Burosumab-twza (Crysvita)

Number: 0932

Table Of Contents

Policy
Applicable CPT / HCPCS / ICD-10 Codes
Background
References

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Policy

Scope of Policy

This Clinical Policy Bulletin addresses burosumab-twza (Crysvita) for commercial medical plans. For Medicare criteria, see Medicare Part B Criteria.

Note: Requires Precertification:

Precertification of burosumab-twza (Crysvita) is required of all Aetna participating providers and members in applicable plan designs. For precertification of burosumab-twza call (866) 752-7021 or fax (888) 267-3277. For Statement of Medical Necessity (SMN) precertification forms, see Specialty Pharmacy Precertification.

Note: Site of Care Utilization Management Policy applies for burosumab-twza (Crysvita). For information on site of service, see Utilization Management Policy on Site of Care for Specialty Drug Infusions.

1. Criteria for Initial Approval

   Aetna considers burosumab-twza (Crysvita) medically necessary for the following indications:
   

   1. X-linked hypophosphatemia (XLH)

      When both of the following criteria are met:

      1. Member meets one of the following:

         1. Genetic testing was conducted to confirm a phosphate regulating gene with homology to endopeptidases located on the X chromosome (PHEX) mutation in the member and genetic testing results were submitted confirming diagnosis; or
         2. Genetic testing was conducted to confirm a PHEX mutation in a directly related family member with appropriate X-linked inheritance and genetic testing results were submitted confirming diagnosis; or
         3. Member’s fibroblast growth factor 23 (FGF23) level is above the upper limit of normal or abnormal for the assay and lab test results were submitted confirming diagnosis; and

      2. Member has radiographic evidence of rickets or other bone disease attributed to XLH;

   2. Tumor-induced osteomalacia (TIO)

      When the following criteria are met:

      1. Member’s diagnosis is confirmed by all of the following and lab test results were submitted confirming diagnosis:

         1. FGF23 level is above the upper limit of normal or abnormal for the assay; and
         2. Fasting serum phosphorus levels are less than 2.5 mg/dL; and
         3. Ratio of renal tubular maximum reabsorption rate of phosphate to glomerular filtration rate (TmP/GFR) is less than 2.5 mg/dL; and

      2. Member’s disease is associated with phosphaturic mesenchymal tumors that cannot be curatively resected or localized.

   Aetna considers all other indications as experimental and investigational (for additional information, see Experimental and Investigational and Background sections).

2. Continuation of Therapy

   Aetna considers the continuation of burosumab-twza (Crysvita) therapy medically necessary in members requesting reauthorization for an indication listed in Section I who are currently receiving the requested medication through a previously authorized pharmacy or medical benefit and who are experiencing benefit from therapy as evidenced by disease improvement or disease stability (e.g., increase or normalization in serum phosphate, improvement in bone and joint pain, reduction in fractures, improvement in skeletal deformities).

Dosage and Administration

Burosumab-twza (Crysvita) is available for injection as 10 mg/mL, 20 mg/mL, or 30 mg/mL in a single-dose vial. Crysvita is administered by subcutaneous (SC) injection and should be administered by a healthcare provider. The maximum volume of Crysvita per injection is 1.5 mL. If multiple injections are required, administer at different injection sites.

Pediatric X-linked hypophosphatemia (XLH) (6 months to 17 years of age)

• For pediatrics 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 pediatrics who weigh more than 10 kg, 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 X-linked hypophosphatemia (XLH) (18 years of age and older)

The recommended 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 tumor-induced osteomalacia (TIO) (2 years to 17 years of age)

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

Adult TIO (18 years of age and older)

Starting dose is 0.5 mg/kg body weight rounded to the nearest 10 mg every four weeks. Dose may be increased up to 2 mg/kg not to exceed 180 mg, administered every two weeks.

Source: Kyowa Kirin, 2023

Experimental and Investigational

Aetna considers burosumab-twza (Crysvita) as experimental and investigational for the following indications (not an all-inclusive list) because the safety and effectiveness for these indications has not been established:

• cutaneous-skeletal hypophosphatemia syndrome (also known as epidermal nevus syndrome or linear sebaceous nevus syndrome)
• fibrous dysplasia
• tyrosinemia type 1.

