (FDA) in the treatment X-linked Hypophosphatemia (XLH) for individuals at least one year of age or older.

A randomized, open-label study in 52 XLH children under 12 years of age compared burosumab administered every 2 weeks versus every 4 weeks. Upon completion of a 16-week dose titration, participants were administered burosumab every 2 weeks for 48-weeks. None of the study participants discontinued burosumab and all completed at least the 64 weeks of treatment duration during the study. Dosing was individualized to achieve a target fasting serum phosphorus concentration of 3.5 to 5.0 mg/dL based on the fasting phosphorus level the day of dosing. Twenty-six of the total 52 received burosumab every 2 weeks up to a maximum dose of 2 mg/kg. The average dose was 0.73 mg/kg at week 16, 0.98 mg/kg at week 40 and 1.04 mg/kg (range: 0.4, 2.0) at week 60. The other 26 enrollees were treated with burosumab every 4 weeks. At the beginning of the study, the average age of participants was 8.5 years with 46% male participants. Regarding treatment with oral phosphate and active vitamin D analogs, 96% of enrollees had received these for a mean (Standard Deviation [SD]) duration of 7 (2.4) years. In addition, discontinuation of oral phosphate and active vitamin D analogs occurred prior to study enrollment. 94% of study participants presented with radiographic evidence of rickets at baseline. In this study, individuals receiving burosumab experienced a mean (SD) increase in serum phosphorus levels from 2.4 (0.40) at baseline to 3.3 (0.40) and 3.4 (0.45) mg/dL at week 40 and week 64 respectively, in the trial participants who received burosumab every 2 weeks. The 10-point Thacher Rickets Severity Score (RSS) and the 7-point Radiographic Global Impression of Change (RGI-C) were used to evaluate rickets. The RGI-C score is assigned based on images of the wrist and knee from a single time point, and higher scores indicating greater rickets severity. After 40 weeks of therapy, mean total RSS decreased from 1.9 to 0.8 and the mean RGI-C Global score increased to +1.7 in individuals receiving burosumab every 2 weeks. Eighteen of the 26 achieved an RGI-C score of ≥ +2.0, which was defined as radiographical evidence of substantial healing in the study. These findings were consistent at 64 weeks.

In a phase 2 trial open-label study, researchers evaluated pediatric individuals aged 5 years or less (n=13), on serum phosphate levels at 64 weeks. Individuals in the study received burosumab at a dose of 0.8 mg/kg every 2 weeks with titration up to 1.2 mg/kg based on serum phosphorus levels. All participants completed treatment with burosumab. The average age was 2.9 years at study entry. At baseline, all study participants had radiographic evidence of rickets and had received oral phosphate and active vitamin D analogs for a average duration of 16.9 months. All participants discontinued treatment with oral phosphate and active vitamin D analogs occurred prior to study initiation. The researchers presented results of the first 40 weeks. At week 40, participants experienced serum phosphorus levels increases of an average (SD) from 2.5 (0.28) mg/dL at baseline to 3.5 (0.49) mg/d. After 40 weeks of treatment, mean total RSS decreased from 2.9 to 1.2 and the mean (SE) RGI-C Global score was +2.3 (0.08). The entire study population achieved a RGI-C global score ≥ +2.0. Lower limb deformity as assessed by RGI-C, using standing long leg radiographs, which resulted in an average increase of +1.3. This study was limited by the small sample size, although that is to be expected based on rarity of disease and age of participants.

