Study of Burosumab (KRN23) in Adults With Tumor-Induced Osteomalacia (TIO) or Epidermal Nevus Syndrome (ENS)

NCT02304367 | Completed Phase 2 Results

• 1 other identifier: UX023T-CL201
• Study Type: interventional
• Target: 17
• Locations: 1 country
• Sites: 7

Brief Summary

The primary objectives of this study are to evaluate the effect of burosumab treatment on:

• Increasing serum phosphorus levels in adults with TIO or ENS-associated osteomalacia
• Improvement in TIO/ENS-associated osteomalacia as determined by osteoid thickness (O.Th), osteoid surface/bone surface (OS/BS), osteoid volume/bone volume (OV/BV) and mineralization lag time (MLt).

Conditions

Tumor Induced Osteomalacia (TIO); Epidermal Nevus Syndrome (ENS)

Keywords

TIO; ENS; FGF23; KRN23

Outcome Measures

Primary Outcomes (5)

• Percentage of Participants Achieving Mean Serum Phosphorus Levels Above 2.5 mg/dL at the Mid-Point of the Dose Intervals Between Baseline and Week 24

  The percentage of participants achieving mean serum phosphorus levels above the lower limit of normal (LLN; 2.5 mg/dL \[0.81 mmol/L\]) at the mid-point of the dose interval (2 weeks after dosing), as averaged across dose cycles between Baseline and Week 24 (i.e. the average of serum phosphorus levels at Weeks 2, 6, 10, 14 and 22).

  Mid-point of each dose interval from Baseline to Week 24 (Weeks 2, 6, 10, 14 and 22 [there was no study visit at Week 18])

• Change From Baseline to Week 48 in Osteoid Thickness

  Histomorphometry of trans-iliac crest bone biopsies was assessed by a blinded, central reader. Osteoid thickness is the mean thickness of osteoid seams.

  Baseline, Week 48

• Change From Baseline to Week 48 in Osteoid Surface/Bone Surface (OS/BS)

  Histomorphometry of trans-iliac crest bone biopsies was assessed by a blinded, central reader. Osteoid surface/bone surface is expressed as the percentage of bone surface covered in osteoid.

  Baseline, Week 48

• Change From Baseline to Week 48 in Osteoid Volume/Bone Volume (OV/BV)

  Histomorphometry of trans-iliac crest bone biopsies was assessed by a blinded, central reader. Osteoid volume/bone volume is expressed as the percentage of a given volume of bone tissue that consists of unmineralized bone (osteoid).

  Baseline, Week 48

• Change From Baseline to Week 48 in Mineralization Lag Time (MLt)

  Mineralization lag time is a dynamic modeling parameter representing the mean time interval between the formation of osteoid and its subsequent mineralization which can be measured using histomorphometry with double tetracycline labeling. Mlt was calculated by dividing the osteoid width by the mineralizing apposition rate (MAR; the average rate at which new bone mineral is being added on any actively forming surface). If Mlt could not be calculated directly due to low tetracycline uptake, Mlt was imputed according to the following: Mlt = O.Th/(MAR\*MS/OS), where O.Th = osteoid thickness, MAR is imputed as 0.3 μm/day, MS/OS=mineralizing surface/osteoid surface, each measured at the same visit.

  Baseline, Week 48

Secondary Outcomes (44)

• Percentage of Participants Achieving Mean Serum Phosphorus Levels Above 2.5 mg/dL at the End of the Dose Intervals Between Baseline and Week 24

  End of each dose interval from Baseline to Week 24 (Weeks 4, 8, 12, 16, 20, and 24)

• Mean Change From Baseline in Serum Phosphorus Levels at the Mid-Point of the Dose Interval, as Averaged Across Dose Cycles Between Baseline and Week 24

  Baseline and the mid-point of each dose interval from Baseline to Week 24 (Weeks 2, 6, 10, 14 and 22)

• Percent Change From Baseline in Serum Phosphorus Levels at the Mid-Point of the Dose Interval, as Averaged Across Dose Cycles Between Baseline and Week 24

  Baseline and the mid-point of each dose interval from Baseline to Week 24 (Weeks 2, 6, 10, 14 and 22)

• Mean Change From Baseline in Serum Phosphorus Levels at the End of the Dosing Cycle, as Averaged Across Dose Cycles Between Baseline and Week 24

  Baseline and Weeks 4, 8, 12, 16, 20, and 24

• Percent Mean Change From Baseline in Serum Phosphorus Levels at the End of the Dosing Cycle, as Averaged Across Dose Cycles Between Baseline and Week 24

  Baseline and Weeks 4, 8, 12, 16, 20, and 24

Other Outcomes (2)

• Number of Participants With Adverse Events (AEs), Treatment Emergent AEs (TEAEs), Serious TEAEs, and TEAEs Leading to Discontinuation

  From first dose of study drug up to database lock date (July 07, 2021); median duration of treatment in the TIO analysis set was 1594.0 (range: 168-2106) days.

• Number of Participants With Anti-burosumab Antibodies

  From first dose of study drug up to database lock date (July 07, 2021); median duration of treatment in the TIO analysis set was 1594.0 (range: 168-2106) days.

Study Arms (1)

Burosumab

EXPERIMENTAL

Participants received burosumab at a starting dose of 0.3 mg/kg administered subcutaneously (SC) every 4 weeks (Q4W). Doses may have been titrated up to a maximum of 2.0 mg/kg every 2 weeks (Q2W) in order to achieve fasting peak serum phosphorus levels within the target range of 2.5 to 4.0 mg/dL.

