Epidermal Nevus Syndrome
Conditions
Keywords
epidermal nevus syndrome, burosumab-twza
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.
Interventions
DRUGCrysvita (burosumab-twza) Treatment
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.
Sponsors
Ultragenyx Pharmaceutical Inc
University of Alabama at Birmingham
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
MALE
Age
6 Months to No maximum
Healthy volunteers
No
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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 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
| Measure | Time frame | Description |
|---|---|---|
| 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 |
Countries
United States
Participant flow
Recruitment details
recruited 1 patient with Epidermal nevus and hypophosphatemia
Participants by arm
| Arm | Count |
|---|---|
| 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.
Crysvita (burosumab-twza) Treatment: 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.
The primary measure of the study is to see a rise of the phosphorus level to the normal range or as close as possible to the normal range. | 1 |
| Total | 1 |
Baseline characteristics
| Characteristic | Crysvita (Burosumab-twza) Treatment |
|---|---|
| Age, Categorical <=18 years | 1 Participants |
| Age, Categorical >=65 years | 0 Participants |
| Age, Categorical Between 18 and 65 years | 0 Participants |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 1 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Race (NIH/OMB) White | 1 Participants |
| Region of Enrollment United States | 1 participants |
| Sex: Female, Male Female | 0 Participants |
| Sex: Female, Male Male | 1 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | 0 / 1 |
| other Total, other adverse events | 0 / 1 |
| serious Total, serious adverse events | 0 / 1 |
Outcome results
Primary
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
Time frame: every 2 week, from baseline to 52 weeks.
Population: Same as above with only 1 patient
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Crysvita (Burosumab-twza) Treatment | The Participant Will Achieve Normal Age-adjusted Phosphorous Levels as Tested by Fasting Serum Lab Values | baseline | 0.8 mg/dl |
| Crysvita (Burosumab-twza) Treatment | The Participant Will Achieve Normal Age-adjusted Phosphorous Levels as Tested by Fasting Serum Lab Values | 2 week | 1.2 mg/dl |
| Crysvita (Burosumab-twza) Treatment | The Participant Will Achieve Normal Age-adjusted Phosphorous Levels as Tested by Fasting Serum Lab Values | 4 week | 1.3 mg/dl |
| Crysvita (Burosumab-twza) Treatment | The Participant Will Achieve Normal Age-adjusted Phosphorous Levels as Tested by Fasting Serum Lab Values | 6 week | 1.1 mg/dl |
| Crysvita (Burosumab-twza) Treatment | The Participant Will Achieve Normal Age-adjusted Phosphorous Levels as Tested by Fasting Serum Lab Values | 8 week | 1.4 mg/dl |
| Crysvita (Burosumab-twza) Treatment | The Participant Will Achieve Normal Age-adjusted Phosphorous Levels as Tested by Fasting Serum Lab Values | 10 week | 1.7 mg/dl |
| Crysvita (Burosumab-twza) Treatment | The Participant Will Achieve Normal Age-adjusted Phosphorous Levels as Tested by Fasting Serum Lab Values | 12 week | 1.9 mg/dl |
| Crysvita (Burosumab-twza) Treatment | The Participant Will Achieve Normal Age-adjusted Phosphorous Levels as Tested by Fasting Serum Lab Values | 14 week | 1.3 mg/dl |
| Crysvita (Burosumab-twza) Treatment | The Participant Will Achieve Normal Age-adjusted Phosphorous Levels as Tested by Fasting Serum Lab Values | 16 week | 2 mg/dl |
