Study to Assess the Safety, Pharmacokinetics and Efficacy of KRN23 in Pediatric Chinese Patients With XLH

Study Overview
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Brief Summary
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The purpose of this study is to assess the safety, pharmacokinetics and efficacy of KRN23 in pediatric Chinese patients with XLH

Official Title
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An Open-label, Multi-center, Single-cohort, Post-marketing Phase 4 Study to Evaluate the Efficacy, Pharmacodynamics, and Safety of the Anti-FGF23 Antibody, KRN23, in Pediatric Chinese Patients With X-linked Hypophosphatemic Rickets/Osteomalacia (XLH)

Conditions
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X-linked Hypophosphatemia (XLH)

Intervention / Treatment
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* Drug: KRN23


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Male or female Chinese patients, aged 1 to ≤12 years at ICF signature with radiographic evidence of rickets Diagnosis of XLH supported by either of the following: Confirmed PHEX mutation (prior to the study with historic record) in the patient or a directly related family member with approximate X linked inheritance Serum intact FGF23 level ≥30 pg/mL by Kainos assay at Screening Able to receive conventional therapy (oral phosphate and pharmacologic vitamin D) Biochemical findings associated with XLH: Serum phosphorus <3.0 mg/dL (0.97 mmol/L). Serum phosphorus may be re tested (once only) at least 7 days after discontinuation of therapy, if applicable ([see Section 3.1]) Serum creatinine within age-adjusted normal range (based on overnight fasting [minimum 4 hours] values collected at Screening) Serum 25(OH)D above or equal to the lower limit of normal (≥16 ng/mL) at Screening. If 25(OH)D levels are below the normal range, 25(OH)D supplementation will be prescribed. Assuming a patient meets all other eligibility requirements, the patient may be re tested for serum 25(OH)D after a minimum of 7 days of treatment Willing to provide access to prior medical records for the collection of historical growth and radiographic data and disease history Written or verbal assent (as appropriate for the patient and region) by the patient and written informed consent by legally authorized representatives provided after the nature of the study has been explained, and prior to any research-related procedures Be willing and able to complete all aspects of the study, adhere to the study visit schedule and comply with the assessments, as judged by the investigator or subinvestigator Female patients who have reached menarche must have a negative pregnancy test at Screening and be willing to have additional pregnancy testing during the study. If sexually active, male and female patients must be willing to use an effective method of contraception for the duration of the study and for 12 weeks after the last dose of IP Exclusion Criteria: Positive for human immunodeficiency virus (HIV) antibody, hepatitis B surface antigen (HBsAg), and/or hepatitis C virus (HCV) antibody at Screening Tanner stage 4 or higher through physical examination Height percentile >50% based on country specific norms Use of a pharmacologic vitamin D, its metabolites, or analogs, oral phosphate for treatment of XLH, aluminum hydroxide antacids, acetazolamide, thiazide diuretics, and/or systemic corticosteroids within 7 days prior to Week -14 Current or prior use of leuprorelin, triptorelin, goserelin, or other drugs known to delay puberty Use of growth hormone therapy within 12 months before ICF signature Have uncontrolled diabetes mellitus, defined as glycated hemoglobin (HbA1c) >8.5% at Screening Presence of nephrocalcinosis on renal ultrasound Grade 4 based on the following scale: Planned or recommended orthopedic surgery (implantation or removal), including staples, 8 plates, or osteotomy, within the first 40 weeks of the study Hypocalcemia or hypercalcemia, defined as serum calcium levels outside the age adjusted normal limits (based on overnight fasting [minimum 4 hours] values collected at the Screening) Evidence of hyperparathyroidism (parathyroid hormone [PTH] levels 2.5 × ULN) Use of medication to suppress PTH (e.g., Sensipar®, cinacalcet, calcimimetics) within 2 months prior to ICF signature Presence or history of any condition that, in the view of the investigator or subinvestigator, 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 therapeutic mAb within 90 days prior to ICF signature or history of allergic or anaphylactic reactions to any mAb Presence or history of any hypersensitivity to KRN23 excipients that, in the judgment of the investigator or subinvestigator, places the patient at increased risk for adverse effects Use of any investigational product or investigational medical device within 30 days prior to ICF signature, or need for the use of any investigational agent prior to completion of all scheduled study assessments Other patients who are considered to be ineligible for the study by the investigator or subinvestigator for reasons other than the above

