Subject:
Burosumab-twza (Crysvita)
Description:
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IMPORTANT NOTE:
The purpose of this policy is to provide general information applicable to the administration of health benefits that Horizon Blue Cross Blue Shield of New Jersey and Horizon Healthcare of New Jersey, Inc. (collectively “Horizon BCBSNJ”) insures or administers. If the member’s contract benefits differ from the medical policy, the contract prevails. Although a service, supply or procedure may be medically necessary, it may be subject to limitations and/or exclusions under a member’s benefit plan. If a service, supply or procedure is not covered and the member proceeds to obtain the service, supply or procedure, the member may be responsible for the cost. Decisions regarding treatment and treatment plans are the responsibility of the physician. This policy is not intended to direct the course of clinical care a physician provides to a member, and it does not replace a physician’s independent professional clinical judgment or duty to exercise special knowledge and skill in the treatment of Horizon BCBSNJ members. Horizon BCBSNJ is not responsible for, does not provide, and does not hold itself out as a provider of medical care. The physician remains responsible for the quality and type of health care services provided to a Horizon BCBSNJ member.
Horizon BCBSNJ medical policies do not constitute medical advice, authorization, certification, approval, explanation of benefits, offer of coverage, contract or guarantee of payment.
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X-Linked hypophosphatemia (XLH) is a dominant disorder characterized by low levels of phosphate in the blood. XLH is caused by mutations in the PHEX gene which is involved in regulating the amount of phosphate in the body. The mutation causes an increased amount of fibroblast growth factor 23 (FGF23), causing a reduction in the amount of phosphate being reabsorbed by the kidneys. XLH occurs in approximately one case per 20,000 live births.
Burosumab-twza (Crysvita) binds to and inhibits the biological activity of the FGF23 restoring renal phosphate reabsorption and increasing the serum concentration of 1,25 dihydroxy vitamin D.
FDA approval of Crysvita was based on the safety and efficacy of four separate clinical trials. Study 1 was a randomized, open-label, dose finding, phase 2 study in 52 XLH patients ranging from 5 to 12 years of age. The study compared Crysvita given once every 2 weeks to every 4 weeks for the initial 16 weeks, at which point all patients continued until week 64 receiving Crysvita every 2 weeks. Patients mean serum phosphorus levels increased from 2.4 at baseline to 3.3 at week 40 and 3.4 at week 64 of the trial. The ratio of renal tubular maximum reabsorption rate of phosphate to glomerular filtration rate (TmP/GFR) increased in these patients from mean of 2.2 at baseline to 3.3 and 3.4 mg/dL at week 40 and week 64. The members XLH was rated on the 10 point thatcher rickets severity score (RSS) and the 7 point radiographic global impression of change. Baseline RSS scores were 1.9 and decreased to 0.8 at week 40 for patients receiving Crysvita. Serum alkaline phosphatase activity also decreased from 462 U/L at baseline to 354 U/L at week 64.
Study 2 was a 64 week open-label, phase 2 study to assess the safety, pharmacodynamics, and efficacy of Crysvita in children 1 to 4 years old with XLH. Patients received Crysvita at a dose of 0.8 mg/kg every two weeks with titration up to 1.2 mg/kg based on serum phosphorus measurements. All patients had radiographic evidence of rickets at baseline and had received oral phosphate and active vitamin D analogs for a mean (SD) duration of 16.9 (13.9) months. The mean SD level was 2.5 mg/dL at baseline to 3.5 mg/dL at week 40. The RSS score in members decreased from 2.9 at baseline to 1.2 at week 40. Additionally the serum alkaline phosphatase activity also decreased from 549 U/L at baseline to 355 U/L at week 40.
In study 3, Crysvita was studied in a randomized, double blind, placebo controlled, phase 3 study with open-label extension to assess the safety and efficacy of Crysvita in 134 adults with XLH. Patients received Crysvita 1 mg/kg every 4 weeks for 24 weeks. At study entry, the mean age of patients was 40 years (range 19 to 66 years) and all patients had skeletal pain associated with XLH or osteomalacia. The baseline mean serum phosphorus concentration was below the lower limit of normal at 1.98 mg/dL. At week 24 8% of patients in the placebo group achieved a serum phosphorous above the lower limit of normal while 94% of the Crysvita group achieved this (05% CI 85.8-97.7%, P-value <0.001). Additionally, at week 24, patients in the Crysvita group experienced bone healing in 43% of total bone total bone fractures compared to 8% of total fractures in the placebo group.
