Burosumab for Fibroblast Growth Factor-23 Mediated Hypophosphatemia in Fibrous Dysplasia

Number participants with any adverse events by grade, up to 4 weeks after the final burosumab dose, was assessed using the National Cancer Institute (NCI), Common Terminology Criteria for Adverse Events (CTCAE), Version 5.0.

Grade 1 Mild; asymptomatic or mild symptoms; clinical or diagnostic observations only; intervention not indicated.

Grade 2 Moderate; minimal, local or noninvasive intervention indicated; limiting age appropriate instrumental ADL.

Grade 3 Severe or medically significant but not immediately life-threatening; hospitalization or prolongation of hospitalization indicated; disabling; limiting self care ADL.

Grade 4 Life-threatening consequences; urgent intervention indicated.

Grade 5 Death related to AE.

Participants with related adverse events up to 4 weeks after the final burosumab dose (48 weeks for adult subjects, 50 weeks for pediatric subjects). Adverse event was assessed using the National Cancer Institute (NCI), Common Terminology Criteria for Adverse Events (CTCAE), Version 5.0. Related adverse event means that there are available evidence that suggests that there is a reasonable possibility that the study drug caused the adverse event.

The proportion of participants who achieved serum phosphate levels within the target range (Z-score -1 to +2) at week 24. Analysis was done by dividing the number of number of participants who achieved serum level by the number of participants analyzed.

The proportion of participants who achieved serum phosphate levels above the target range (Z-score >+2) at any timepoint between baseline and week 48. Analysis was done by dividing the number of number of participants who achieved serum level above the target range by the number of participants analyzed.

Change in serum phosphate level from baseline to week 48. Measurements were taken at baseline and week 48. Analysis was done as change in median value between baseline and week 48. Change = week 48 minus baseline.

Percent change in serum phosphate level from baseline to week 48. Measurements were taken at baseline and week 48. Analysis was done as percent change in median value between baseline and week 48. Change = week 48 minus baseline.

Change in serum 1,25-dihydroxyvitamin D level from baseline to week 48. Measurements were taken at baseline and week 48. Analysis was done as change in median value between baseline and week 48. Change = week 48 minus baseline.

Percent change in serum 1,25-dihydroxyvitamin D level from baseline to 48 weeks. Measurements were taken at baseline and week 48. Analysis was done as percent change in median value between baseline and week 48. Change = 48 weeks minus baseline.

Change in serum ratio of renal tubular maximum reabsorption rate of phosphate to glomerular filtration rate (TmP/GFR) from baseline to week 48. Measurements were taken at baseline and week 48. Analysis was done as change in median value between baseline and week 48. Change = week 48 minus baseline.

Percent change in serum ratio of renal tubular maximum reabsorption rate of phosphate to glomerular filtration rate (TmP/GFR) from baseline to week 48. Measurements were taken at baseline and week 48. Analysis was done as percent change in median value between baseline and week 48. Change = week 48 minus baseline.

Change in fibrous dysplasia lesion activity using Fluorine-18 Sodium Fluoride Positron Emission Tomography/Computed Tomography (18F-NaF PET/CT) scan from baseline to week 48. 18F-NaF PET/CT scan was done at baseline and week 48 and total lesion activity units were calculated from each scan. Change in lesion activity was compared between timepoints, baseline and week 48. Change = 48 weeks minus baseline.

Change in serum procollagen 1 N-terminal propeptide (P1NP) level from baseline to week 48. Measurements were taken at baseline and week 48. Analysis was done as change in median value between baseline and week 48. Change = week 48 minus baseline.

Percent change in serum procollagen 1 N-terminal propeptide (P1NP) level from baseline to week 48. Measurements were taken at baseline and week 48. Analysis was done as percent change in median value between baseline and week 48. Change = week 48 minus baseline.

Change in serum beta crosslaps C-telopeptides (CTX) level from baseline to week 48. Measurements were taken at baseline and week 48. Analysis was done as change in median value between baseline and week 48. Change = week 48 minus baseline.

Percent change in serum beta crosslaps C-telopeptides (CTX) level from baseline to week 48. Measurements were taken at baseline and week 48. Analysis was done as percent change in median value between baseline and week 48. Change = week 48 minus baseline.

Change in serum osteocalcin level from baseline to week 48. Measurements were taken at baseline and week 48. Analysis was done as change in median value between baseline and week 48. Change = week 48 minus baseline.

Percent change in serum osteocalcin level from baseline to week 48. Measurements were taken at baseline and week 48. Analysis was done as percent change in median value between baseline and week 48. Change = week 48 minus baseline.

