Burosumab for CSHS
Burosumab for CSHS
Burosumab (also known as the drug, Crysvita®) 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. This drug is already approved
 for use in patients with X-linked hypophosphatemia (XLH), but not for Cutaneous Skeletal
 Hypophosphatemia Syndrome (CSHS). It is hypothesized that burosumab may provide clinical
 benefit to a patient with CSHS 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.
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.
 Burosumab has been FDA-approved for one of these disorders, X-linked hypophosphatemia (XLH).
 In single- and repeat-dose clinical studies in subjects with XLH, subcutaneous (SC)
 administration of burosumab consistently increased and sustained serum phosphorus levels and
 tubular reabsorption of phosphate (TRP) and improved radiologic rickets, without a major
 impact on urine calcium levels. Positive results were also observed in a nonclinical
 pharmacology model of XLH. It is hypothesized that burosumab 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.
Inclusion Criteria:

 In order to be eligible to participate in this study, an individual must meet all of the
 following criteria:

 1. Patient has confirmed CSHS by physician diagnosis

 2. Patient has confirmed FGF23 elevations in the context of a low fasting serum
 phosphorous < 2.5 mg/dL

 3. Patient able to tolerate burosumab treatment

 4. Have a corrected serum calcium level < 10.8 mg/dL

 5. Have an eGFR >25 mL/min/1.73m2 (using CKD-EPI equation)

 6. Must be willing in the opinion of the investigators, to comply with study procedures
 and schedule

 7. Provide written informed consent by the subject or a Legal Authorized Representative
 (LAR) after the study has been explained and prior to any research related procedures
 begin

 8. Must have a negative pregnancy test at Screening and be willing to have additional
 pregnancy tests during the study.

 9. Must be willing to use a highly effective method of contraception for the duration of
 the study and for at least 12 weeks after the last dose of the study drug. Highly
 effective methods of contraception include: combined (estrogen and progestogen
 containing) hormonal contraception associated with inhibition of ovulation (e.g.,
 oral, intravaginal, transdermal), progestogen-only hormonal contraception associated
 with inhibition of ovulation (e.g., oral, injectable, implantable), intrauterine
 device (IUD) or intrauterine hormone-releasing system (IUS), bilateral tubal
 occlusion, or sexual abstinence (i.e., refraining from heterosexual intercourse during
 the entire period of risk associated with the study treatments, when this is in line
 with the preferred and usual lifestyle of the subject)

 Exclusion Criteria:

 An individual who meets any of the following criteria will be excluded from participation
 in this study:

 1. Concomitant use of active vitamin D (i.e. calcitriol) and/or exogenous phosphate
 supplementation during burosumab therapy. Subjects will be allowed over the counter
 Vitamin D should levels drop below <20 ng/ml

 2. Blood phosphorus level within or above the normal range while not taking phosphate or
 active Vitamin D.

 3. Severe renal impairment or end-stage renal disease, defined as an eGFR of less than 25
 ml/min/1.73m2

 4. The use or enrollment in studies using other investigational therapies including other
 monoclonal antibodies

 5. Subject or Legally Authorized Representative not willing or not able to give written
 informed consent

 6. In the investigator's opinion, the subject may not be able to meet all the
 requirements for study participation

 7. History of hypersensitivity to burosumab excipients that in the opinion of the
 investigator, places the subject at an increased risk of adverse effects

 8. Subject has a condition that in the opinion of the investigator could present a
 concern for subject safety or data interpretation.