In phase 3 randomized, double-blind, placebo-controlled study (RCT) in 134 adult individuals with XLH evaluated the proportion of participants achieving serum phosphate levels above 2.5 mg/dL at the dose interval mid-points of the dose interval between baseline and week 24 and osteomalacia related-fracture and pseudofractures. Researchers indicate that burosumab was administered at a dose of 1 mg/kg every 4 weeks. At study entry, the age of participant ranged from 16 to 66 years, with an average age of 40 years. At baseline, all participants had skeletal pain associated with XLH or osteomalacia. The baseline mean (SD) serum phosphorus concentration was below the lower limit of normal at 1.98 (0.31) mg/dL. Oral phosphate and active vitamin D analogs were not allowed during the study with one study entrant in the burosumab group discontinued treatment. At the completion of 24 weeks, a total of 94% of participants treated with burosumab achieved a serum phosphorus level above the lower limit of normal at mid-point of the dose interval compared to 8% in the placebo group (P<0.0001). Assessment of active fracture/pseudofractures at week 24 demonstrated a higher rate of complete healing in the group receiving burosumab (44%) compared to placebo (18%). During the study, a total of 6 new fractures or pseudofractures appeared in 68 participants receiving burosumab, compared to 8 new abnormalities in 66 in the placebo treatment arm. The study comprised a 24- week placebo-controlled phase, after which point individuals in the placebo arm could cross-over into a 72-week open-label trial to be treated with 1 mg/kg burosumab. Although the strongest methodologically, as the only phase 3 RCT trial, this study had the shortest follow-up.

A 48-week, open-label, single-arm study was completed in 14 adult XLH individuals to determine the effects of burosumab on improvement of osteomalacia as based on histologic and histomorphometric evaluation of iliac crest bone biopsies. Treatment was 1 mg/kg burosumab every 4 weeks. At the initiation of the study, the mean age was 40 years (range 25 to 52 years) and 43% were male. Oral phosphate and active vitamin D analogs were not allowed during the study. After 48 weeks of treatment, healing of osteomalacia was observed in 10 individuals as demonstrated by decreases in Osteoid volume/Bone volume from a mean (SD) score of 26% (12.4) at baseline to 11% (6.5), a change of -57%. Osteoid thickness declined in eleven participants. Mineralization lag time declined in 6 from a mean (SD) of 594 (675) days to 156 (77) days, a change of -74%.

SAFETY

Burosumab-twza (Crysvita®) should be interrupted if an individual's phosphorus level exceed above upper limit of normal, which may increase the risk of nephrocalcinosis; dose adjustment or therapy interruption may be required based on phosphorus levels. Other safety concerns that require monitoring during burosumab-twza (Crysvita®) therapy include previous serious hypersensitivity reaction to burosumab-twza (Crysvita®).

OFF-LABEL INDICATIONS

There may be additional indications contained in the Policy section of this document due to evaluation of criteria highlighted in the Company’s off-label policy, and/or review of clinical guidelines issued by leading professional organizations and government entities.
References


Children's Hospital of Philadelphia. Pathology & laboratory medicine. Reference range document. 10/23/2017. Available at: https://media.chop.edu/data/files/pdfs/chop-labs-reference-ranges.pdf. Accessed July 6, 2018.

Crysvita® (burosumab-twza). Ultragenyx website. http://www.ultragenyx.com/pipeline/krn23-xlh/. Published April 2018. Accessed May 21, 2018.

Elsevier Gold's Clinical Pharmacology Compendium. Burosumab-twza (Crysvita®). [Clinical Key Web site]. 04/25/2018. Available at: https://www.clinicalkey.com/pharmacology/ [via subscription only]. Accessed June 13, 2018.

Lexi-Drugs Compendium. Burosumab-twza (Crysvita®). [Lexicomp Online Web site]. 06/11/2018. Available at: http://online.lexi.com/lco/action/home [via subscription only]. Accessed June 13, 2018.

Ruppe MD , Zhang X , Imel EA , et al. Effect of four monthly doses of a human monoclonal anti-FGF23 antibody (KRN23) on quality of life in X-linked hypophosphatemia. Bone Rep. 2016; 5:158-162.

Truven Health Analytics. Micromedex® DrugDex® Compendium. DrugDex®. burosumab-twza (Crysvita®). [Micromedex® Solutions Web site]. May 07, 2018. Available at: http://www.micromedexsolutions.com/micromedex2/librarian [via subscription only]. Accessed May 21, 2018.

