Study of KRN23 (Burosumab), a Recombinant Fully Human Monoclonal Antibody Against Fibroblast Growth Factor 23 (FGF23), in Pediatric Subjects With X-linked Hypophosphatemia (XLH)

A Randomized, Open-Label, Dose Finding, Phase 2 Study to Assess the Pharmacodynamics and Safety of the Anti-FGF23 Antibody, KRN23, in Pediatric Patients With X-linked Hypophosphatemia (XLH)

The objectives of the study are to:

• Identify a dose and dosing regimen of burosumab, based on safety and pharmacodynamic (PD) effect, in pediatric XLH participants
• Establish the safety profile of burosumab for the treatment of children with XLH including ectopic mineralization risk, cardiovascular effects, and immunogenicity profile
• Characterize the pharmacokinetic (PK)/PD profile of the KRN23 doses tested in the monthly (Q4) and biweekly (Q2) dose regimens in pediatric XLH patients
• Determine the PD effects of burosumab treatment on markers of bone health in pediatric XLH patients
• Obtain a preliminary assessment of the clinical effects of burosumab on bone health and deformity, muscle strength, and motor function
• Obtain a preliminary assessment of the effects of burosumab on participant-reported outcomes, including pain, disability, and quality of life in pediatric XLH patients
• Evaluate the long-term safety and efficacy of burosumab

Inclusion

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

3. Diagnosis of XLH supported by ONE 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 FGF23 level > 30 pg/mL by Kainos assay

4. Biochemical findings associated with XLH including:

   • Serum phosphorus ≤ 2.8 mg/dL (0.904 mmol/L)*
   • Serum creatinine within age-adjusted normal range*

5. Standing height < 50th percentile for age and gender using local normative data.

6. Radiographic evidence of active bone disease including rickets in the wrists and/or knees, AND/OR femoral/tibial bowing, OR, for expansion subjects, a Rickets Severity Score (RSS) score in the knee of at least 1.5 as determined by central read.

7. Willing to provide access to prior medical records for the collection of historical growth, biochemical and radiographic data, and disease history.

8. Provide written or verbal assent (if possible) and written informed consent by a legally authorized representative after the nature of the study has been explained, and prior to any research-related procedures.

9. 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.

10. Females who have reached menarche must have a negative pregnancy test at Screening and undergo additional pregnancy testing during the study. If sexually active, male and female subjects must be willing to use an acceptable method of contraception for the duration of the study.

    • Criteria to be determined based on overnight fasting (minimum 4 hours) values collected at Screening Visit 2

Exclusion

1. Use of a pharmacologic vitamin D metabolite or analog (e.g. calcitriol, doxercalciferol, alfacalcidiol, 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 calcimimetics, 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 therapy within 3 months before 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 *

9. Evidence of tertiary hyperparathyroidism as determined by the Investigator

10. Use of medication to suppress parathyroid hormone (PTH) (e.g. Sensipar®, cinacalcet, calcimimetics) 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. Previously diagnosed with 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 recombinant human immunoglobulin G1 (IgG1) monoclonal antibody to FGF23 (burosumab) 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

    • Criteria to be determined based on overnight fasting (minimum 4 hours) values collected at Screening Visit 2