Ages Eligible for Study
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Minimum Age: 1 Year
Maximum Age: 12 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: KRN23<br>KRN23 0.8 mg/kg starting dose, administered Q2W by SC injection up to Week 64. Before KRN23 treatment, all patients will receive oral phosphate and vitamin D analogs for 12 weeks of Run-in period. | Drug: KRN23<br>* KRN23 is a sterile clear colourless and preservative free solution supplied in single use 5 mL vials containing 1 mL of KRN23 at a concentration of 30mg/mL<br>* Other names: Crysvita;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change from Baseline (CFB) in mean serum phosphorus level at the end of the dose cycle |  | Weeks 2, 4, 8, 12, 16, 24, 32, 40, 52, and 64 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in rickets at Weeks 40 and 64 as examined by the Radiograph Global Impression of Change (RGI-C) global score | Changes in the severity of rickets and bowing were assessed using a disease specific qualitative RGI-C scoring system. The RGI-C is a 7-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). | Weeks 40 and 64 | 
| Change in Rickets Severity Score (RSS) total score at Weeks 40 and 64 | 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, lucency, separation, 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 (the total score is the sum of the wrist and knee score). Higher scores indicate greater rickets severity. | Weeks 40 and 64 | 
| Change in lower extremity skeletal abnormalities, including genu varum and genu valgus, as determined by the RGI-C long leg score at Weeks 40 and 64 | Changes in the severity of lower extremity skeletal abnormalities, including genu varum and genu valgus, were assessed using a disease specific qualitative RGI-C scoring system. The RGI-C is a 7-point ordinal scale with possible values: +3 = very much better (complete or near complete healing), +2 = much better (substantial healing), +1 = minimally better (i.e., minimal healing), 0 = unchanged, -1 = minimally worse (minimal worsening), -2 = much worse (moderate worsening), -3 = very much worse (severe worsening). | Weeks 40 and 64 | 
| Change in serum phosphorus over time |  | Weeks 0, 1, 2, 4, 8, 12, 16, 24, 32, 40, 52, 64, and 74 | 
| Change in serum 1,25-dihydroxyvitamin D (1,25(OH)2D) over time |  | Weeks 0, 1, 2, 4, 8, 12, 16, 24, 32, 40, 52, 64, and 74 | 
| Change in alkaline phosphatase (ALP) over time |  | Weeks 0, 1, 2, 4, 8, 12, 16, 24, 32, 40, 52, 64, and 74 | 
| Change in urinary phosphorus over time |  | Weeks 0, 1, 2, 4, 8, 12, 16, 24, 32, 40, 52, 64, and 74 | 
| Change in ratio of renal tubular maximum reabsorption rate of phosphate to glomerular filtration rate (TmP/GFR; algorithm method) over time |  | Weeks 0, 1, 2, 4, 8, 12, 16, 24, 32, 40, 52, 64, and 74 | 
| Change in recumbent length/standing height in cm, height for age z scores |  | Weeks 0, 24, 40 and 64 | 
| Change in growth velocity from pre-treatment and post-treatment over time |  | Weeks 0, 24, 40 and 64 | 
| Change in growth velocity z scores from pre-treatment and post-treatment over time |  | Weeks 0, 24, 40 and 64 | 
| Six-minute walking test (6MWT) results to examine walking ability (total distance; patients ≥5 years at the time of signing the ICF only) |  | Weeks 0, 24, 40 and 64 | 
| Six-minute walking test (6MWT) results to examine walking ability (percent of predicted normal; patients ≥5 years at the time of signing the ICF only) |  | Weeks 0, 24, 40 and 64 | 
| Ten-item Short Form Health Survey for Children (SF-10) physical domain scores to examine health-related Quality of Life | The SF-10 is a brief, 10-item, guardian-completed assessment designed to measure the physical and psychosocial functioning of children. The physical functioning (PHS) domain includes 5 questions that assess limitations in physical activities because of health problems. The PHS domain score was calculated using norm-based scoring so that 50 is the average score and the standard deviation equals 10. Higher scores are associated with better functioning/quality of life; a positive change from Baseline score indicates an improvement. | Weeks 0, 24, 40 and 64 | 
| Ten-item Short Form Health Survey for Children (SF-10) Psychosocial scores to examine health-related Quality of Life | The SF-10 is a brief, 10-item, guardian-completed assessment designed to measure the physical and psychosocial functioning of children. The Psychosocial functioning (PSS) domain includes 5 questions that assess limitations in psychosocial activities because of health problems. The PHS domain score was calculated using norm-based scoring so that 50 is the average score and the standard deviation equals 10. Higher scores are associated with better functioning/quality of life; a positive change from Baseline score indicates an improvement. | Weeks 0, 24, 40 and 64 | 
| Face Pain Scale-Revised (FPS-R) scores to examine health-related Quality of Life | The FPS-R is a dimensionless 10 point Likert scale used to assess self-reported pain intensity on a scale from 0 (no pain) to 10 (most pain you can imagine). Greater pain scores are indicative of more severe pain. | Weeks 0, 24, 40 and 64 | 
| Patient-Reported Outcomes Measurement Information System (PROMIS) scores to examine health-related Quality of Life | The PROMIS was developed by the National Institutes of Health and uses domain-specific measures to assess patient well-being (Broderick et al. 2013), (NIH 2015). It uses a T-score metric in which 50 is the mean of a relevant reference population and 10 is the standard deviation (SD) of that population. For the Pain Interference Domain, decreases indicate less pain, for the Physical Function Mobility Domain, increases indicate greater mobility and for the Fatigue Domain, decreases indicate less fatigue. | Weeks 0, 24, 40 and 64 |