Burosumab (also known as the drug, Crysvita®) is a fully human immunoglobulin G1 (IgG1) monoclonal antibody (mAb) that binds to and inhibits the activity of fibroblast growth factor 23 (FGF23), leading to an increase in serum phosphorus levels. This drug is already approved for use in patients with X-linked hypophosphatemia (XLH), but not for Cutaneous Skeletal Hypophosphatemia Syndrome (CSHS). It is hypothesized that burosumab may provide clinical benefit to a patient with CSHS due to the common underlying feature in this patient and in patients with XLH - abnormally elevated FGF23 in the context of low age -adjusted serum phosphorous levels.
There are multiple disorders (each with a unique underlying cause) that result in unusually high circulating levels of FGF23, which in turn result in renal phosphate wasting and reduced (or aberrantly normal in relationship to elevated FGF23) levels of 1,25-dihydroxy vitamin D (1,25\[OH\]2D). Across these disorders the clinical symptoms are similar and often include osteomalacia (and, in children, rickets), muscle weakness, fatigue, bone pain, and fractures. Burosumab has been FDA-approved for one of these disorders, X-linked hypophosphatemia (XLH). In single- and repeat-dose clinical studies in subjects with XLH, subcutaneous (SC) administration of burosumab consistently increased and sustained serum phosphorus levels and tubular reabsorption of phosphate (TRP) and improved radiologic rickets, without a major impact on urine calcium levels. Positive results were also observed in a nonclinical pharmacology model of XLH. It is hypothesized that burosumab may provide clinical benefit in this patient due to the common underlying feature in this patient and in patients with XLH - abnormally elevated FGF23 in the context of low age -adjusted serum phosphorous levels.
Study Type
INTERVENTIONAL
Allocation
NA
Purpose
TREATMENT
Masking
NONE
Enrollment
1
Burosumab, the investigational product, is a recombinant human IgG1 monoclonal antibody targeting FGF23. It is supplied as a sterile, clear, colorless and preservative-free solution and is administered via subcutaneous injection.
Children's National Hospital
Washington D.C., District of Columbia, United States
Serum Phosphorus change
Change from baseline over 52 weeks in serum phosphorus with burosumab treatment.
Time frame: 52 weeks
Changes in 1,25(OH)2-Vitamin D
Changes from baseline over 52 weeks in 1,25(OH)2-Vitamin D
Time frame: 52 weeks
Changes in tubular reabsorption of phosphate (TRP)
Changes from baseline over 52 weeks in tubular reabsorption of phosphate (TRP)
Time frame: 52 weeks
Changes in TmP/GFR (the ratio of renal tubular maximum phosphate reabsorption rate to glomerular filtration rate
Changes from baseline over 52 weeks in TmP/GFR (the ratio of renal tubular maximum phosphate reabsorption rate to glomerular filtration rate
Time frame: 52 weeks
Biomechanical Marker
Effect of burosumab over 52 weeks on biochemical marker of bone turnover that reflects osteomalacia severity: alkaline phosphatase (ALP).
Time frame: 52 weeks
6-minute walk test
Change in walking capacity over 52 weeks as assessed by 6-Minute Walk Test (6MWT)
Time frame: 52 weeks
Sit-to-Stand test (STST)
Change in proximal muscle function over 52 weeks as assessed by the Sit-to-Stand test (STST)
Time frame: 2 weeks
Brief Pain Inventory (BPI)
Change in Patient/parent-Reported Outcomes over 52 weeks as assessed by Brief Pain Inventory (BPI)
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Time frame: 52 weeks
Brief Fatigue Inventory (BFI)
Change in Patient/parent-Reported Outcomes over 52 weeks as assessed by Brief Fatigue Inventory (BFI)
Time frame: 52 weeks
SF36 item short health survey (SF-36)
Change in Patient/parent-Reported Outcomes over 52 weeks as assessed by SF36 item short health survey (SF-36)
Time frame: 52 weeks
PROMIS Pain Intensity
Change in Patient/parent-Reported Outcomes over 52 weeks as assessed by PROMIS Pain Intensity instrument. Pain is rated on a scale of 0-10 where 0 represents no pain and 10 represents the worst possible pain.
Time frame: 52 weeks
PROMIS Pain Interference
Change in Patient/parent-Reported Outcomes over 52 weeks as assessed by PROMIS Pain Interference instrument. Responses are aggregated and converted to a T-score from 0-100 where 50 is the mean and every 10 is one standard deviation from the mean.
Time frame: 52 weeks
PROMIS Physical Function with Mobility Aid
Change in Patient/parent-Reported Outcomes over 52 weeks as assessed by PROMIS Physical Function with Mobility Aid instrument. Responses are aggregated and converted to a T-score from 0-100 where 50 is the mean and every 10 is one standard deviation from the mean.
Time frame: 52 weeks
PROMIS Fatigue
Change in Patient/parent-Reported Outcomes over 52 weeks as assessed by PROMIS Fatigue instrument. Responses are aggregated and converted to a T-score from 0-100 where 50 is the mean and every 10 is one standard deviation from the mean.
Time frame: 52 weeks