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Table:

CPT Codes / HCPCS Codes / ICD-10 Codes

Code	Code Description
Information in the [brackets] below has been added for clarification purposes.   Codes requiring a 7th character are represented by "+" :
Other CPT codes related to the CPB:
84100	Phosphorus inorganic (phosphate)
96372	Therapeutic, prophylactic, or diagnostic injection (specify substance or drug); subcutaneous or intramuscular
HCPCS codes covered if selection criteria are met:
J0584	Injection, burosumab-twza 1 mg
Other HCPCS codes related to the CPB:
J0636	Injection, calcitriol, 0.1 mcg
J1270	Injection, doxercalciferol, 1 mcg
J2501	Injection, paricalcitol, 1 mcg
J8562	Fludarabine phosphate, oral, 10 mg
S0169	Calcitrol, 0.25 microgram
ICD-10 codes covered if selection criteria are met:
E83.31	Familial hypophosphatemia [for X-linked hypophosphatemia (XLH)]
M83.8	Other adult osteomalacia [tumor-induced osteomalacia (TIO)]
ICD-10 codes not covered for indications listed in the CPB:
E70.21	Tyrosinemia
E83.39	Other disorders of phosphorus metabolism [cutaneous-skeletal hypophosphatemia syndrome (also known as epidermal nevus syndrome or linear sebaceous nevus syndrome)]
M85.00 - M85.09	Fibrous dysplasia (monostotic)

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Background

U.S. Food and Drug Administration (FDA)-Approved Indications

Crysvita (burosumab-twza) is indicated for the treatment of:

• X-linked hypophosphatemia (XLH) in adult and pediatric patients 6 months of age and older;
• FGF23-related hypophosphatemia in tumor induced osteomalacia (TIO) associated with phosphaturic mesenchymal tumors that cannot be curatively resected or localized in adult and pediatric patients 2 years of age and older.

Burosumab-twza for injection is available as Crysvita (Kyowa Kirin, Inc.). Crysvita is a fibroblast growth factor 23 (FGF23) blocking antibody.

Crysvita is contraindicated with oral phosphate and/or active vitamin D analogs, when serum phosphorus is within or above the normal range for age, and in patients with severe renal impairment or end stage renal disease. 

Labeled warnings and precautions include hypersensitivity, hyperphosphatemia and risk of nephrocalcinosis, and injection site reactions. The most common adverse reactions (25% or more in the Crysvita group and greater than Active Control) in pediatric XLHpatients included pyrexia, injection site reaction, cough, vomiting, pain in extremity, headache, tooth abscess, and dental caries. The most common adverse reactions (greater than 5% and in at least 2 patients more than placebo) in adult XLH patients included back pain, headache, tooth infection, restless legs syndrome, vitamin D decreased, dizziness, constipation, muscle spasms, and blood phosphorus increased. The most common adverse reactions (greater than 10%) in TIO patients included tooth abscess, muscle spasms, dizziness, constipation, injection site reaction, rash, and headache. 

X-linked Hypophosphatemia (XLH)

Hereditary hypophosphatemic rickets is characterized by hypophosphatemia and rickets (and/or osteomalacia) that resembles vitamin D deficiency but does not respond to vitamin D replacement or pharmacologic doses of vitamin D because the underlying cause is renal phosphate wasting rather than true vitamin D resistance. X-linked hypophosphatemia (XLH) is the most common heritable form of rickets and osteomalacia, with a prevalence of approximately one case per 20,000 live births. XLH causes low levels of phosphorus in the blood. X-linked hypophosphatemia is caused by excess fibroblast growth factor 23 (FGF23) which suppresses renal tubular phosphate reabsorption and the renal production of 1,25 dihydroxy vitamin D. Most children with XLH experience bowed or bent legs, short stature, bone pain and severe dental pain. Some adults with XLH experience persistent discomfort or complications, such as joint pain, impaired mobility, tooth abscesses and hearing loss. 

Burosumab-twza binds to and inhibits the biological activity of FGF23 restoring renal phosphate reabsorption and increasing the serum concentration of 1,25 dihydroxy vitamin D. On April 17, 2018, the FDA approved burosumab-twza (Crysvita) with a Breakthrough Therapy designation, under which the FDA provides intensive guidance to the company on efficient drug development, and expedites its review of drugs that are intended to treat serious conditions where clinical evidence shows the drug may represent a substantial improvement over other available therapies. Burosumab-twza also received Orphan Drug designation, which provides incentives to assist and encourage the development of drugs for rare diseases. 