Study 4 (NCT 02537431) is a 48-week, open-label, single-arm study in 14 adult XLH patients to assess the effects of Crysvita on improvement of osteomalacia as determined by histologic and histomorphometric evaluation of iliac crest bone biopsies. Patients received 1 mg/kg Crysvita every four weeks. After 48 weeks of treatment, healing of osteomalacia was observed in ten patients as demonstrated by decreases in Osteoid volume/Bone volume (OV/BV) from a mean score of 26% at baseline to 11%, a change of -57%. Osteoid thickness declined in eleven patients from a mean of 17 micrometers to 12 micrometers, a change of -33%. Mineralization lag time declined in 6 patients from a mean of 594 days to 156 days, a change of -74%.
On June 18, 2020, the U.S Food and Drug Administration approved Crysvita (burosumab-twza) injection to treat patients age two and older with tumor-induced osteomalacia (TIO), a rare disease that is characterized by the development of tumors that cause weakened and softened bones. The tumors associated with TIO release a peptide hormone-like substance known as fibroblast growth factor 23 (FGF23) that lowers phosphate levels. FGF23 regulates levels of phosphate, an electrolyte that plays important roles in bone maintenance, energy production by cells and nerve function. When there is not enough phosphate in the body, bones begin to soften and weaken, causing osteomalacia (marked softening of bones).
The safety and efficacy of Crysvita were evaluated in two studies that together enrolled 27 adults with TIO. In both studies, patients received Crysvita every four weeks. For the first study, half of patients achieved normal phosphate levels through week 24 and maintained normal or near normal phosphate levels through week 144. In the second study, 69% of participants achieved normal phosphate levels through week 24 and maintained normal or near normal phosphate levels through week 88. The results of bone scans for patients in the first study also suggested healing of the bone lesions related to osteomalacia (softening of the bones).
The most common side effects reported in adults with TIO taking Crysvita were tooth abscess (infection), muscle spasms, dizziness, constipation, injection site reaction, rash and headaches.
Policy:
(Note: For Medicare Advantage, please refer to the Medicare Coverage Section below for coverage guidance.)
The requirements of the Horizon BCBSNJ Burosumab-twza (Crysvita) Program may require a precertification/prior authorization via MagellanRx Management. These requirements are member-specific: please verify member eligibility and requirements through the Horizon Provider Portal (www.horizonblue.com/provider). Ordering clinicians should request pre-certification from MagellanRx Management at ih.magellanrx.com or call 1-800-424-4508 (when applicable).
I. Burosumab-twza (Crysvita) is considered medically necessary based on the FDA approved indications:
A. Treatment of X-linked hypophosphatemia (XLH) when ALL of the following criteria are met:
· The prescriber is a specialist in the area of the patient's diagnosis (e.g. endocrinologist) or has consulted with a specialist in the area of the patient's diagnosis
· Member is 6 months of age or older
· One of the following:
o Patients epiphyseal plate has not fused OR
o Patients epiphyseal plate has fused AND the patient is experiencing symptoms of XLH (e.g. bone pain, fractures, limited mobility)
· Diagnosis of XLH supported by documentation of one of the following:
o Confirmed PHEX mutation in patient or directly related family member with appropriate x-linked inheritance
o Serum FGF23 level > 30 pg/mL
· Member has not used an oral phosphate and active vitamin D analogue (e.g. calcitriol, paricalcitol, doxercalciferol, calcifediol) 1 week prior to treatment and will not be using concurrently while on Crysvita
· Fasting serum phosphorus is below the normal range for age
· Member does not have severe renal impairment or end stage renal disease defined as a estimated glomerular filtration rate < 30 mL/min (pediatric patients) or creatinine clearance < 30 mL/min (adult patients)
· Reduced renal tubular phosphate resorption of phosphate corrected for glomerular filtration rate (TmP/GFR).
B. Treatment of FGF23-related hypophophatemia in tumor-induced osteomalacia (TIO) associated with phosphaturic mesenchymal tumors that cannot be curatively resected or localized when ALL of the following criteria are met:
· The prescriber is a specialist in the area of the patient's diagnosis (e.g. endocrinologist, oncologist) or has consulted with a specialist in the area of the patient's diagnosis
· Member is 2 years of age or older
· Member has not used an oral phosphate and active vitamin D analogue (e.g. calcitriol, paricalcitol, doxercalciferol, calcifediol) 1 weeks prior to treatment and will not be using concurrently while on Crysvita
· Fasting serum phosphorus is below the normal range for age
· Member does not have severe renal impairment or end stage renal disease defined as estimated glomerular filtration rate < 30 mL/min (pediatric patients) or creatinine clearance < 30 mL/min (adult patients)
II. When burosumab-twza (Crysvita) is medically necessary, therapy will be approved for a period of one year at the following FDA-approved doses:
A. Treatment of X-linked hypophosphatemia (XLH)
· For pediatric patients (6 months of age to under 18 years of age)
· Patients who weigh less than 10 kg, starting dose is 1 mg/kg of body weight rounded to the nearest 1 mg given SQ once every 2 weeks
· Patients who weight more than 10 kg, starting dose is 0.8 mg/kg of body weight, rounded to the nearest 10 mg given SQ once every 2 weeks. The minimum starting dose is 10 mg and the maximum dose is 90 mg.
