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

NCT02163577 | Completed Phase 2 Results DMC

• 1 other identifier: UX023-CL201
• Study Type: interventional
• Target: 52
• Locations: 4 countries
• Sites: 9

Brief Summary

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

Conditions

X-linked Hypophosphatemia

Keywords

X-linked hypophosphatemia; XLH; FGF23; KRN23

Outcome Measures

Primary Outcomes (4)

• Change From Baseline in RSS Total Score Over Time

  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.

  Baseline, Week 40, 64, 160

• Change From Baseline in Serum Phosphorus Over Time

  Baseline, Week 40, 64, 160

• Change From Baseline in Serum 1,25(OH)2D Over Time

  Baseline, Week 40, 64, 160

• Change From Baseline in TmP/GFR Over Time

  Data for urinary phosphorus and TRP were used in calculation TmP/GFR.

  Baseline, Week 40, 64, 160

Secondary Outcomes (25)

• Change From Baseline in RSS Knee Scores Over Time

  Baseline, Week 40, 64, 160

• Change From Baseline in RSS Wrist Scores Over Time

  Baseline, Week 40, 64, 160

• Radiographic Global Impression of Change (RGI-C) Global Scores Over Time

  Baseline, Week 40, 64, 160

• RGI-C Knee Scores Over Time

  Baseline, Week 40, 64, 160

• RGI-C Wrist Scores Over Time

  Baseline, Week 40, 64, 160

Study Arms (2)

Burosumab Q2W

EXPERIMENTAL

Burosumab subcutaneous (SC) injections every 2 weeks (Q2W). Dose was determined by the participant's weight and prescribed dose by their study doctor.

Biological: burosumab

Burosumab Q4W Then Q2W

EXPERIMENTAL

Burosumab SC injections every 4 weeks (Q4W). Dose was determined by the participant's weight and prescribed dose by their study doctor. Participants in Q4W were to switch to Q2W beginning with Week 64 dosing.

Biological: burosumab

Interventions

burosumab BIOLOGICAL

solution for SC injection

Also known as: KRN23, Crysvita®, UX023

Burosumab Q2W; Burosumab Q4W Then Q2W

Eligibility Criteria

• Age: 5 Years - 12 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17)

You may qualify if:

• Male or female, aged 5 - 12 years, inclusive, with open growth plates
• Tanner stage of 2 or less based on breast and testicular development
• 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
• Biochemical findings associated with XLH including:
• Serum phosphorus ≤ 2.8 mg/dL (0.904 mmol/L)\*
• Serum creatinine within age-adjusted normal range\*
• Standing height \< 50th percentile for age and gender using local normative data.
• 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.
• Willing to provide access to prior medical records for the collection of historical growth, biochemical and radiographic data, and disease history.
• 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.
• 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.
• 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

You may not qualify if:

• 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
• Use of oral phosphate within 7 days prior to Screening Visit 2; washout will take place during the Screening Period
• Use of calcimimetics, aluminum hydroxide antacids (e.g. Maalox® and Mylanta®), systemic corticosteroids, and thiazides within 7 days prior to Screening Visit 1
• Use of growth hormone therapy within 3 months before Screening Visit 1
• Use of bisphosphonates for 6 months or more in the 2 years prior to Screening Visit 1
• 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
• 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 \*
• Evidence of tertiary hyperparathyroidism as determined by the Investigator
• Use of medication to suppress parathyroid hormone (PTH) (e.g. Sensipar®, cinacalcet, calcimimetics) within 2 months prior to Screening Visit 1
• 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
• Previously diagnosed with human immunodeficiency virus antibody, hepatitis B surface antigen, and/or hepatitis C antibody
• History of recurrent infection or predisposition to infection, or of known immunodeficiency
• 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

Sponsors & Collaborators

• Kyowa Kirin, Inc.: lead
• Kyowa Kirin Co., Ltd.: collaborator

Study Sites (9)