The safety and efficacy of burosumab-twza were studied in four clinical trials, two in pediatric patients (Study 1 and Study 2) and two in adult patients (Study 3 and Study 4). Radiographs from 52 burosumab-twza-treated XLH patients in Study 1 and 13 patients in Study 2 were examined to assess XLH-related rickets using the 10-point Thacher Rickets Severity Score (RSS) and the 7-point Radiographic Global Impression of Change (RGI-C). The RSS score is assigned based on images of the wrist and knee from a single time-point, with higher scores indicating greater rickets severity. The RGI-C score is assigned based on side-by-side comparisons of wrist and knee radiographs from two time-points, with higher scores indicating greater improvement in radiographic evidence of rickets. A RGI-C score of +2.0 was defined as radiographic evidence of substantial healing.

Study 1 (NCT 02163577) was a randomized, phase 2, open-label study in 52 prepubescent XLH patients, 5 to 12 years old, which compared treatment with burosumab-twza administered every 2 weeks versus every 4 weeks. Following an initial 16-week dose titration phase, patients completed 48-weeks of treatment with burosumab-twza every 2 weeks. All 52 patients completed at least 64 weeks on study; no patient discontinued. Burosumab-twza dose was adjusted to target a 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 52 patients received burosumab-twza every two weeks up to a maximum dose of 2 mg/kg. The average dose was 0.73 mg/kg (range: 0.3, 1.5) at week 16, 0.98 mg/kg (range: 0.4, 2.0) at week 40 and 1.04 mg/kg (range: 0.4, 2.0) at week 60. The remaining 26 patients received burosumab-twza every four weeks. At study entry, the mean age of patients was 8.5 years and 46% were male. Ninety-six percent had received oral phosphate and active vitamin D analogs for a mean (SD) duration of 7 (2.4) years. Oral phosphate and active vitamin D analogs were discontinued prior to study enrollment. Ninety-four percent of patients had radiographic evidence of rickets at baseline. Burosumab-twza increased mean (SD) 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 in the patients who received burosumab-twza every 2 weeks. The ratio of renal tubular maximum reabsorption rate of phosphate to glomerular filtration rate (TmP/GFR) increased in these patients from mean (SD) of 2.2 (0.49) at baseline to 3.3 (0.60) and 3.4 (0.53) mg/dL at week 40 and week 64. The baseline mean (SD) RSS total score was 1.9 (1.17) in patients receiving burosumab-twza every two weeks. After 40 weeks of treatment with burosumab-twza, mean total RSS decreased from 1.9 to 0.8. After 40 weeks of treatment with burosumab-twza, the mean RGI-C Global score was +1.7 in patients receiving burosumab-twza every two weeks. Eighteen out of 26 patients achieved an RGI-C score of ≥ +2.0. These findings were maintained at week 64. The mean (SD) serum total alkaline phosphatase activity was 462 (110) U/L at baseline and decreased to 354 (73) U/L at Week 64 (-23%, p < 0.0001) in the patients who received burosumab-twza every 2 weeks. Burosumab-twza treatment for 64 weeks increased standing mean (SD) height Z score from -1.72 (1.03) at baseline to -1.54 (1.13) in the patients who received burosumab-twza every two weeks (LS mean change of +0.19 (95% CI: 0.09 to 0.29).

Study 2 (NCT 02750618) was a 64-week open-label study in 13 pediatric XLH patients, 1 to 4 years old. Patients received burosumab-twza 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 completed at least 40 weeks on study; no patients discontinued. At study entry, the mean age of patients was 2.9 years and 69% were male. 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. Oral phosphate and active vitamin D analogs were discontinued prior to study enrollment. Burosumab-twza increased mean (SD) serum phosphorus levels from 2.5 (0.28) mg/dL at baseline to 3.5 (0.49) mg/dL at week 40. Baseline mean (SD) total RSS was 2.9 (1.37) in 13 patients. After 40 weeks of treatment with burosumab-twza, mean total RSS decreased from 2.9 to 1.2 and the mean (SE) RGI-C Global score was +2.3 (0.08). All 13 patients achieved a RGI-C global score ≥ +2.0. The mean (SE) lower limb deformity as assessed by RGI-C, using standing long leg radiographs, was +1.3 (0.14). The mean (SD) serum total alkaline phosphatase activity was 549 (194) U/L at baseline and decreased to 335 (88) U/L at Week 40 (mean change: -36%).

