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

Primary Purpose

Epidermal Nevus Syndrome

Status

Completed

Phase

Phase 4

Locations

United States

Study Type

Interventional

Intervention

Crysvita (burosumab-twza) Treatment

About this trial

This is an interventional treatment trial for Epidermal Nevus Syndrome focused on measuring epidermal nevus syndrome, burosumab-twza

Eligibility Criteria

6 Months - undefined (Child, Adult, Older Adult)MaleDoes not accept healthy volunteers

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.

Sites / Locations

University of Alabama at Birmingham

Arms of the Study

Arm 1

Arm Type

Experimental

Arm Label

Crysvita (burosumab-twza) Treatment

Arm Description

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.

Outcomes

Primary Outcome Measures

The Participant Will Achieve Normal Age-adjusted Phosphorous Levels as Tested by Fasting Serum Lab Values

Checking PO4 levels every two weeks and adjusting doses every 4 weeks in blood

Secondary Outcome Measures

Participant Will Achieve Improving Vitamin D Levels as Measured by Serum Blood Tests.

check Vitamin D 1,25 in blood every 3 months

Participant Will Achieve Improving iPTH Levels as Measured by Serum Blood Tests.

measure PTH levels approximately every 3 months

Participant Will Achieve Improving Calcium Levels as Measured by Serum Blood Tests.

measure Calcium level every 3 months

Participant Will Achieve Improvement of Underlying Skeletal Disease/Rickets as Assessed by Standard Radiographs.

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)

obtain Alkaline phosphatase in blood every 3 months

Full Information

NCT ID

NCT04320316

First Posted

March 11, 2020

Last Updated

September 9, 2022

Sponsor

University of Alabama at Birmingham

Collaborators

Ultragenyx Pharmaceutical Inc

1. Study Identification

Unique Protocol Identification Number

NCT04320316

Brief Title

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

Acronym

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

2. Study Status

Record Verification Date

September 2022

Overall Recruitment Status

Completed

Study Start Date

July 31, 2020 (Actual)

Primary Completion Date

July 31, 2021 (Actual)

Study Completion Date

August 31, 2021 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title

Principal Investigator

Name of the Sponsor

University of Alabama at Birmingham

Collaborators

Ultragenyx Pharmaceutical Inc

4. Oversight

Studies a U.S. FDA-regulated Drug Product

Yes

Studies a U.S. FDA-regulated Device Product

Data Monitoring Committee

5. Study Description

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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study

Epidermal Nevus Syndrome

Keywords

epidermal nevus syndrome, burosumab-twza

7. Study Design

Primary Purpose

Treatment

Study Phase

Phase 4

Interventional Study Model

Single Group Assignment

Masking

None (Open Label)

Allocation

N/A

Enrollment

1 (Actual)

8. Arms, Groups, and Interventions

Arm Title

Crysvita (burosumab-twza) Treatment

Arm Type

Experimental

Arm Description

Intervention Type

Drug

Intervention Name(s)

Crysvita (burosumab-twza) Treatment

Other Intervention Name(s)

no other names available

Intervention Description

KRN23 is a fully human IgG1monoclonal antibody that binds to and inhibits the activity of FGF23, leading to an increase in serum phosphorus levels. It is a potential therapeutic candidate for the treatment of XLH, Tumor-Induced Osteomalacia (TIO), and the rickets/osteomalacia resulting from Epidermal Nevus Syndrome (ENS). All of these conditions are diseases of bone hypomineralization, caused by urinary phosphate wasting due to elevated levels of FGF23.

Primary Outcome Measure Information:

Title

The Participant Will Achieve Normal Age-adjusted Phosphorous Levels as Tested by Fasting Serum Lab Values

Description

Checking PO4 levels every two weeks and adjusting doses every 4 weeks in blood

Time Frame

every 2 week, from baseline to 52 weeks.

Secondary Outcome Measure Information:

Title

Participant Will Achieve Improving Vitamin D Levels as Measured by Serum Blood Tests.

Description

check Vitamin D 1,25 in blood every 3 months

Time Frame

1 year

Title

Participant Will Achieve Improving iPTH Levels as Measured by Serum Blood Tests.

Description

measure PTH levels approximately every 3 months

Time Frame

every 3 months, From Baseline to 52 weeks

Title

Participant Will Achieve Improving Calcium Levels as Measured by Serum Blood Tests.

Description

measure Calcium level every 3 months

Time Frame

every 3 months, From Baseline to 52 weeks

Title

Participant Will Achieve Improvement of Underlying Skeletal Disease/Rickets as Assessed by Standard Radiographs.

Description

Time Frame

baseline scans prior to drug administration

Title

Participant Will Achieve Improving Levels of Alkaline Phosphatase (ALP)

Description

obtain Alkaline phosphatase in blood every 3 months

Time Frame

every 3 months, From baseline to 52 weeks

10. Eligibility

Sex

Male

Minimum Age & Unit of Time

6 Months

Accepts Healthy Volunteers

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.

Overall Study Officials:

First Name & Middle Initial & Last Name & Degree

Hussein Abdul-Latif, MD

Organizational Affiliation

University of Alabama at Birmingham

Official's Role

Principal Investigator

Facility Information:

Facility Name

University of Alabama at Birmingham

City

Birmingham

State/Province

Alabama

ZIP/Postal Code

35233

Country

United States

12. IPD Sharing Statement

Plan to Share IPD

IPD Sharing Plan Description

To be determined

Citations:

PubMed Identifier

35899095

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.

Results Reference

derived

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

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