| Crysvita (Burosumab-twza) Treatment | The Participant Will Achieve Normal Age-adjusted Phosphorous Levels as Tested by Fasting Serum Lab Values | 18 week | 2.3 mg/dl |
| Crysvita (Burosumab-twza) Treatment | The Participant Will Achieve Normal Age-adjusted Phosphorous Levels as Tested by Fasting Serum Lab Values | 20 week | 1.8 mg/dl |
| Crysvita (Burosumab-twza) Treatment | The Participant Will Achieve Normal Age-adjusted Phosphorous Levels as Tested by Fasting Serum Lab Values | 22 week | 2.1 mg/dl |
| Crysvita (Burosumab-twza) Treatment | The Participant Will Achieve Normal Age-adjusted Phosphorous Levels as Tested by Fasting Serum Lab Values | 24 week | 2.1 mg/dl |
| Crysvita (Burosumab-twza) Treatment | The Participant Will Achieve Normal Age-adjusted Phosphorous Levels as Tested by Fasting Serum Lab Values | 26 week | 2.3 mg/dl |
| Crysvita (Burosumab-twza) Treatment | The Participant Will Achieve Normal Age-adjusted Phosphorous Levels as Tested by Fasting Serum Lab Values | 28 week | 2.6 mg/dl |
| Crysvita (Burosumab-twza) Treatment | The Participant Will Achieve Normal Age-adjusted Phosphorous Levels as Tested by Fasting Serum Lab Values | 30 week | 2 mg/dl |
| Crysvita (Burosumab-twza) Treatment | The Participant Will Achieve Normal Age-adjusted Phosphorous Levels as Tested by Fasting Serum Lab Values | 32 week | 1.9 mg/dl |
| Crysvita (Burosumab-twza) Treatment | The Participant Will Achieve Normal Age-adjusted Phosphorous Levels as Tested by Fasting Serum Lab Values | 34 week | 1.8 mg/dl |
| Crysvita (Burosumab-twza) Treatment | The Participant Will Achieve Normal Age-adjusted Phosphorous Levels as Tested by Fasting Serum Lab Values | 36 week | 2.1 mg/dl |
| Crysvita (Burosumab-twza) Treatment | The Participant Will Achieve Normal Age-adjusted Phosphorous Levels as Tested by Fasting Serum Lab Values | 38 week | 2.5 mg/dl |
| Crysvita (Burosumab-twza) Treatment | The Participant Will Achieve Normal Age-adjusted Phosphorous Levels as Tested by Fasting Serum Lab Values | 40 week | 2.9 mg/dl |
| Crysvita (Burosumab-twza) Treatment | The Participant Will Achieve Normal Age-adjusted Phosphorous Levels as Tested by Fasting Serum Lab Values | 42 weeks | 2.7 mg/dl |
| Crysvita (Burosumab-twza) Treatment | The Participant Will Achieve Normal Age-adjusted Phosphorous Levels as Tested by Fasting Serum Lab Values | 44 weeks | 1.8 mg/dl |
| Crysvita (Burosumab-twza) Treatment | The Participant Will Achieve Normal Age-adjusted Phosphorous Levels as Tested by Fasting Serum Lab Values | 46 week | 2.4 mg/dl |
| Crysvita (Burosumab-twza) Treatment | The Participant Will Achieve Normal Age-adjusted Phosphorous Levels as Tested by Fasting Serum Lab Values | 48 weeks | 2.6 mg/dl |
| Crysvita (Burosumab-twza) Treatment | The Participant Will Achieve Normal Age-adjusted Phosphorous Levels as Tested by Fasting Serum Lab Values | 50 | 2.5 mg/dl |
| Crysvita (Burosumab-twza) Treatment | The Participant Will Achieve Normal Age-adjusted Phosphorous Levels as Tested by Fasting Serum Lab Values | 52 | 3.3 mg/dl |
Secondary
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.
Time frame: baseline scans prior to drug administration
Population: same as above
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Crysvita (Burosumab-twza) Treatment | Participant Will Achieve Improvement of Underlying Skeletal Disease/Rickets as Assessed by Standard Radiographs. | -3.9 Z score |
Secondary
Participant Will Achieve Improving Calcium Levels as Measured by Serum Blood Tests.