University of California San Francisco

San Francisco, California, 94158, United States

Location

Yale University School of Medicine

New Haven, Connecticut, 06520-8064, United States

Location

Indiana University Hospital

Indianapolis, Indiana, 46202, United States

Location

Shriners Hospital for Children

St Louis, Missouri, 63110, United States

Location

Bicetre Hospital

Le Kremlin-Bicêtre, 94275, France

Location

University Medical Center Groningen

Groningen, 9700RB, Netherlands

Location

Royal Manchester Hospital

Manchester, Lancashire, M13 9WL, United Kingdom

Location

Birmingham Children's University

Birmingham, B4 6NH, United Kingdom

Location

Great Ormond Street Hospital

London, WC1N3JH, United Kingdom

Location

Related Publications (3)

• Linglart A, Imel EA, Whyte MP, Portale AA, Hogler W, Boot AM, Padidela R, Van't Hoff W, Gottesman GS, Chen A, Skrinar A, Scott Roberts M, Carpenter TO. Sustained Efficacy and Safety of Burosumab, a Monoclonal Antibody to FGF23, in Children With X-Linked Hypophosphatemia. J Clin Endocrinol Metab. 2022 Feb 17;107(3):813-824. doi: 10.1210/clinem/dgab729.

  PMID: 34636899 DERIVED

• Mao M, Carpenter TO, Whyte MP, Skrinar A, Chen CY, San Martin J, Rogol AD. Growth Curves for Children with X-linked Hypophosphatemia. J Clin Endocrinol Metab. 2020 Oct 1;105(10):3243-9. doi: 10.1210/clinem/dgaa495.

  PMID: 32721016 DERIVED

• Carpenter TO, Whyte MP, Imel EA, Boot AM, Hogler W, Linglart A, Padidela R, Van't Hoff W, Mao M, Chen CY, Skrinar A, Kakkis E, San Martin J, Portale AA. Burosumab Therapy in Children with X-Linked Hypophosphatemia. N Engl J Med. 2018 May 24;378(21):1987-1998. doi: 10.1056/NEJMoa1714641.

  PMID: 29791829 DERIVED

MeSH Terms

Conditions

Familial Hypophosphatemic Rickets

Interventions

burosumab

Condition Hierarchy (Ancestors)

Rickets, Hypophosphatemic; Rickets; Bone Diseases, Metabolic; Bone Diseases; Musculoskeletal Diseases; Hypophosphatemia, Familial; Renal Tubular Transport, Inborn Errors; Kidney Diseases; Urologic Diseases; Female Urogenital Diseases; Female Urogenital Diseases and Pregnancy Complications; Urogenital Diseases; Male Urogenital Diseases; Metal Metabolism, Inborn Errors; Metabolism, Inborn Errors; Genetic Diseases, Inborn; Congenital, Hereditary, and Neonatal Diseases and Abnormalities; Metabolic Diseases; Nutritional and Metabolic Diseases; Calcium Metabolism Disorders; Hypophosphatemia; Phosphorus Metabolism Disorders; Vitamin D Deficiency; Avitaminosis; Deficiency Diseases; Malnutrition; Nutrition Disorders

Results Point of Contact

• Title: Medical Information
• Organization: Ultragenyx Pharmaceutical Inc

medinfo@ultragenyx.com

1-888-756-8567

Study Officials

• Medical Director

  Ultragenyx Pharmaceutical Inc

  STUDY DIRECTOR

Publication Agreements

• PI is Sponsor Employee: No
• Restriction Type: OTHER
• Restrictive Agreement: Yes

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR
• Expanded Access: Yes

Study Record Dates

• First Submitted: June 9, 2014
• First Posted: June 13, 2014
• Study Start: July 2, 2014
• Primary Completion: October 30, 2018
• Study Completion: October 30, 2018
• Last Updated: May 6, 2024
• Results First Posted: May 22, 2019

Record last verified: 2024-05

Locations

US (4); GB (3); FR (1); NL (1)