Long-Term Extension Study of KRN23 in Adult Subjects With X-Linked Hypophosphatemia (XLH)

A Phase 2b, Open-Label, Long-Term Extension Study to Evaluate the Safety and Pharmacodynamics of KRN23 in Adult Subjects With X-Linked Hypophosphatemia (XLH)

The primary objectives of this study are to:

• Assess the long-term safety of KRN23 subcutaneous (SC) administration in adult subjects with XLH
• Assess the proportion of subjects achieving serum phosphorus levels in the normal range (2.5-4.5 mg/dL) with long-term administration of KRN23
• Assess long-term pharmacodynamics (PD) of KRN23 as measured by changes in the following: serum intact parathyroid hormone (iPTH); serum and urinary phosphorus; ratio of renal tubular maximum phosphate reabsorption rate to glomerular filtration rate (TmP/GFR) and tubular reabsorption of phosphate (TRP); serum 1,25-dihydroxy vitamin D (1,25[OH]2D); serum fibroblast growth factor 23 (FGF23); bone biomarkers: serum alkaline phosphatase (ALP), bone-specific ALP (BALP), carboxy terminal crosslinked telopeptide of type I collagen (CTx), and procollagen type 1 N-terminal propeptide (P1NP)
• Assess long-term immunogenicity of KRN23 as measured by presence of anti-KRN23 antibody (ADA)

Study Overview

• Status: Completed
• Conditions: X-Linked Hypophosphatemia
• Intervention / Treatment: Biological: KRN23

• Study Type: Interventional
• Enrollment (Actual): 20
• Phase: Phase 2

Expanded Access

Available outside the clinical trial. See expanded access record.

Contacts and Locations

Study Locations

• United States
  • California
    • San Francisco, California, United States, 94143
      • University California San Francisco Hospital
  • Connecticut
    • New Haven, Connecticut, United States, 06510
      • Yale University School of Medicine
  • Indiana
    • Indianapolis, Indiana, United States, 46202
      • Indiana University Hospital
  • North Carolina
    • Durham, North Carolina, United States, 27710
      • Duke University
  • Texas
    • Houston, Texas, United States, 77030
      • Houston Methodist Reasearch Institute

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Child; Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

1. Have participated in Kyowa Hakko Kirin Pharma, Inc.'s KRN23-INT-001 (NCT01340482) or KRN23-INT-002 (NCT01571596) studies (received at least 2 doses of KRN23)
2. Estimated glomerular filtration rate (eGFR) ≥ 60 mL/min or eGFR of 45 to < 60 mL/min at Screening with confirmation that the renal insufficiency was not due to nephrocalcinosis.
3. Sexually active subjects must be willing to use an acceptable method of contraception (e.g., double barrier method) while participating in the study and for 30 days after receiving the last dose of KRN23.

Exclusion Criteria:

1. Subject experienced a safety-related event in the KRN23-INT-001 or KRN23-INT-002 study that, in the opinion of the investigator and sponsor, precludes resuming KRN23 treatment.
2. Presence of nephrocalcinosis on renal ultrasound that, in the opinion of the investigator and sponsor, precludes resuming KRN23 treatment.
3. Pregnant or breastfeeding at Screening or planning to become pregnant (self or partner) at any time during the study.
4. Participation in an investigational drug or device trial within 30 days of enrollment (other than KRN23-INT-001 or KRN23-INT-002).
5. Use of a pharmacologic vitamin D metabolite or analog (e.g., calcitriol, doxercalciferol, and paricalcitol), phosphate, or aluminum hydroxide antacids (e.g., Maalox® and Mylanta®) within 21 days prior to Screening or during the study.
6. Use of medication to suppress parathyroid hormone (PTH) (e.g., Sensipar®, cinacalcet, calcimimetics) within 2 months prior to Screening.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: KRN23; KRN23 subcutaneous (SC) injections every 4 weeks. Starting doses will be based on the subject's last dose in study KRN23-INT-001 (NCT02312687) or KRN23-INT-002 (NCT01571596). Doses may be titrated to achieve the target peak serum phosphorus range.	Biological: KRN23; solution for SC injection; Other Names: Crysvita®; burosumab

