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

A Phase 2 Open-Label Trial to Assess the Efficacy and Safety of KRN23, an Antibody to FGF23, in Subjects With Tumor-Induced Osteomalacia (TIO) or Epidermal Nevus Syndrome (ENS)-Associated Osteomalacia

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).

Inclusion Criteria:

1. 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).
2. Be ≥ 18 years of age
3. Have a fasting serum phosphorus level < 2.5 mg/dL
4. Have an FGF23 level ≥ 100 pg/mL by Kainos assay
5. Have a ratio of renal tubular maximum reabsorption rate of phosphate to glomerular filtration rate (TmP/GFR) < 2.5 mg/dL
6. 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.
7. Have a corrected serum calcium level < 10.8 mg/dL
8. 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.
9. 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.
10. Be willing to provide access to prior medical records to determine eligibility including imaging, biochemical, and diagnostic, medical, and surgical history data
11. Provide written informed consent after the nature of the study has been explained, and prior to any research-related procedures
12. 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)

Exclusion Criteria:

1. Have a prior diagnosis of human immunodeficiency virus (HIV), hepatitis B and/or hepatitis C
2. Have a history of recurrent infection, a predisposition to infection, or a known immunodeficiency
3. Are pregnant or breastfeeding at Screening or are planning to become pregnant (self or partner) at any time during the study
4. 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
5. 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
6. 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
7. 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
8. Have used medication to suppress parathyroid hormone (PTH) (e.g., Sensipar®, cinacalcet, calcimimetics) within 2 months prior to Screening
9. 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
10. Have donated blood or blood products within 60 days prior to Screening
11. 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
12. 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