Study 3 (NCT 02526160) was a randomized, double-blind, placebo-controlled study in 134 adult XLH patients. The study comprised a 24-week placebo-controlled treatment phase. Burosumab-twza was administered at a dose of 1 mg/kg every 4 weeks. At study entry, the mean age of patients was 40 years (range 19 to 66 years) and 35% were male. All patients had skeletal pain associated with XLH/osteomalacia at baseline. 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. One patient in the burosumab-twza group discontinued treatment. At baseline, mean (SD) serum phosphorus was 1.9 (0.32) and 2.0 (0.30) mg/dL in the placebo and burosumab-twza groups respectively. During the initial 24 weeks of treatment, mean (SD) serum phosphorus across the midpoints of dose intervals (2 weeks post dose) was 2.1 (0.30) and 3.2 (0.53) mg/dL in the placebo and burosumab-twza groups, and mean (SD) serum phosphorus across the ends of dose intervals was 2.0 (0.30) and 2.7 (0.45) mg/dL in the placebo and burosumab-twza groups. A total of 94% of patients treated with burosumab-twza achieved a serum phosphorus level above the lower limit of normal (LLN) compared to 8% in the placebo group through week 24. At baseline, the mean (SD) ratio of renal tubular maximum reabsorption rate of phosphate to glomerular filtration rate (TmP/GFR) was 1.60 (0.37) and 1.68 (0.40) mg/dL in the placebo and burosumab-twza groups respectively. At week 22 (midpoint of a dose interval), mean (SD) TmP/GFR was 1.69 (0.37) and 2.73 (0.75) mg/dL in the placebo and burosumab-twza groups. At week 24 (end of a dose interval), mean (SD) TmP/GFR was 1.73 (0.42) and 2.21 (0.48) mg/dL in the placebo and burosumab-twza groups. A skeletal survey was conducted at baseline to identify osteomalacia-related fractures and pseudofractures. Osteomalacia-related fractures are defined as atraumatic lucencies extending across both bone cortices and pseudofractures are defined as atraumatic lucencies extending across one cortex. There were 52% of patients who had either active (unhealed) fractures (12%) or active pseudofractures (47%) at baseline. The active fractures and pseudofractures were predominantly located in the femurs, tibia/fibula, and metatarsals of the feet. Assessment of these active fracture/pseudofracture sites at week 24 demonstrated a higher rate of complete healing in the burosumab-twza group compared to placebo. During treatment through week 24, a total of 6 new fractures or pseudofractures appeared in 68 patients receiving burosumab-twza, compared to 8 new abnormalities in 66 patients receiving placebo.

Study 4 (NCT 02537431) was 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 burosumab-twza every four weeks. At study entry, the mean age of patients 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 ten patients as demonstrated by decreases in Osteoid volume/Bone volume (OV/BV) from a mean (SD) score of 26% (12.4) at baseline to 11% (6.5), a change of -57%. Osteoid thickness (O.Th) declined in eleven patients from a mean (SD) of 17 (4.1) micrometers to 12 (3.1) micrometers, a change of -33%. Mineralization lag time (MLt) declined in 6 patients from a mean (SD) of 594 (675) days to 156 (77) days, a change of -74%.

The most common adverse reactions in adults taking burosumab-twza were back pain, headache, restless leg syndrome, decreased vitamin D, dizziness and constipation. The most common adverse reactions in children were headache, injection site reaction, vomiting, decreased vitamin D and pyrexia (fever). Patients taking burosumab-twza may need dose interruption and/or dose reduction based on their serum phosphorus levels.

Tumor-induced Osteomalacia (TIO)

Tumor-induced osteomalacia (TIO), also known as oncogenic osteomalacia, is a rare disease characterized by slow-growing tumors that release excess levels of FGF23, which suppresses renal tubular phosphate reabsorption and the renal production of 1,25 dihydroxy vitamin D. This acquired paraneoplastic syndrome includes biochemical and bone mineralization abnormalities that closely resemble genetic forms of hypophosphatemic rickets. Although primarily found in adults, TIO can occur in children and adolescents. Children with TIO present with clinical features of rickets, including gait disturbances, growth retardation, and skeletal deformities. Burosumab-twza has been found to bind to and inhibit the biological activity of FGF23 restoring renal phosphate reabsorption and increasing the serum concentration of 1,25 dihydroxy vitamin D (Park, 2020; Scheinman et al., 2020; Ultragenyx, 2020a).