US Food and Drug Administration. Center for Drug Evaluation and Research. burosumab-twza (Crysvita®) Product Labeling. [FDA Web site] Available at:https://www.accessdata.fda.gov/drugsatfda_docs/nda/2018/761068Orig1s000Lbl.pdf. Accessed on May 21, 2018.

US Food and Drug Administration. Center for Drug Evaluation and Research. burosumab-twza (Crysvita®) Approval Letter. [FDA Web site]. Available at:https://www.accessdata.fda.gov/drugsatfda_docs/nda/2018/761068Orig1s000Approv.pdf. Accessed on May 21, 2018.

US National Library of Medicine. National Institute of Health. Patterns of inheritance. 07/03/2018. Available at: https://ghr.nlm.nih.gov/primer/inheritance/inheritancepatterns. Accessed July 6, 2018.

US National Library of Medicine. National Institute of Health. Genetic and rare disease information center. X-linked hypophosphatemia. 02/01/2018. Available at: https://rarediseases.info.nih.gov/diseases/12943/x-linked-hypophosphatemia. Accessed May 21, 2018.




Coding

Inclusion of a code in this table does not imply reimbursement. Eligibility, benefits, limitations, exclusions, precertification/referral requirements, provider contracts, and Company policies apply.

The codes listed below are updated on a regular basis, in accordance with nationally accepted coding guidelines. Therefore, this policy applies to any and all future applicable coding changes, revisions, or updates.

In order to ensure optimal reimbursement, all health care services, devices, and pharmaceuticals should be reported using the billing codes and modifiers that most accurately represent the services rendered, unless otherwise directed by the Company.

The Coding Table lists any CPT, ICD-9, ICD-10, and HCPCS billing codes related only to the specific policy in which they appear.

CPT Procedure Code Number(s)

N/A


Professional and outpatient claims with a date of service on or before September 30, 2015, must be billed using ICD-9 codes. Professional and outpatient claims with a date of service on or after October 1, 2015, must be billed using ICD-10 codes.

Facility/Institutional inpatient claims with a date of discharge on or before September 30, 2015, must be billed with ICD-9 codes. Facility/Institutional inpatient claims with a date of discharge on or after October 1, 2015, must be billed with ICD-10 codes.


ICD - 10 Procedure Code Number(s)

N/A


Professional and outpatient claims with a date of service on or before September 30, 2015, must be billed using ICD-9 codes. Professional and outpatient claims with a date of service on or after October 1, 2015, must be billed using ICD-10 codes.

Facility/Institutional inpatient claims with a date of discharge on or before September 30, 2015, must be billed with ICD-9 codes. Facility/Institutional inpatient claims with a date of discharge on or after October 1, 2015, must be billed with ICD-10 codes.


ICD -10 Diagnosis Code Number(s)

E83.31 Familial hypophosphatemia


HCPCS Level II Code Number(s)



THE FOLLOWING CODES ARE USED TO REPRESENT BUROSUMAB-TWZA (CRYSVITA®)

C9399 Unclassified drugs or biologicals

J0584 Injection, burosumab-twza 1 mg


Revenue Code Number(s)

N/A

Coding and Billing Requirements

If there is no specific HCPCS code available for the drug administered, then the drug must be reported with the most appropriate unlisted code along with the corresponding National Drug Code (NDC).

Cross References


Policy History

08.01.49a

01/01/2019This version of the policy will become effective 01/01/2019.

The following HCPCS codes has been added to the policy: J0584.

The following HCPCS code has been deleted from this policy: J3590.

08.01.49
08/13/2018This version of the policy will become effective 08/13/2018. The following new policy has been developed to communicate Company's coverage criteria for burosumab-twza (Crysvita®) injection.

Version Effective Date: 01/01/2019
Version Issued Date: 01/03/2019
Version Reissued Date: N/A

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