Change in serum alkaline phosphatase level from baseline to week 48. Measurements were taken at baseline and week 48. Analysis was done as change in median value between baseline and week 48. Change = week 48 minus baseline.

Percent change in serum alkaline phosphatase level from baseline to week 48. Measurements were taken at baseline and week 48. Analysis was done as percent change in median value between baseline and week 48. Change = week 48 minus baseline.

Change in fibrous dysplasia lesion cellularity was assessed by minimally invasive bone biopsies at baseline and week 48 in only adult participants with capacity to consent to procedure. Bone biopsies assessed the count of cell density. Analysis was done as change in median cell density value between baseline and week 48. Change = week 48 minus baseline.

Muscle strength was assessed using the manual muscle test (MMT) scale. MMT is a clinical technique to assess the strength of individual muscles or muscle groups based on ability to move against gravity and resist applied external pressure on a 0-5 scale, with 0 (no contraction), 1 (trace), 2 (poor) (movement with gravity eliminated), 3 (fair) (movement against gravity), 4 (good) (movement against gravity with moderate resistance), and 5 (normal strength). Higher number indicates better muscle resistance and strength. Each muscle group was assessed at baseline and week 48. Analysis was done for each muscle as change between baseline and week 48 (week 48 - baseline).

Muscle range-of-motion was measured as the degree of movement of muscles. Assessment was done at baseline and week 48. Analysis was done as change in median value between baseline and week 48. Change = week 48 minus baseline.

Change in walking speed was measured by the 9-minute walk test from baseline to week 48. The 9-minute walk test (9MWT) is a measure of physical capacity and participants are instructed to run or walk over a time period of nine minutes. The 9-minute walk test distance (9MWD) is the total distance walked in meters during the 9MWT and greater distance walked means better physical capacity. Measurements were taken at baseline and week 48. Analysis was done as change in median value between baseline and week 48. Change = week 48 minus baseline.

The change in quality of life for the adult participants was assessed using the Short Form Health Survey (SF-36). SF-36 is a 36-item patient-reported survey of patient health status that consists of eight scaled scores, which are the weighted sums of the questions in their section. Each scale is directly transformed into a 0-100 scale. The higher the score, the less disability. Measurements were taken at baseline and week 48. Analysis was done as change in median value between baseline and week 48. Change = week 48 minus baseline.

The change in quality of life for the pediatric participants was assessed using the Short-Form Health Survey-10 (SF-10). The Short-Form Health Survey (SF-10) is a 10-item parent-completed questionnaire that covers a wide range of domains affecting a child's functional health and well-being. The SF-10 is scored to produce two norm-based summary scores: a Physical Summary Score (PHS) and a Psychosocial Summary Score (PSS), each with a mean of 50 and a standard deviation of 10. Analysis was based on the PHS. The PHS scale is directly transformed into a 0-100 scale. The higher the score, the less disability. Measurements were taken for the Physical Summary Score (PHS) at baseline and week 48. Analysis was done as change in median value between baseline and week 48. Change = week 48 minus baseline.

The Patient-Reported Outcomes Measurement Information System (PROMIS) Pain Intensity (Pediatric and Parent Proxy version 1.0) domain measures pain intensity in children, with pediatric self-report versions for ages 8-17 and parent proxy-report versions for children aged 5-17. This measure uses a standard scale to assess the level of pain over the past seven days, and for the current moment, providing a quantitative score that reflects the severity of the pain. The scale consist of three items with each scored on a 5-point Likert scale, 1-5 with lowest score of 3 and highest of 15. The raw score is converted to a T-score with a mean of 50 and standard deviation of 10. Higher scores indicates greater pain intensity. Measurements were taken at baseline and week 48. Analysis was done as change in median value between baseline and week 48. Change = week 48 minus baseline.

The Patient-Reported Outcomes Measurement Information System (PROMIS) Pain Intensity (Adult version 2.0) - Pain Intensity domain is a universal, self-report measure of how much pain a person is experiencing. This measure uses a standard scale to assess the level of pain over the past seven days, and for the current moment, providing a quantitative score that reflects the severity of the pain. The scale consist of three items with each scored on a 5-point Likert scale, 1-5 with lowest score of 3 and highest of 15. The raw score is converted to a T-score with a mean of 50 and standard deviation of 10. Higher scores indicates greater pain intensity. Measurements were taken at baseline and week 48. Analysis was done as change in median value between baseline and week 48. Change = week 48 minus baseline.