· Doses may be increased up to approximately 2 mg/kg (maximum 90 mg), administered every 2 weeks to achieve normal serum phosphorous
[INFORMATIONAL: As per the FDA approved package insert, this drug has to be administered by healthcare professional. As per the FDA approved package insert, after initiation of treatment, measure fasting serum phosphorus every 4 weeks for the first 3 months of treatment, and thereafter as appropriate. If phosphorus levels are below reference range of age, the dose should be adjusted by 2mg/kg, administered once every two weeks, according to the table below
|
| Starting Dose (mg) | First Dose Increase (mg) | Second dose Increase to (mg) |
|
| 10 | 15 | 20 |
|
| 10 | 20 | 30 |
|
| 20 | 30 | 40 |
|
| 30 | 40 | 60 |
|
| 40 | 60 | 80 |
|
| 50 | 70 | 90 |
|
| 60 | 90 | 90 |
|
| 70 | 90 | 90 |
|
| 80 | 90 | 90 |
|
| 90 | 90 | 90 |
If serum phosphorus is above 5 mg/dL withhold the next dose and reassess level in 4 weeks. Member may reinitiate therapy once phosphorus is below reference range for age according to the dosing schedule below.
Previous dose | Re-Initiation Dose (mg) |
10 | 5 |
15 | 10 |
20 | 10 |
30 | 10 |
40 | 20 |
50 | 20 |
60 | 30 |
70 | 30 |
80 | 40 |
90 | 40 |
· For adult patients (18 years of age and older)
· 1 mg/kg body weight, rounded to the nearest 10 mg up to maximum of 90 mg given SQ once every 4 weeks
[INFORMATIONAL: As per the FDA approved package insert, after initiation of treatment, measure fasting serum phosphorus every 4 weeks for the first 3 months of treatment, and thereafter as appropriate. If phosphorus levels are above the normal range, hold the next dose and reassess level after 4 weeks. Once within the normal range, treatment may be restarted at approximately half the initial starting dose up to a maximum dose of 40 mg every 4 weeks. Phosphorus levels should be obtained fasting 12 hours or more without food or drink except for water and after an adequate washout period after supplements.]
B. Treatment of FGF23-related hypophophatemia in tumor-induced osteomalacia (TIO)
· For pediatric patients (2 years to less than 18 years of age and older)
· Starting dose is 0.4 mg/kg body weight rounded to the nearest 10 mg given SQ once every 2 weeks
· Dose may be increased up to 2 mg/kg not to exceed 180 mg, administered every 2 weeks
· For adults patients (18 years of age and older)
· Starting dose is 0.5 mg/kg body weight rounded to the nearest 10 mg given SQ every 4 weeks
· Dose may be increased up to 2 mg/kg not to exceed 180mg, administered every 2 weeks
III. Continuation of burosumab-twza (Crysvita) for duration of 12 months will be approved when ALL of the following are met:
· Member has the absence of unacceptable toxicity from the medication; AND
· Member has experienced normalization of serum phosphate while on therapy; AND
· Member experiences disease response indicated by:
- X-linked hypophosphatemia (XLH)
o Without fused epiphyseal plates, any of the following clinical improvements: (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); or
o With fused epiphyseal plates, any of the following clinical improvements: (e.g. improvement in bone pain, enhanced mobility, improvement in osteomalacia, and improvement in fracture healing; or
- FGF23-related hypophophatemia in tumor-induced osteomalacia (TIO)
o Any of the following clinical improvements: e.g. radiographic evidence or bone histomorphometry of improvements of osteomalacia, healing of bone lesions related to osteomalaica
IV. Burosumab-twza (Crysvita) is considered investigational for all other indications.
Medicare Coverage
There is no National Coverage Determination (NCD) or Local Coverage Determination (LCD) for jurisdiction JL specifically for this drug. Burosumab-twza (Crysvita) is administered subcutaneously. Per Local Coverage Article A53127, Drugs ADMINISTERED subcutaneously are considered to be usually SELF-ADMINISTERED. If a drug is SELF-ADMINISTERED by more than 50 percent of Medicare beneficiaries, the drug is excluded from coverage under Medicare Part B. Therefore, for Medicare Advantage Products, Burosumab-twza (Crysvita) is noncovered.
For members with a Medicare drug plan (Part D) Burosumab-twza (Crysvita) may be covered under that plan.
