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 6 months of age and older, and for the treatment of fibroblast growth factor 23 (FGF23)-related hypophosphatemia in tumor-induced osteomalacia (TIO) associated with phosphaturic mesenchymal tumors (PMTs) that cannot be curatively resected or localized in individuals at least 2 years of age.
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).
TIO is an extremely rare paraneoplastic syndrome where PMTs secrete excessive FGF23 and cause phosphate wasting and chronic hypophosphatemia. PMTs are small, and slow-growing, and can occur in soft tissue or in the bones throughout the body. Clinical manifestations include bone pain, skeletal deformities, fractures, muscle weakness, and gait disturbances. Treatments includes surgical excision when the tumor is resectable, or medical treatment for tumors that are not resectable, not completely excised, have recurred, or metastasized.
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 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%.
A Phase 2, open-label, single-arm study enrolled 14 adult individuals with a confirmed diagnosis of FGF23-related hypophosphatemia produced by an underlying tumor that was not amenable to surgical excision or could not be located. Individuals received burosumab-twza (Crysvita®) every 4 weeks at a weight based starting dose of 0.3 mg/kg that was titrated to achieve a fasting serum phosphorus level of 2.5 to 4.0 mg/dL. CRYSVITA increased mean serum phosphorus levels from 1.60 (0.47) mg/dL at baseline to 2.64 (0.76) mg/dL averaged across the midpoint of dose intervals through Week 24 with 50% of patients achieving a mean serum phosphorus level above the lower limits of normal (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. Treatment was associated with improved serum phosphorus levels, as well as fewer symptoms of osteomalacia. Improved mobility, reduction in fatigue and a decrease in pain levels were also seen.
A Phase 2, open-label, single-arm study with 13 adult individuals with a confirmed diagnosis of TIO received burosumab-twza (Crysvita®). Of the 13 TIO individuals who received treatment, six were male, and ranged from 41 years to 73 years of age. Individuals received burosumab-twza (Crysvita®) every 4 weeks at a weight based starting dose of 0.3 mg/kg that was titrated to achieve a fasting serum phosphorus level of 2.5 to 4.0 mg/dL. Burosumab-twza (Crysvita®) increased mean serum phosphorus levels from 1.62 (0.49) mg/dL at baseline to 2.63 (0.87) mg/dL averaged across the midpoint of dose intervals through Week 24 with 69% of individuals 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 increased from a mean (SD) of 1.15 (0.43) mg/dL at baseline to 2.30 mg/dL (0.48) mg/dL at Week 48. Improved phosporus levels were noted, as well as fewer symptoms of osteomalacia. No changes in reported levels of fatigue were noted.
Safety and effectiveness in pediatric individuals 6 months to 1 year are supported by evidence from the studies in pediatric individuals with additional modeling and simulation of adult and pediatric pharmacokinetic (PK) and pharmacodynamic (PD) data to inform dosing.
Burosumab-twza (Crysvita®) should be interrupted if an individual's phosphorus levels 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 are individuals with a previous serious hypersensitivity reaction to burosumab-twza (Crysvita®).
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.