The Patient Reported Outcome Measurement Information System (PROMIS) (Pediatric and Parent Proxy version 2.0) - Pain Inference Domain assesses how pain impacts daily life, sleep, and enjoyment in children, with the Pediatric version being self-reported by children aged 8-17 and the Parent Proxy version completed by a parent or guardian for their child aged 5-17. This measure uses a standard scale to assess the level of pain interference over the past seven days, and for the current moment, providing a quantitative score that reflects the severity of the pain interference. Each item is rated on a 5-point scale (1-5). The scores are then summed and converted into a T-score, with a mean of 50 and standard deviation of 10. Higher scores indicate greater pain interference. Measurements were taken at baseline and week 48. Analysis was done as change in median value between baseline and week 48. Change = week 48 minus baseline.

The Patient-Reported Outcomes Measurement Information System (PROMIS) (Adult version 1.1) - Pain Inference scale assesses the impact of pain on social, physical, cognitive, emotional, and recreational activities, as well as sleep and life enjoyment. The scale consists of 12 items and each item is rated on a 5-point scale (1-5). The scores are then summed and converted into a T-score, with a mean of 50 and standard deviation of 10. Higher scores indicate greater pain interference. Measurements were taken at baseline and week 48. Analysis was done as change in median value between baseline and week 48. Change = week 48 minus baseline.

The Patient Reported Outcome Measurement Information System (PROMIS) (Pediatric and Parent Proxy version 2.0) Mobility Lower Extremity domain assesses self-perceived mobility in children, with the Pediatric version being self-reported by children aged 8-17 and the Parent Proxy version completed by a parent or guardian for their child aged 5-17. This measure uses a standard scale to assess lower extremity mobility by asking about activities such as getting up from a chair or running over the past seven days. Each item is rated on a 5-point scale (1-5). The scores are then summed and converted into a T-score, with a mean of 50 and standard deviation of 10. Higher scores indicate greater mobility. Measurements were taken at baseline and week 48. Analysis was done as change in median value between baseline and week 48. Change = week 48 minus baseline.

The Patient Reported Outcome Measurement Information System (PROMIS) (Adult version 2.0) Mobility Lower Extremity Domain assesses an adult's self-perceived ability to perform physical tasks related to mobility and lower extremity function, such as getting out of a chair or walking. This measure uses a standard scale to assess lower extremity mobility by asking about mobility activities over the past seven days. Each item is rated on a 5-point scale (1-5). The scores are then summed and converted into a T-score, with a mean of 50 and standard deviation of 10. Higher scores indicate greater mobility. Measurements were taken at baseline and week 48. Analysis was done as change in median value between baseline and week 48. Change = week 48 minus baseline.

The Patient Reported Outcome Measurement Information System (PROMIS) (Pediatric and Parent Proxy version 2.0) Fatigue domain assess the level and impact of fatigue in children and adolescents, with the Pediatric version being self-reported by children aged 8-17 and the Parent Proxy version completed by a parent or guardian for their child aged 5-17. This measure uses a standard scale to assess the level of fatigue over the past seven days. Each item is rated on a 5-point scale (1-5). The scores are then summed and converted into a T-score, with a mean of 50 and standard deviation of 10 based on a US general population. Higher scores indicate worsening fatigue. Measurements were taken at baseline and week 48. Analysis was done as change in median value between baseline and week 48. Change = week 48 minus baseline.

The Patient Reported Outcome Measurement Information System (PROMIS) Functional Assessment of Chronic Illness Therapy Fatigue (FACIT-F) Scale is a 13-item patient-reported outcome (PRO) questionnaire that captures the individual's subjective experience of their fatigue. The fatigue domain is scored on a 5-point Likert scale and converted into standardized T-scores with a mean of 50 and a standard deviation of 10 based on a US general population. Higher score indicates less fatigue. Measurements were taken at baseline and week 48. Analysis was done as change in median value between baseline and week 48. Change = week 48 minus baseline.

Proportion of participants with change in activities of daily living (ADL) questions from baseline to week 48 was assessed using a study developed questionnaire. Participants and/or caregivers were asked to provide a list of three activities of daily living that were affected by fibrous dysplasia skeletal features at home or school/work (e.g., mobility, climbing stairs, dressing, playing with peers, catching a bus, etc.) and to rate the extent of impact upon their activity level using one of the option:

• Very Much Improved
• Much Improved
• Minimally Improved
• No Change
• Minimally Worse
• Much Worse
• Very Much Worse

These activities were assessed at baseline, then reassessed at Week 24 and Week 48. Analysis was done as proportion of participants reporting "much improved" or "very much improved" in Activities of Daily Living Questions. Change = Week 48 minus baseline.