Study of the Safety, Pharmacodynamics (PD) and Efficacy of KRN23 in Children From 1 to 4 Years Old With X-linked Hypophosphatemia (XLH)

Study Overview
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Brief Summary
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The primary objectives of the study are to: Establish the safety profile of KRN23 for the treatment of XLH in children between 1 and 4 years old Determine the PD effects of KRN23 treatment on serum phosphorus and other PD markers that reflect the status of phosphate homeostasis in children between 1 and 4 years old with XLH

Official Title
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An Open-Label, Phase 2 Study to Assess the Safety, Pharmacodynamics, and Efficacy of KRN23 in Children From 1 to 4 Years Old With X-linked Hypophosphatemia (XLH)

Conditions
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X-Linked Hypophosphatemia

Intervention / Treatment
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* Biological: Burosumab


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Male or female, aged ≥1 year and <5 years Diagnosis of XLH supported by ONE or more of the following Confirmed phosphate regulating gene with homology to endopeptidases located on the X chromosome (PHEX) mutation in the patient or a directly related family member with appropriate X-linked inheritance Serum fibroblast growth factor 23 (FGF23) level > 30 pg/mL by Kainos assay Biochemical findings associated with XLH including: Serum phosphorus < 3.0 mg/dL (0.97 mmol/L) Serum creatinine within age-adjusted normal range Radiographic evidence of rickets Willing to provide access to prior medical records for the collection of historical growth, biochemical, and radiographic data and disease history Provide written informed consent by a legally authorized representative after the nature of the study has been explained, and prior to any research-related procedures Must, in the opinion of the investigator, be willing and able to complete all aspects of the study, adhere to the study visit schedule, and comply with the assessments Exclusion Criteria: Unwilling to stop treatment with oral phosphate and/or pharmacologic vitamin D metabolite or analog (e.g. calcitriol, alfacalcidol) during the screening period and for the duration of the study Presence of nephrocalcinosis on renal ultrasound grade 4 based on the following scale: 0 = Normal, 1 = Faint hyperechogenic rim around the medullary pyramids, 2 = More intense echogenic rim with echoes faintly filling the entire pyramid, 3 = Uniformly intense echoes throughout the pyramid, 4 = Stone formation: solitary focus of echoes at the tip of the pyramid Planned or recommended orthopedic surgery including staples, 8-plates or osteotomy, within the clinical trial period Hypocalcemia or hypercalcemia, defined as serum calcium levels outside the age-adjusted normal limits Presence or history of any condition that, in the view of the investigator, places the subject at high risk of poor treatment compliance or of not completing the study Presence of a concurrent disease or condition that would interfere with study participation or affect safety History of recurrent infection or predisposition to infection, or of known immunodeficiency Use of any investigational product or investigational medical device within 30 days prior to screening, or requirement for any investigational agent prior to completion of all scheduled study assessments

