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

Study Overview
=================
Brief Summary
-----------------
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)

Official Title
-----------------
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)

Conditions
-----------------
X-Linked Hypophosphatemia

Intervention / Treatment
-----------------
* Biological: KRN23


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: 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) 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. 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: 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. Presence of nephrocalcinosis on renal ultrasound that, in the opinion of the investigator and sponsor, precludes resuming KRN23 treatment. Pregnant or breastfeeding at Screening or planning to become pregnant (self or partner) at any time during the study. Participation in an investigational drug or device trial within 30 days of enrollment (other than KRN23-INT-001 or KRN23-INT-002). 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. Use of medication to suppress parathyroid hormone (PTH) (e.g., Sensipar®, cinacalcet, calcimimetics) within 2 months prior to Screening.
Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

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 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<br>* solution for SC injection<br>* Other names: Crysvita®;|

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 | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
XLH, FGF23, KRN23