A Trial to Assess the Safety and Efficacy of KRN23 in Epidermal Nevus Syndrome (ENS)

Phase 4

Completed

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.

Recruitment & Eligibility

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.

Arm && Interventions

Group	Intervention	Description
Crysvita (burosumab-twza) Treatment	Crysvita (burosumab-twza) Treatment	The starting dose will be 0.3 mg/kg to be given every 2 weeks. If required dose may be titrated with increments of 0.1 mg/kg/dose every 4 weeks up to a maximum of dose of 2.0mg/kg (not to exceed 90mg per dose) until phosphorus level is WNL. Patient will receive study drug via SC injection to the abdomen, upper arms, thighs, or buttocks; the injection site will be rotated with each injection. If the dose level exceeds 1.5 mL in volume, the dose should be administered at two injection sites. Duration of treatment is 52 weeks. Subjects that complete treatment through week 52 may have the option to continue KRN23 treatment. If this is warranted based on preliminary efficacy, the current protocol will be amended to allow for an extension.

Primary Outcome Measures

Name	Time	Method
The Participant Will Achieve Normal Age-adjusted Phosphorous Levels as Tested by Fasting Serum Lab Values	every 2 week, from baseline to 52 weeks.	Checking PO4 levels every two weeks and adjusting doses every 4 weeks in blood

Secondary Outcome Measures

Name	Time	Method
Participant Will Achieve Improving Vitamin D Levels as Measured by Serum Blood Tests.	1 year	check Vitamin D 1,25 in blood every 3 months
Participant Will Achieve Improving iPTH Levels as Measured by Serum Blood Tests.	every 3 months, From Baseline to 52 weeks	measure PTH levels approximately every 3 months
Participant Will Achieve Improving Calcium Levels as Measured by Serum Blood Tests.	every 3 months, From Baseline to 52 weeks	measure Calcium level every 3 months
Participant Will Achieve Improvement of Underlying Skeletal Disease/Rickets as Assessed by Standard Radiographs.	baseline scans prior to drug administration	DEXA (dual energy X-ray Absorbometry) scans and whole body x-rays will be taken at baseline. A lower Z score is indicative of poor results. Z score compares the standard deviations of the reading with matched aged persons. The normal range is +2 to - 2 Standard deviations and those are what we call Z scores. A Z score of 0 is the population mean.
Participant Will Achieve Improving Levels of Alkaline Phosphatase (ALP)	every 3 months, From baseline to 52 weeks	obtain Alkaline phosphatase in blood every 3 months

Locations (1): University of Alabama at Birmingham
🇺🇸
Birmingham, Alabama, United States