X-linked hypophosphatemia (XLH) is a disorder of renal phosphate wasting, and the most common heritable form of rickets. In XLH patients, high circulating levels of fibroblast growth factor 23 (FGF23) impair normal phosphate reabsorption in the kidney. Low serum phosphorus levels result in hypomineralization of bone and associated abnormalities including rickets, bowing of the legs, and short stature. MedDRA version: 20.0 Level: LLT Classification code 10016206 Term: Familial hypophosphataemi
Conditions
Interventions
Product Name: (recombinant human IgG1 monoclonal antibodu to fibroblast growth factor 23 [FGF-23])
Product Code: KRN23
Pharmaceutical Form: Solution for injection
INN or Proposed INN: burosumab
CAS N
Sponsors
Ultragenyx Pharmaceuticals Inc.
Eligibility
Sex/Gender
All
Inclusion criteria
Inclusion criteria: Individuals eligible to participate in this study must meet all of the following criteria: 1) Male or female, aged 5 – 12 years, inclusive, with open growth plates 2) Tanner stage of 2 or less based on breast and testicular development (assessed only in children = 8 years of age) 3) Diagnosis of XLH supported by ONE of the following: - Confirmed PHEX mutation in the patient or a directly related family member with appropriate X-linked inheritance - Serum iFGF23 level > 30 pg/mL by Kainos assay 4) Biochemical findings associated with XLH including: - Serum phosphorus = 2.8 mg/dL (0.904 mmol/L) [criteria to be determined based on overnight fasting (min. 4 hours) values collected at SV2] - Serum creatinine within age-adjusted normal range [criteria to be determined based on overnight fasting (min. 4 hours) values collected at SV2] 5) Standing height =65 years) no F.1.3.1 Number of subjects for this age range 0
Exclusion criteria
Exclusion criteria: Individuals who meet any of the following exclusion criteria will not be eligible to participate in the study: 1) Use of a pharmacologic vitamin D metabolite or analog (e.g. calcitriol, doxercalciferol, and paricalcitol) within 14 days prior to Screening Visit 2; washout will take place during the Screening Period 2) Use of oral phosphate within 7 days prior to Screening Visit 2; washout will take place during the Screening Period 3) Use of aluminum hydroxide antacids (e.g. Maalox® and Mylanta®), systemic corticosteroids, and thiazides within 7 days prior to Screening Visit 1 4) Use of growth hormone from 1 year to 3 months prior to Screening Visit 1 5) Use of bisphosphonates for 6 months or more in the 2 years prior to Screening Visit 1 6) Presence of nephrocalcinosis on renal ultrasound graded = 3 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 7) Planned or recommended orthopedic surgery, including staples, 8-plates or osteotomy, within the clinical trial period 8) Hypocalcemia or hypercalcemia, defined as serum calcium levels outside the age-adjusted normal limits [means criteria to be determined based on overnight fasting (min. 4 hours) values collected at SV2] 9) Evidence of tertiary hyperparathyroidism as determined by the Investigator 10) Use of medication to suppress PTH (e.g. Sensipar®, cinacalcet) within 2 months prior to Screening Visit 1 11) 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. 12) Presence of a concurrent disease or condition that would interfere with study participation or affect safety 13) Positive for human immunodeficiency virus antibody, hepatitis B surface antigen, and/or hepatitis C antibody 14) History of recurrent infection or predisposition to infection, or of known immunodeficiency 15) Use of a therapeutic monoclonal antibody within 90 days prior to Screening Visit 1 or history of allergic or anaphylactic reactions to any monoclonal antibody 16) Presence or history of any hypersensitivity to KRN23 excipients that, in the judgment of the investigator, places the subject at increased risk for adverse effects. 17) 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.
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Secondary Objective: Not applicable;Main Objective: The objectives of the study are to: • Identify a dose and dosing regimen of KRN23, based on safety and PD effect, in pediatric XLH patients • Establish the safety profile of KRN23 for the treatment of children with XLH including ectopic mineralization risk, cardiovascular effects, and immunogenicity profile • Characterize the PK/PD of the KRN23 doses tested in the monthly (Q4) and biweekly (Q2) dose regimens in pediatric XLH patients • Determine the PD effects of KRN23 treatment on markers of bone health in pediatric XLH patients • Obtain a preliminary assessment of the clinical effects of KRN23 on bone health and deformity, muscle strength, and motor function • Obtain a preliminary assessment of the effects of KRN23 on patient-reported outcomes, including pain, disability, and quality of life in pediatric XLH patients ;Primary end point(s): Pharmacodynamic*: • Serum phosphorus • Serum 1,25(OH)2D • Urinary phosphorus • Phosphate reabsorption: ratio of renal tubular maximum reabsorption rate of phosphate to glomerular filtration rate (TmP/GFR), and tubular reabsorption of phosphate (TRP) • Bone biomarkers: procollagen type 1 N-propeptide (P1NP), carboxy-terminal cross-linked telopeptide of type I collagen (CTx), and alkaline phosphatase (ALP) * Blood and urine to be collected after a minimum overnight fasting time of 8 hours and prior to drug administration (if applicable) per dosing regimen Efficacy – Bone Health: • Growth: standing height, sitting height, arm length and leg length will be measured. Growth percentiles based on standing height will be derived prior to and following treatment if historical data are available • Severity of rickets and epiphyseal (growth plate) abnormalities: central readings of bilateral posteroanterior (PA) hand/wrist and anteroposterior (AP) knee radiographs using a disease-specific qualitative Radiograph Global Impression of Change (RGI-C) scoring system and a mo | — |
Secondary
| Measure | Time frame |
|---|---|
| Secondary end point(s): Not applicable;Timepoint(s) of evaluation of this end point: Not applicable | — |
Countries
France, Netherlands, United Kingdom, United States
Contacts
Public ContactRegulatory Affairs
Icon Clinical research Ltd
Outcome results
None listed