Clinical trial NCT04320316: A Trial to Assess the Safety and Efficacy of KRN23 in Epidermal Nevus Syndrome (ENS)
Official title: An Open Label Trial to Assess the Safety and Efficacy of KRN23, an Investigational Antibody to FGF23, in a Single Pediatric Patient With Epidermal Nevus Syndrome (ENS) and Associated Hypophosphatemic Rickets
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE4
Conditions: Epidermal Nevus Syndrome
Keywords: epidermal nevus syndrome
burosumab-twza
Lead sponsor: University of Alabama at Birmingham
Sponsor class: OTHER
Collaborators: name: Ultragenyx Pharmaceutical Inc
First posted: 2020-03-25
Enrollment: 1
Sex: MALE
Minimum age (years): 6
Standard ages: CHILD
ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

Brief summary: KRN23 is a fully human immunoglobulin monoclonal antibody (mAb) that binds to and inhibits the activity of fibroblast growth factor 23 (FGF23), leading to an increase in serum phosphorus levels. There are multiple disorders that result in unusually high circulating levels of FGF23, which in turn result in renal phosphate wasting and reduced levels of 1,25-dihydroxy vitamin D (1,25\[OH\]2D). Across these disorders the clinical symptoms are similar and often include osteomalacia (and, in children, rickets), muscle weakness, fatigue, bone pain, and fractures. KRN23 has been studied in one of these disorders, X-linked hypophosphatemia (XLH). In single- and repeat-dose clinical studies in subjects with XLH, subcutaneous (SC) administration of KRN23 consistently increased and sustained serum phosphorus levels and tubular reabsorption of phosphate (TRP) without a major impact on urine calcium levels or vitamin D metabolism. Positive results were also observed in a nonclinical pharmacology model of XLH. It is hypothesized that KRN23 may provide clinical benefit in this patient due to the common underlying feature in this patient and in patients with XLH - abnormally elevated FGF23 in the context of low age -adjusted serum phosphorous levels. The primary objective is to study the effect of KRN23 treatment on normalizing age-adjusted fasting serum phosphorous levels in a single pediatric patient with Epidermal Nevus Syndrome associated hypophosphatemic rickets.

Detailed description: KRN23 is a fully human immunoglobulin G1 (IgG1) monoclonal antibody (mAb) that binds to and inhibits the activity of fibroblast growth factor 23 (FGF23), leading to an increase in serum phosphorus levels. There are multiple disorders (each with a unique underlying cause) that result in unusually high circulating levels of FGF23, which in turn result in renal phosphate wasting and reduced (or aberrantly normal in relationship to elevated FGF23) levels of 1,25-dihydroxy vitamin D (1,25\[OH\]2D). Across these disorders the clinical symptoms are similar and often include osteomalacia (and, in children, rickets), muscle weakness, fatigue, bone pain, and fractures. KRN23 has been studied in one of these disorders, X-linked hypophosphatemia (XLH). In single- and repeat-dose clinical studies in subjects with XLH, subcutaneous (SC) administration of KRN23 consistently increased and sustained serum phosphorus levels and tubular reabsorption of phosphate (TRP) without a major impact on urine calcium levels or vitamin D metabolism. Positive results were also observed in a nonclinical pharmacology model of XLH. It is hypothesized that KRN23 may provide clinical benefit in this patient due to the common underlying feature in this patient and in patients with XLH - abnormally elevated FGF23 in the context of low age -adjusted serum phosphorous levels.

Eligibility criteria: Inclusion Criteria:

* Patient has confirmed ENS by physician diagnosis
* Patient has confirmed FGF23 elevations in the context of low serum phosphorous \< 4.1 mg/dL
* Patient able to tolerate KRN23 treatment
* Have a corrected serum calcium level \< 10.8mg/dL
* Have an eGFR \>60 ml/min
* Must be willing in the opinion of the investigator, to comply with study procedures and schedule
* Provide written informed consent by a parent after

Exclusion Criteria:

* Patient should not use CRYSVITA with Oral phosphate or active Vitamin D analogs.
* Patient and investigator should not initiate CRYSVITA if Phosphorus level is within or above normal.
* CRYSVITA is contraindicated in patients with severe renal impairment or end stage renal disease because these conditions are associated with abnormal mineral metabolism.
* The use or enrollment in studies using other investigational therapies including other monoclonal antibodies
* Subject and their Parent not willing or not able to give written informed consent
* In the Investigators opinion, the subject may not be able to meet all the requirements for study participation
* Subject has a history of hypersensitivity to KRN23 excipients that in the opinion of the investigator, places the subject at an increased risk of adverse effects
* Subject has a condition that in the opinion of the investigator could present a concern for subject safety or data interpretation.

Primary outcomes:
measure: The Participant Will Achieve Normal Age-adjusted Phosphorous Levels as Tested by Fasting Serum Lab Values
timeFrame: every 2 week, from baseline to 52 weeks.
Secondary outcomes:
measure: Participant Will Achieve Improving Vitamin D Levels as Measured by Serum Blood Tests.
timeFrame: 1 year
measure: Participant Will Achieve Improving iPTH Levels as Measured by Serum Blood Tests.
timeFrame: every 3 months, From Baseline to 52 weeks
measure: Participant Will Achieve Improving Calcium Levels as Measured by Serum Blood Tests.
timeFrame: every 3 months, From Baseline to 52 weeks
measure: Participant Will Achieve Improvement of Underlying Skeletal Disease/Rickets as Assessed by Standard Radiographs.
timeFrame: baseline scans prior to drug administration
measure: Participant Will Achieve Improving Levels of Alkaline Phosphatase (ALP)
timeFrame: every 3 months, From baseline to 52 weeks
Other outcomes:
Locations:
city: Birmingham
country: United States
facility: University of Alabama at Birmingham
state: Alabama
Study officials:
affiliation: University of Alabama at Birmingham
name: Hussein Abdul-Latif, MD
role: PRINCIPAL_INVESTIGATOR
References:
citation: Huynh C, Gillis A, Fazendin J, Abdullatif H. A case report to assess the safety and efficacy of Burosumab, an investigational antibody to FGF23, in a single pediatric patient with Epidermal Nevus Syndrome and associated hypophosphatemic rickets. Bone Rep. 2022 Jul 20;17:101605. doi: 10.1016/j.bonr.2022.101605. eCollection 2022 Dec.