Medicaid Coverage
For Horizon NJ Health members, please follow this link for the corresponding HNJH drug policy https://services3.horizon-bcbsnj.com/ddn/NJhealthWeb.nsf
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Horizon BCBSNJ Medical Policy Development Process:
This Horizon BCBSNJ Medical Policy (the “Medical Policy”) has been developed by Horizon BCBSNJ’s Medical Policy Committee (the “Committee”) consistent with generally accepted standards of medical practice, and reflects Horizon BCBSNJ’s view of the subject health care services, supplies or procedures, and in what circumstances they are deemed to be medically necessary or experimental/ investigational in nature. This Medical Policy also considers whether and to what degree the subject health care services, supplies or procedures are clinically appropriate, in terms of type, frequency, extent, site and duration and if they are considered effective for the illnesses, injuries or diseases discussed. Where relevant, this Medical Policy considers whether the subject health care services, supplies or procedures are being requested primarily for the convenience of the covered person or the health care provider. It may also consider whether the services, supplies or procedures are more costly than an alternative service or sequence of services, supplies or procedures that are at least as likely to produce equivalent therapeutic or diagnostic results as to the diagnosis or treatment of the relevant illness, injury or disease. In reaching its conclusion regarding what it considers to be the generally accepted standards of medical practice, the Committee reviews and considers the following: all credible scientific evidence published in peer-reviewed medical literature generally recognized by the relevant medical community, physician and health care provider specialty society recommendations, the views of physicians and health care providers practicing in relevant clinical areas (including, but not limited to, the prevailing opinion within the appropriate specialty) and any other relevant factor as determined by applicable State and Federal laws and regulations.
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Index:
Burosumab-twza (Crysvita)
Crysvita (Burosumab-twza)
References:
1. CrysvitaTM Prescribing Information. Ultragenyx. Novato, CA. June 2020.
2. Crysvita AMCP Dossier. Ultragyenx. Novato, CA. May 2018.
3. Scheinman S., Drezner M. Hereditary hypophosphatemic rickets and tumor induced osteomalacia. UpToDate. Updated 26 Sept. 2017. Accessed 20 May 2018. Available from: www.uptodate.com.
4. Carpenter TO, Whyte MP, Imel EA, et al. Burosumab Therapy in Children with X-Linked Hypophosphatemia. N Engl J Med. 2018;378(21):1987-1998.
5. Imel E, Carpenter T, Gottesman GC, et al. The effect of burosumab (KRN23), a fully human anti-FGF23 monoclonal antibody, on phosphate metabolism and rickets in 1 to 4-year-old children with X-linked hypophosphatemia (XLH). (Meeting abstract). J Bone Miner Res. 2017;32(S1)
6. Eisenga MF, Londen M, Leaf DE, et al. C-terminal fibroblast growth factor 23, iron deficiency, and mortality in renal transplant recipients. JASN. Dec 2017 (12) 3639-3646.
7. Food and Drug Administration. Center for Drug Evaluation and Research. BLA 761068. April 2018.
8. Chang AR, Grams M. Serum phosphorus and mortality in a national health and nutrition examination survey (NHANES III): effect modification by fasting. Am J Kidney Dis 2014 Oct;64(4):567-573
9. ClinicalTrials.gov. Study of KRN23 in Adult Subjects With Tumor-Induced Osteomalacia (TIO) or Epidermal Nevus Syndrome (ENS). NCT02304367. Available at: https://clinicaltrials.gov/ct2/show/NCT02304367
10. ClinicalTrials.gov. A Study of KRN23 in Subjects With Tumor-Induced Osteomalacia or Epidermal Nevus Syndrome. NCT02722798. Available at: https://clinicaltrials.gov/ct2/show/NCT02722798
Codes:
(The list of codes is not intended to be all-inclusive and is included below for informational purposes only. Inclusion or exclusion of a procedure, diagnosis, drug or device code(s) does not constitute or imply authorization, certification, approval, offer of coverage or guarantee of payment.)
CPT*
HCPCS
J0584
* CPT only copyright 2020 American Medical Association. All rights reserved. CPT is a registered trademark of the American Medical Association.
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Medical policies can be highly technical and are designed for use by the Horizon BCBSNJ professional staff in making coverage determinations. Members referring to this policy should discuss it with their treating physician, and should refer to their specific benefit plan for the terms, conditions, limitations and exclusions of their coverage.
The Horizon BCBSNJ Medical Policy Manual is proprietary. It is to be used only as authorized by Horizon BCBSNJ and its affiliates. The contents of this Medical Policy are not to be copied, reproduced or circulated to other parties without the express written consent of Horizon BCBSNJ. The contents of this Medical Policy may be updated or changed without notice, unless otherwise required by law and/or regulation. However, benefit determinations are made in the context of medical policies existing at the time of the decision and are not subject to later revision as the result of a change in medical policy
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