In June 2020, the FDA approved Crysvita (burosumab-twza; Ultragenyx) for the treatment of fibroblast growth factor 23 (FGF23)-related hypophosphatemia in tumor-induced osteomalacia associated with phosphaturic mesenchymal tumors that cannot be curatively resected or localized in patients aged 2 years of age and older. FDA approval was based on data from 2 single-arm phase 2 studies [Study 1 (NCT02304367) and Study 2 (NCT02722798)] that included a total of 27 adults with TIO who received burosumab-twza every 4 weeks. "Results from Study 1 showed that 50% of patients (n=7 out of 14) achieved normal phosphate levels with a mean (SD) increase from 1.60 (0.47) mg/dL at baseline to 2.64 (0.76) mg/dL through week 24, which were sustained near or above the lower limit of normal (LLN) through week 144. In Study 2, 69% of patients (n=9 out of 13) achieved normal phosphate levels with a mean (SD) increase from 1.62 (0.49) mg/dL at baseline to 2.63 (0.87) mg/dL through week 24 and were sustained near or above the LLN through week 88. Additionally, radiographic evaluation of patients in Study 1 showed a reduction in the number of areas of tracer uptake with long-term treatment, suggesting healing of bone lesions related to osteomalacia. In TIO, increased tracer uptake is presumed to be nontraumatic fractures and pseudofractures" (Park, 2020).

Study 1 (NCT02304367) and Study 2 (NCT02722798) inclusion criteria consisted of adult participants having a fasting serum phosphorus level less than 2.5 mg/dL, an iFGF23 level greater than or equal to 100 pg/mL by Kainos assay, a ratio of renal tubular maximum reabsorption rate of phosphate to glomerular filtration rate (TmP/GFR) less than 2.5 mg/dL, and a clinical diagnosis of TIO/ENS based on evidence of excessive FGF23 that is not amenable to cure by surgical excision of the offending tumor/lesion (Ultragenyx, 2019, 2020b).

Safety and effectiveness of Crysvita in pediatric patients 2 years and older with TIO are supported by evidence from the studies in adult patients with TIO with additional modeling and simulation of PK data from adult and pediatric XLH patients and adult TIO patients to inform dosing (Ultragenyx, 2020a).

Scheinman et al (2020) state that clinical trials of burosumab in adults with TIO resulted in improved parameters of osteomalacia as observed in bone biopsies following one year of monthly injections. Thus, burosumab may be an ideal therapy for the patient with an unresectable TIO tumor or one in which localization has not been realized.

Other Indications

Cutaneous-Skeletal Hypophosphatemia Syndrome 

Khadora and Mughal (2021) stated that cutaneous skeletal hypophosphatemia syndrome (CSHS), also known as epidermal nevus syndrome (ENS) or linear sebaceous nevus syndrome (LSNS), is a rare disorder caused by somatic mosaicism for the gain of function RAS mutations.  Affected patients have segmental epidermal nevi, dysplastic cortical bony lesions, and FGF23-mediated hypophosphatemic rickets.  These researchers described the case of an Emirati girl with CSHS, whose hypophosphatemic rickets and osteomalcic pseudo-fractures and dysplastic bony lesions failed to recover due to poor adherence to treatment with oral phosphate supplements and alfacalcidol (conventional treatment).  Treatment with burosumab led to normalization of serum inorganic phosphate and alkaline phosphatase levels, radiographic healing of rickets, partial healing of pseudo-fractures, improvement in 6-minute walk test (6MWT), and the physical scale of the Pediatric Quality of Life Inventory.  The authors concluded that burosumab was effective in the treatment of CSHS; however, results of the ongoing phase-II clinical trial in adults are awaited. 

Merz et al (2022) noted that epidermal nevus syndromes encompass a highly heterogeneous group of systemic disorders, characterized by epidermal nevi, and a spectrum of neuromuscular, ocular, and bone abnormalities.  Cutaneous-skeletal hypophosphatemia syndrome constitutes a specific sub-entity in which elevated levels of FGF23 cause hypophosphatemic rickets that are, to- date, not amenable to causal therapy.  These investigators report the 1st long-term follow-up of causal treatment with burosumab in a 3-year-old girl with CSHS.  At 4 weeks after initiation of burosumab treatment, serum phosphate normalized to age-appropriate levels.  In addition, long-term follow-up of 42 months revealed significant improvement of linear growth and gross physical functions, including respiratory insufficiency.  Radiographic rickets severity as well as subjective bone pain were strongly reduced, and no side effects were observed over the course of treatment.  The authors concluded that the had gathered first evidence for long-term control of mineral homeostasis, bone morphology and physical activity in a pediatric patient with CSHS and treatment with burosumab.  Moreover, these researchers stated that systematic studies are needed to examine the safety and effectiveness of burosumab for the treatment of CSHS in a larger cohort of pediatric CSHS patients. 

