X-linked hypophosphatemia (XLH) is a disorder of renal phosphate wasting, defective bone mineralisation, and impaired growth plate or endochondral ossification caused by inactivating mutations in the PHEX gene (phosphate-regulating gene with homologies to endopeptidases on the X chromosome), and is the most common form of heritable rickets. MedDRA version: 19.1 Level: LLT Classification code 10016206 Term: Familial hypophosphataemic rickets System Organ Class: 100000004850
Conditions
Interventions
Product Name: Recombinant human IgG1 monoclonal antibody to fibroblast growth factor 23 [FGF23]
Product Code: KRN23
Pharmaceutical Form: Solution for injection
INN or Proposed INN: Burosumab
CAS Numbe
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 1 to =12 years with radiographic evidence of rickets with a minimum rickets severity score (RSS) total score of 2 as determined by central read 2) PHEX mutation or variant of uncertain significance in either the patient or in a directly related family member with appropriate X-linked inheritance 3) Biochemical findings associated with XLH: Serum phosphorus =65 years) no F.1.3.1 Number of subjects for this age range
Exclusion criteria
Exclusion criteria: Individuals who meet any of the following exclusion criteria will not be eligible to participate in the study: 1) Tanner stage 4 or higher through physical examination 2) Height percentile >50% based on country-specific norms 3) Use of aluminum hydroxide antacids (e.g. Maalox® and Mylanta®), systemic corticosteroids, acetazolamide, and thiazides within 7 days prior to the Screening Visit 4) Current or prior use of leuprorelin (e.g., Lupron®, Viadur®, Eligard®), triptorelin (TRELSTAR®), goserelin (Zoladex®), or other drugs known to delay puberty 5) Use of growth hormone therapy within 12 months before the Screening Visit 6) 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 7) Planned or recommended orthopedic surgery (implantation or removal), including staples, 8-plates or osteotomy, within first 40 weeks of the study 8) Hypocalcemia or hypercalcemia, defined as serum calcium levels outside the age-adjusted normal limits* 9) Evidence of hyperparathyroidism (parathyroid hormone [PTH] levels 2.5X upper limit of normal [ULN]) 10) Use of medication to suppress PTH (e.g., cinacalcet, calcimimetics) within 2 months prior to the Screening Visit 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) History of recurrent infection or predisposition to infection, or of known immunodeficiency 14) Use of a therapeutic monoclonal antibody within 90 days prior to the Screening Visit or history of allergic or anaphylactic reactions to any monoclonal antibody 15) 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 16) 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 OR, in Japan, use of any investigational product or investigational medical device within 4 months prior to screening, or requirement for any investigational agent prior to completion of all scheduled study assessments. * Criteria to be determined based on overnight fasting (min. 4 hours) values collected at the Screening and/or Baseline Visit ** If 25(OH)D levels are below the normal range, 25(OH)D supplementation will be prescribed. Assuming a subject meets all other eligibility requirements, the subject may be rescreened after a minimum of 7 days of treatment.
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Main Objective: • Evaluate the effect of KRN23 therapy in improving rickets in children with XLH compared with active control (oral phosphate/active vitamin D) ;Secondary Objective: Secondary Efficacy Objectives: Evaluate the effects of KRN23 as compared with active control on: • Growth velocity and lower extremity deformity • Pharmacodynamic markers that reflect the status of phosphorus homeostasis, including serum 1,25(OH) 2 D, serum and urinary phosphorus, ratio of renal tubular maximum reabsorption rate of phosphate to glomerular filtration rate (TmP/GFR), and tubular reabsorption of phosphate (TRP) • Biochemical markers of bone turnover that reflect rickets severity (alkaline phosphatase [ALP]) • Walking ability and patient-/parent-reported pain, fatigue, and physical function/mobility Pharmacokinetic Objective: Assess the PK of KRN23 throughout the dosing cycle Safety Objective: Evaluate the safety and tolerability profile of KRN23 in the treatment of children with XLH (aged 1 to =12 years), including adverse events (AEs) (e.g., nephrocalcinosis), as compared with active control, and immunogenicity profile ;Primary end point(s): The primary endpoint will be compared between the KRN23 and active control groups: • Change in rickets at Week 40 as assessed by the RGI-C global score;Timepoint(s) of evaluation of this end point: week 40 | — |
Secondary
| Measure | Time frame |
|---|---|
| Secondary end point(s): Secondary Efficacy Endpoints: The following secondary endpoints will be compared between the KRN23 and active control groups: • Proportion of subjects with a mean RGI-C global score =+2.0 (substantial healing) at Week 40 and Week 64 • Change in rickets at Week 64 as assessed by the RGI-C global score • Change from baseline in RSS total score at Weeks 40 and 64 • Change in lower extremity skeletal abnormalities, including genu varum and genu valgus, as assessed by the RGI-C long leg score at Weeks 40 and 64 • Change in standing height (or recumbent length in children <2 years) from baseline to Weeks 24, 40, and 64 in cm • Change in height-for-age z-scores from baseline to Weeks 24, 40, 64 • Change in growth velocity from pre-treatment and post-treatment at Weeks 40 and 64 in cm/yr • Pharmacodynamic* assessments including o Change from baseline over time in serum phosphorus o Change from baseline over time in serum 1,25(OH) 2 D, urinary phosphorus, ratio of renal tubular maximum reabsorption rate of phosphate to glomerular filtration rate (TmP/GFR), and tubular reabsorption of phosphate (TRP) o Change and percent change from baseline over time in biochemical markers of bone turnover that reflects rickets severity (alkaline phosphatase [ALP]) * Blood and urine to be collected after a minimum overnight fasting time of 4 hours and prior to drug administration (if applicable) per dosing regimen • Pain, fatigue and physical function: Change from baseline in the PROMIS (Patient-Reported Outcomes Measurement Information System) Pediatric Pain Interference, Physical Function Mobility and Fatigue domain scores (for subjects = 5 years of age at the Screening Visit) at Weeks 24, 40 and 64 • Pain intensity: Change from baseline in the Faces Pain Scale- Revised (FPS-R) (for subjects = 5 years of age at the Screening Visit) at Weeks 24, 40 and 64 • Walking ability: Change from baseline in the Six Minute Walk Test (6MWT) total | — |
Countries
Australia, Canada, Denmark, France, Germany, Ireland, Italy, Japan, Korea, Republic of, Spain, Sweden, United Kingdom, United States
Contacts
Public ContactRegulatory Affairs
Icon Clinical research Ltd
Outcome results
None listed