Ages Eligible for Study
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Minimum Age: 1 Year
Maximum Age: 4 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Burosumab Q2W<br>Burosumab subcutaneous (SC) injections every 2 weeks (Q2W) for a total of 160 weeks. | Biological: Burosumab<br>* solution for subcutaneous injection<br>* Other names: UX023;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change From Baseline at Week 40 in Serum Phosphorus | The Generalized Estimation Equation (GEE) model includes the change from baseline as the dependent variable, time as the categorical variable and adjusted for baseline measurement, with exchangeable covariance structure. | Baseline, Week 40 | 
| Number of Participants With Adverse Events (AEs), Treatment Emergent AEs (TEAEs), Serious TEAEs, and TEAEs Leading to Discontinuation | An AE was defined as any untoward medical occurrence associated with the use of a drug, whether or not considered drug related. A serious AE was defined as an AE that at any dose, in the view of either the Investigator or Sponsor, results in any of the following outcomes: death, a life-threatening AE, inpatient hospitalization or prolongation of existing hospitalization, persistent or significant incapacity or disability, a congenital anomaly/birth defect, or other important medical events (according to the investigator). An AE was considered a TEAE if it occurred on or after the first dose and was not present prior to the first dose, or it was present prior to the first dose but increased in severity during the study. Events were graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) version 4.0: grade 1 (mild), grade 2 (moderate), grade 3 (severe), grade 4 (life-threatening), grade 5 (death). | From first dose of study drug through the end of the study (Week 160). Maximum duration of exposure to study drug was 160 weeks. | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Radiographic Global Impression of Change (RGI-C) Score at Week 40 | Changes in the severity of rickets and bowing were assessed centrally by three independent pediatric radiologists contracted by a central imaging facility using a disease specific qualitative RGI-C scoring system. The RGI-C is a seven point ordinal scale with possible values: +3 = very much better (complete or near complete healing of rickets), +2 = much better (substantial healing of rickets), +1 = minimally better (i.e., minimal healing of rickets), 0 = unchanged, -1 = minimally worse (minimal worsening of rickets), -2 = much worse (moderate worsening of rickets), -3 = very much worse (severe worsening of rickets). The Analysis of Covariance (ANCOVA) model includes the RGI-C score as the dependent variable, age and RSS at baseline as covariates. | Week 40 | 
| RGI-C Score at Week 64 | Changes in the severity of rickets and bowing were assessed centrally by three independent pediatric radiologists contracted by a central imaging facility using a disease specific qualitative RGI-C scoring system. The RGI-C is a seven point ordinal scale with possible values: +3 = very much better (complete or near complete healing of rickets), +2 = much better (substantial healing of rickets), +1 = minimally better (i.e., minimal healing of rickets), 0 = unchanged, -1 = minimally worse (minimal worsening of rickets), -2 = much worse (moderate worsening of rickets), -3 = very much worse (severe worsening of rickets). The GEE model includes the RGI-C score as the dependent variable, visit as a factor, age and RSS at baseline as covariates, with exchangeable covariance structure. | Week 64 | 
| Change From Baseline in Rickets at Week 40 as Assessed by the RSS Total Score | The RSS system is a 10-point radiographic scoring method that was developed to assess the severity of nutritional rickets in the wrists and knees based on the degree of metaphyseal fraying, cupping, and the proportion of the growth plate affected. Scores are assigned for the unilateral wrist and knee X-rays deemed by the rater to be the more severe of the bilateral images. The maximum total score on the RSS is 10 points and the minimum score is 0, with a total possible score of 4 points for the wrists and 6 points for the knees. Higher scores indicate greater rickets severity.The ANCOVA model includes the RGI-C score as the dependent variable, age and RSS at baseline as covariates. | Baseline, Week 40 | 
| Change From Baseline in Rickets at Week 64 as Assessed by the RSS Total Score | The RSS system is a 10-point radiographic scoring method that was developed to assess the severity of nutritional rickets in the wrists and knees based on the degree of metaphyseal fraying, cupping, and the proportion of the growth plate affected. Scores are assigned for the unilateral wrist and knee X-rays deemed by the rater to be the more severe of the bilateral images. The maximum total score on the RSS is 10 points, with a total possible score of 4 points for the wrists and 6 points for the knees. Higher scores indicate greater rickets severity. The GEE model includes the change from baseline in RSS as the dependent variable, visit as a factor, age and RSS at baseline as covariates, with exchangeable covariance structure. | Baseline, Week 64 | 
| RGI-C Lower Limb Deformity Score at Week 40 | Changes in the severity of lower extremity skeletal abnormalities were assessed centrally by three independent pediatric radiologists contracted by a central imaging facility using a disease specific qualitative RGI-C scoring system. The RGI-C is a seven point ordinal scale with possible values: +3 = very much better (complete or near complete healing of rickets), +2 = much better (substantial healing of rickets), +1 = minimally better (i.e., minimal healing of rickets), 0 = unchanged, -1 = minimally worse (minimal worsening of rickets), -2 = much worse (moderate worsening of rickets), -3 = very much worse (severe worsening of rickets). The ANCOVA model includes the RGI-C score as the dependent variable, age and RSS at baseline as covariates. | Week 40 | 
| RGI-C Lower Limb Deformity Score at Week 64 | Changes in the severity of lower extremity skeletal abnormalities were assessed centrally by three independent pediatric radiologists contracted by a central imaging facility using a disease specific qualitative RGI-C scoring system. The RGI-C is a seven point ordinal scale with possible values: +3 = very much better (complete or near complete healing of rickets), +2 = much better (substantial healing of rickets), +1 = minimally better (i.e., minimal healing of rickets), 0 = unchanged, -1 = minimally worse (minimal worsening of rickets), -2 = much worse (moderate worsening of rickets), -3 = very much worse (severe worsening of rickets). The GEE model includes the RGI-C score as the dependent variable, visit as a factor, age and RSS at baseline as covariates, with exchangeable covariance structure. | Week 64 | 
| Change From Baseline Over Time in Recumbent Length/Standing Height |  | Baseline, Weeks 12, 24, 40, 64, 88, 112, 136, 160 | 
| Change From Baseline Over Time in Recumbent Length/Standing Height as Assessed by Height-for-Age Z-Scores | Recumbent length/Standing height z scores are measures of height adjusted for a child's age and sex. The Z-score indicates the number of standard deviations away from a reference population (from the CDC growth charts) in the same age range and with the same sex. A Z-score of 0 is equal to the mean with negative numbers indicating values lower than the mean and positive values higher. Higher Z-scores indicate a better outcome. | Baseline, Weeks 12, 24, 40, 64, 88, 112, 136, 160 | 
| Change From Baseline Over Time in Recumbent Length/Standing Height as Assessed by Percentiles |  | Baseline, Weeks 12, 24, 40, 64, 88, 112, 136, 160 | 
| Change From Baseline Over Time in Serum Alkaline Phosphatase (ALP) | The GEE model includes the change from baseline as the dependent variable, time as the categorical variable and adjusted for baseline measurement, with exchangeable covariance structure. | Baseline, Weeks 4, 12, 20, 40, 48, 56, 64, 76, 88, 100, 112, 124, 136, 148, 160 | 
| Percent Change From Baseline Over Time in Serum ALP |  | Baseline, Weeks 4, 12, 20, 40, 48, 56, 64, 76, 88, 100, 112, 124, 136, 148, 160 |