Biological: Burosumab

Interventions

Burosumab BIOLOGICAL

Solution for subcutaneous injection

Also known as: KRN23, Crysvita®, UX023

Burosumab

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Have a clinical diagnosis of TIO/ENS-associated osteomalacia based on evidence of excessive fibroblast growth factor 23 (FGF23) that was not amenable to cure by surgical excision of the underlying tumor/lesion (documented by Investigator).
• Be ≥ 18 years of age
• Have a fasting serum phosphorus level \< 2.5 mg/dL
• Have an FGF23 level ≥ 100 pg/mL by Kainos assay
• Have a ratio of renal tubular maximum reabsorption rate of phosphate to glomerular filtration rate (TmP/GFR) \< 2.5 mg/dL
• Have an estimated glomerular filtration rate (eGFR) ≥ 60 mL/min (using Cockcroft-Gault formula). Subjects with eGFR ≥ 30 but \< 60 mL/min will be considered eligible as long as in the opinion of the investigator the decline in renal function is not related to nephrocalcinosis.
• Have a corrected serum calcium level \< 10.8 mg/dL
• Females of child-bearing potential must have a negative urine pregnancy test at Screening and Baseline and be willing to have additional pregnancy tests during the study. Females considered not to be of childbearing potential include those who have not experienced menarche, are post-menopausal (defined as having no menses for at least 12 months without an alternative medical cause) or are permanently sterile due to total hysterectomy, bilateral salpingectomy, or bilateral oophorectomy.
• Be willing to use 2 forms of effective methods of contraception while participating in the study (sexually active subjects) and for 12 weeks after last dose of study drug.
• Be willing to provide access to prior medical records to determine eligibility including imaging, biochemical, and diagnostic, medical, and surgical history data
• Provide written informed consent 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 (in the opinion of the investigator)

You may not qualify if:

• Have a prior diagnosis of human immunodeficiency virus (HIV), hepatitis B and/or hepatitis C
• Have a history of recurrent infection, a predisposition to infection, or a known immunodeficiency
• Are pregnant or breastfeeding at Screening or are planning to become pregnant (self or partner) at any time during the study
• Have participated in an investigational drug or device trial within 30 days prior to Screening or are currently enrolled in another study of an investigational product or device
• Have used a therapeutic monoclonal antibody (mAb), including KRN23, within 90 days prior to Screening or have a history of allergic or anaphylactic reactions to any mAb
• Have or a have a history of any hypersensitivity to KRN23 excipients that, in the judgment of the investigator, places the subject at increased risk for adverse effects
• Have used a pharmacologic vitamin D metabolite or its analog (e.g., calcitriol, doxercalciferol, and paricalcitol), phosphate, or aluminum hydroxide antacids (e.g., Maalox® and Mylanta®) within 2 weeks prior to Screening or during the study
• Have used medication to suppress parathyroid hormone (PTH) (e.g., Sensipar®, cinacalcet, calcimimetics) within 2 months prior to Screening
• Have a history of malignancy within 5 years of study entry with the exception of phosphaturic mesenchymal tumors (PMTs) of the mixed connective tissue type or non-melanoma skin cancers such as basal cell skin cancer
• Have donated blood or blood products within 60 days prior to Screening
• Have a history of allergic reaction to or have shown adverse reactions to a tetracycline (e.g., tetracycline hydrochloride \[HCl\] and demeclocycline), benzodiazepines, fentanyl or lidocaine
• Have any condition, which in the opinion of the investigator and sponsor, could present a concern for either subject safety or difficulty with data interpretation

Sponsors & Collaborators

• Kyowa Kirin, Inc.: lead

Study Sites (7)

Colorado Center for Bone Research at Panorama Orthopedics and Spine Center

Golden, Colorado, 80401, United States

Location

Yale University School of Medicine

New Haven, Connecticut, 06510, United States

Location

Indiana University Hospital

Indianapolis, Indiana, 46202, United States

Location

Johns Hopkins University

Baltimore, Maryland, 21224, United States

Location

Mayo Clinic

Rochester, Minnesota, 55905, United States

Location

Duke University

Durham, North Carolina, 27710, United States

Location

Houston Methodist Research Institute

Houston, Texas, 77030, United States

Location

Related Publications (1)

• Khadora M, Mughal MZ. Burosumab treatment in a child with cutaneous skeletal hypophosphatemia syndrome: A case report. Bone Rep. 2021 Oct 1;15:101138. doi: 10.1016/j.bonr.2021.101138. eCollection 2021 Dec.

  PMID: 34660853 DERIVED

MeSH Terms

Conditions

Oncogenic osteomalacia; Nevus, Sebaceous of Jadassohn

Interventions

burosumab

Condition Hierarchy (Ancestors)

Nevus; Nevi and Melanomas; Neoplasms by Histologic Type; Neoplasms; Neurocutaneous Syndromes; Nervous System Diseases; Abnormalities, Multiple; Congenital Abnormalities; Congenital, Hereditary, and Neonatal Diseases and Abnormalities

Results Point of Contact

• Title: Medical Information
• Organization: Ultragenyx Pharmaceutical Inc

Medinfo@ultragenyx.com

1-888-756-8657

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: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR
• Expanded Access: Yes

Study Record Dates

• First Submitted: November 24, 2014
• First Posted: December 1, 2014
• Study Start: March 24, 2015
• Primary Completion: July 27, 2017
• Study Completion: January 21, 2021
• Last Updated: May 6, 2024
• Results First Posted: July 30, 2020

Record last verified: 2024-05

Locations

US (7)