Huynh et al (2022) stated that ENS is caused by a mosaic somatic mutation of RAS (Rat Sarcoma genes) which leads to abnormally elevated levels of FGF23, which is a major regulator in phosphate homeostasis.  There are multiple disorders, along with ENS, that result in unusually high circulating levels of FGF23.  This increase ultimately leads to renal phosphate wasting and reduced levels of 1,25-dihydroxy vitamin D.  Across these disorders, the clinical symptoms are similar and often include osteomalacia (hypophosphatemic rickets in children), muscle weakness, fatigue, joint deformities, bone pain, and fractures.  Burosumab is an IgG1 monoclonal antibody that binds to the FGF23 receptor and inhibits the activity of FGF23.  This results in an increase in serum phosphate levels.  Burosumab emerged as a potential therapy in FGF23 over-activity disorders.  Burosumab was successful in the treatment of XLH and is now FDA-approved for its treatment.  Studies have indicated that burosumab therapy in subjects with XLH consistently increases and sustains serum phosphorus levels and tubular reabsorption of phosphate without a major impact on urine calcium levels or vitamin D metabolism.  These investigators studied the effect of burosumab treatment in a pediatric patient with ENS.  Serum phosphorus rose gradually as these investigators titrated the dose of burosumab upwards.  During treatment, a persistent elevation of parathyroid hormone (PTH) levels was noted along with a persistent elevation of serum calcium.  The authors presumed the patient had tertiary hyperparathyroidism.  However, after the removal of 3 parathyroid glands, the pathology came back with a single enlarged parathyroid adenoma.  Subsequently, his calcium and PTH, and phosphorus levels stabilized while taking only burosumab.  Moreover, these researchers stated that to their knowledge, this report was one of the first to examine the effects of burosumab in ENS (Khadora and Mughal, 2021).  These investigators hope that this report, in addition to others, will highlight the need for further investigation into the use of burosumab in ENS and other FGF23 over-activity disorders.

Fibrous Dysplasia

Gladding and colleagues (2021) noted that fibrous dysplasia/McCune-Albright syndrome (FD/MAS) is a rare mosaic disorder of Gαs activation.  Fibroblast Growth Factor 23 (FGF23)-mediated hypophosphatemia is a feature of FD/MAS that has been associated with poor skeletal outcomes.  Standard therapy includes oral phosphorus and vitamin D analogs; however, treatment is limited by potential adverse renal and gastro-intestinal (GI) effects.  Burosumab, a monoclonal antibody to FGF23, is FDA-approved for the treatment of X-linked hypophosphatemia (HPP) and TIO.  There is currently no safety or efficacy data to support burosumab use in patients with FD/MAS.  These researchers reported the findings of a 7-year-old boy with severe FD/MAS who presented with persistent HPP and skeletal complications despite conventional treatment with oral phosphate and calcitriol.  He was started on burosumab and achieved sustained normalization of serum phosphorus and marked improvement in alkaline phosphatase (APT) levels.  This was accompanied by an encouraging clinical response, including decreased bone pain, improved muscle strength, and improved ambulation.  No adverse effects of burosumab therapy were observed.  The authors concluded that this was the first reported case of burosumab treatment in a patient with FD/MAS.  These researchers stated that the encouraging biochemical and clinical response in this patient highlighted the need for future studies to examine the safety and efficacy of burosumab in the FD/MAS pediatric population.

Tyrosinemia Type 1

Dos Santos and colleagues (2021) stated that the key clinical features of tyrosinemia type 1 usually appear in the 1st months of life, including fever, diarrhea, vomiting, liver involvement, growth failure, as well as renal proximal tubulopathy with subsequent hypophosphatemic rickets.  An early diagnosis is crucial in order to provide specific management and to prevent complications.  These investigators reported on 2 cases referred primarily to pediatric nephrologists for the diagnosis of "neonatal tubulopathy" and management of "X-linked hypophosphatemia (XLH)," respectively.  The authors emphasized that even a mixed tubulopathy can reveal tyrosinemia; and tyrosinemia is a classic differential diagnosis of XLH that should not be forgotten, especially in the era of the anti-FGF23 burosumab.  

Furthermore, an UpToDate review on “Disorders of tyrosine metabolism” (Grompe, 2021) does not mention burosumab as a management / therapeutic option.

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References