Study of the Anti-FGF23 Antibody, Burosumab, in Adults With XLH
Study of the Anti-FGF23 Antibody, Burosumab, in Adults With XLH
This is phase 3b open-label, international, multicenter study to continue to monitor the
 long-term safety and efficacy of burosumab in adult patients with XLH that participated in
 previous clinical trials with burosumab (UX023-CL303 / UX023-CL304).
XLH is a rare, genetic disorder that is serious, chronically debilitating and represents an
 unmet medical need. XLH is the most common inherited form of rickets and the most common
 inherited defect in renal tubular phosphate transport. XLH is transmitted as an X-linked
 dominant disorder. Mutations resulting in the loss of function of PHEX form the genetic basis
 for XLH. More than 300 different PHEX gene mutations have been identified in patients with
 XLH (PHEXdb); however, few definitive correlations have been observed between specific
 mutations and phenotypic severity.

 Patients with XLH have hypophosphatemia due to excessive serum FGF23 levels. FGF23 reduces
 serum phosphorus levels by two distinct mechanisms of action. The primary mechanism is to
 inhibit phosphate reabsorption in the proximal tubule of the kidney. The secondary mechanism
 is to decrease phosphate absorption by the small intestine through the inhibition of
 1,25(OH)2D production in the kidney.

 Burosumab has the potential to block or reduce FGF23 action and improve phosphate homeostasis
 in XLH patients. Burosumab binds the amino-terminal domain of FGF23 that interacts with the
 FGF-binding portion of the combination FGFR1/Klotho receptor, preventing FGF23 from binding
 to and signaling from its receptor. Both intact and fragmented FGF23 polypeptides are
 immunoprecipitated with burosumab. By inhibiting FGF23, burosumab restores tubular
 reabsorption of phosphate (as measured by the ratio of renal tubular maximum reabsorption
 rate of phosphate to glomerular filtration rate [TmP/GFR]) from the kidney and increases the
 production of 1,25(OH)2D that also enhances intestinal absorption of phosphate. The dual
 action on kidney reabsorption and intestinal absorption improves serum phosphorus levels,
 which is expected to improve bone mineralization and reduce the diverse bone and non-bone
 manifestations associated with hypophosphatemia in XLH patients.
Inclusion Criteria:

 1. Subjects who provide written informed consent after the nature of the study has been
 explained, and prior to any research-related procedures.

 2. Subjects who participated in Study UX023-CL303 or UX023-CL304. Any subjects that did
 not complete Study UX023-CL303 or UX023-CL304 may be included on a case-by-case basis.
 Subjects' enrolment is not dependent on any response to Primary or Secondary endpoints
 in studies UX023-CL303 or UX023-CL304.

 3. Willing to provide access to prior medical records for the collection of historical
 growth, biochemical and radiographic data, and disease history.

 4. Must, in the opinion of the investigator, be willing and able to complete all aspects
 of the study, adhere to the study visit schedule and comply with the assessments.

 5. Females of child-bearing potential must have a negative urine pregnancy test at
 Screening and be willing to have additional pregnancy tests during the study. Females
 considered not to be of child-bearing potential include those who have been in
 menopause for at least two years prior to Screening, or have had tubal ligation at
 least one year prior to Screening, or have had a total hysterectomy or bilateral
 salpingo-oophorectomy. If sexually active, male and female subjects must be willing to
 use one highly effective method of contraception for the duration of the study.

 Exclusion Criteria:

 1. Hypocalcemia or hypercalcemia, defined as serum calcium levels outside the
 age-adjusted normal limits and deemed as clinically significant in the opinion of the
 investigator.

 2. Presence of a concurrent disease or condition that would interfere with study
 participation or affect safety in the opinion of the investigator or Sponsor.

 3. Use of any investigational product other than burosumab or investigational medical
 device within 30 days prior to Screening, or requirement for any investigational agent
 prior to completion of all scheduled study assessments.

 4. Subjects with major protocol deviations in Study UX023-CL303 or UX023-CL304 which in
 the view of the investigator places the subject at high risk of poor treatment
 compliance or of not completing the study.

 5. Subjects who discontinued treatment from Study UX023-CL303 or UX023-CL304 due to
 either a grade ≥3 treatment-related hypersensitivity reaction or a burosumab-related
 hypersensitivity reaction reported as a SAE.