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of Participants With Adverse Events (AEs), Treatment Emergent AEs (TEAEs), Serious AEs (SAEs), and AEs Leading to Discontinuation or Death	An AE is defined as any untoward medical occurrence, whether or not considered drug related. An SAE or serious suspected adverse reaction is an AE or suspected adverse reaction that at any dose, in the view of either the investigator or sponsor, results in any of the following outcomes: death; a life-threatening AE; inpatient hospitalization or prolongation of existing hospitalization; persistent or significant incapacity or substantial disruption of the ability to conduct normal life functions; a congenital anomaly/birth defect; an important medical event. A TEAE is an AE that occurred on or after the first burosumab dose. AEs were graded as 1 (mild), 2 (moderate), 3 (severe), 4 (life-threatening), 5 (death). AEs were classified by the Investigator as possibly related, probably related, or definitely related.	Screening through the end of study plus 4-8 weeks. The mean duration of burosumab exposure was 165.6 weeks (range: 68-184 weeks).
Number of Participants With Clinically Significant Changes From Baseline in Vital Signs	Clinically significant changes from baseline reported as adverse events are presented.	Through Week 184
Number of Participants With Clinically Significant Changes From Baseline in Laboratory Values, by Category	Clinically significant changes from baseline reported as adverse events are presented.	Through Week 184
Number of Participants With Clinically Significant Changes From Baseline in Physical Exams, by Category	Clinically significant changes from baseline reported as adverse events are presented.	Through Week 184
Number of Participants With Clinically Significant Changes From Baseline in Echocardiogram (ECHO) Tests	Clinically significant changes from baseline reported as adverse events are presented.	Through Week 184
Number of Participants With Clinically Significant Changes From Baseline in ECGs	Clinically significant changes from baseline reported as adverse events are presented.	Through Week 184
Number of Participants With Clinically Significant Changes From Baseline in Renal Ultrasound, by Category	Clinically significant changes from baseline reported as adverse events are presented.	Through Week 184
Number of Participants Positive for Anti-KRN23 Antibodies and Neutralizing Antibodies at Baseline and Anytime Post-Baseline		Through Week 184
Percentage of Participants Reaching Serum Phosphorus Normal Range at Baseline and Any Time After Dosing		Through Week 184
Change From Baseline Over Time in Serum Phosphorus		Baseline, Weeks 24, 48, 72, 96, 120, 144
Change From Baseline Over Time in Serum iPTH		Baseline, Weeks 24, 48, 72, 96, 120, 144
Change From Baseline Over Time in Serum Total FGF23		Baseline, Weeks 24, 48, 72, 96, 120, 144
Change From Baseline Over Time in Serum Free FGF23		Baseline, Weeks 24, 48, 72, 96, 120, 144
Change From Baseline Over Time in Serum 1,25(OH)2D		Baseline, Weeks 24, 48, 72, 96, 120, 144
Change From Baseline Ovr Time in 2-hour Urine TmP/GFR		Baseline, Weeks 24, 48, 72, 96, 120, 144
Change From Baseline Over Time in in 2-hour Urine TRP		Baseline, Weeks 24, 48, 72, 96, 120, 144
Change From Baseline Over Time in FEP		Baseline, Weeks 24, 48, 72, 96, 120, 144
Change From Baseline Over Time in 24-hour Urine Phosphorus		Baseline, Weeks 24, 48, 72, 96, 120, 144
Change From Baseline Over Time in 24-Hour Urine Calcium		Baseline, Weeks 24, 48, 72, 96, 120, 144
Change From Baseline Over Time in 24-Hour Urine Creatinine		Baseline, Weeks 24, 48, 72, 96, 120, 144
Change From Baseline Over Time in 24-Hour Urine Calcium/Creatinine Ratio		Baseline, Weeks 24, 48, 72, 96, 120, 144
Change From Baseline Over Time in Total ALP		Baseline, Weeks 24, 48, 72, 96, 120, 144
Change From Baseline Over Time in BALP		Baseline, Weeks 24, 48, 72, 96, 120, 144
Change From Baseline Over Time in CTx		Baseline, Weeks 24, 48, 72, 96, 120, 144
Change From Baseline Over Time in P1NP		Baseline, Weeks 24, 48, 72, 96, 120, 144

Collaborators and Investigators

• Sponsor: Kyowa Kirin, Inc.
• Collaborators: Kyowa Kirin Co., Ltd.

Study record dates

Study Major Dates

• Study Start (Actual): January 30, 2015
• Primary Completion (Actual): November 30, 2018
• Study Completion (Actual): November 30, 2018

Study Registration Dates

• First Submitted: December 3, 2014
• First Submitted That Met QC Criteria: December 5, 2014
• First Posted (Estimate): December 9, 2014

Study Record Updates

• Last Update Posted (Actual): April 18, 2023
• Last Update Submitted That Met QC Criteria: April 14, 2023
• Last Verified: November 1, 2019

More Information

Terms related to this study

• Keywords: FGF23; KRN23; XLH
• Additional Relevant MeSH Terms: Metabolic Diseases; Kidney Diseases; Urologic Diseases; Nutrition Disorders; Genetic Diseases, Inborn; Musculoskeletal Diseases; Avitaminosis; Deficiency Diseases; Malnutrition; Bone Diseases; Metabolism, Inborn Errors; Bone Diseases, Metabolic; Renal Tubular Transport, Inborn Errors; Calcium Metabolism Disorders; Metal Metabolism, Inborn Errors; Phosphorus Metabolism Disorders; Rickets; Vitamin D Deficiency; Rickets, Hypophosphatemic; Hypophosphatemia, Familial; Familial Hypophosphatemic Rickets; Hypophosphatemia
• Other Study ID Numbers: UX023-CL203