measure Calcium level every 3 months
Time frame: every 3 months, From Baseline to 52 weeks
Population: same as above
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Crysvita (Burosumab-twza) Treatment | Participant Will Achieve Improving Calcium Levels as Measured by Serum Blood Tests. | baseline Calcium | 10.5 mg/dl |
| Crysvita (Burosumab-twza) Treatment | Participant Will Achieve Improving Calcium Levels as Measured by Serum Blood Tests. | 3 months | 10.5 mg/dl |
| Crysvita (Burosumab-twza) Treatment | Participant Will Achieve Improving Calcium Levels as Measured by Serum Blood Tests. | 6 months | 11.2 mg/dl |
| Crysvita (Burosumab-twza) Treatment | Participant Will Achieve Improving Calcium Levels as Measured by Serum Blood Tests. | 9 months | 12 mg/dl |
| Crysvita (Burosumab-twza) Treatment | Participant Will Achieve Improving Calcium Levels as Measured by Serum Blood Tests. | 1 year | 13.4 mg/dl |
Secondary
Participant Will Achieve Improving iPTH Levels as Measured by Serum Blood Tests.
measure PTH levels approximately every 3 months
Time frame: every 3 months, From Baseline to 52 weeks
Population: same as above
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Crysvita (Burosumab-twza) Treatment | Participant Will Achieve Improving iPTH Levels as Measured by Serum Blood Tests. | baseline PTH | 334.5 pg/ml |
| Crysvita (Burosumab-twza) Treatment | Participant Will Achieve Improving iPTH Levels as Measured by Serum Blood Tests. | 3 months | 334.1 pg/ml |
| Crysvita (Burosumab-twza) Treatment | Participant Will Achieve Improving iPTH Levels as Measured by Serum Blood Tests. | 6 months | 317 pg/ml |
| Crysvita (Burosumab-twza) Treatment | Participant Will Achieve Improving iPTH Levels as Measured by Serum Blood Tests. | 9 months | 245.9 pg/ml |
| Crysvita (Burosumab-twza) Treatment | Participant Will Achieve Improving iPTH Levels as Measured by Serum Blood Tests. | 1 year | 330.4 pg/ml |
Secondary
Participant Will Achieve Improving Levels of Alkaline Phosphatase (ALP)
obtain Alkaline phosphatase in blood every 3 months
Time frame: every 3 months, From baseline to 52 weeks
Population: same as above
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Crysvita (Burosumab-twza) Treatment | Participant Will Achieve Improving Levels of Alkaline Phosphatase (ALP) | baseline | 672.4 U/L |
| Crysvita (Burosumab-twza) Treatment | Participant Will Achieve Improving Levels of Alkaline Phosphatase (ALP) | 3 months | 468.3 U/L |
| Crysvita (Burosumab-twza) Treatment | Participant Will Achieve Improving Levels of Alkaline Phosphatase (ALP) | 6 months | 313 U/L |
| Crysvita (Burosumab-twza) Treatment | Participant Will Achieve Improving Levels of Alkaline Phosphatase (ALP) | 9 months | 287 U/L |
| Crysvita (Burosumab-twza) Treatment | Participant Will Achieve Improving Levels of Alkaline Phosphatase (ALP) | 1 year | 185.2 U/L |
Secondary
Participant Will Achieve Improving Vitamin D Levels as Measured by Serum Blood Tests.
check Vitamin D 1,25 in blood every 3 months
Time frame: 1 year
Population: one patient with Epidermal nevus and hypophosphatemia
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Crysvita (Burosumab-twza) Treatment | Participant Will Achieve Improving Vitamin D Levels as Measured by Serum Blood Tests. | Baseline Vit D 1,25 | 15 pg/ml |
| Crysvita (Burosumab-twza) Treatment | Participant Will Achieve Improving Vitamin D Levels as Measured by Serum Blood Tests. | 2 months Vit D 1,25 | 68 pg/ml |
| Crysvita (Burosumab-twza) Treatment | Participant Will Achieve Improving Vitamin D Levels as Measured by Serum Blood Tests. | 6 months Vit D 1,25 | 105 pg/ml |
| Crysvita (Burosumab-twza) Treatment | Participant Will Achieve Improving Vitamin D Levels as Measured by Serum Blood Tests. | 9 months Vita D 1,25 | 95 pg/ml |
| Crysvita (Burosumab-twza) Treatment | Participant Will Achieve Improving Vitamin D Levels as Measured by Serum Blood Tests. | 1 year Vit D 1,25 | 115 pg/ml |