Burosumab for Fibroblast Growth Factor-23 Mediated Hypophosphatemia in Fibrous Dysplasia

Background:

Fibrous dysplasia (FD) is a disorder that affects bone growth. Affected bone tissue is weakened, and people with FD are prone to deformities, fractures, and other problems. People with FD may also have low blood phosphate levels. This can make bones even weaker. Better treatments are needed.

Objective:

To test a study drug (burosumab) in people with FD who have low blood phosphate levels.

Eligibility:

People aged 1 year or older who have FD and low blood phosphate levels.

Design:

Participants will visit the NIH 3 times in 48 weeks. Each visit will last 5 to 7 days.

Participants will self-inject burosumab under the skin in their belly, upper arm, or thigh. They (or a caregiver) will do this at home 1 or 2 times a month. They will be trained in person on how to inject the drug. Home injections will be guided via telehealth.

During NIH visits, participants will have a physical exam with blood and urine tests. They will have x-rays of different parts of their body. They will have a radioactive tracer injected into their vein; then they will have a bone scan. They will have tests to assess their strength, walking, and movement. They will complete questionnaires about their pain, mobility, and fatigue levels.

Adult participants may have bone biopsies. These will be done under anesthesia with sedation. Small samples of FD-affected bone will be removed for study.

Between NIH visits, participants will go to a local laboratory for blood and urine tests.

Child participants will have an additional follow-up visit 2 weeks after the final NIH visit.

Study Description:

This will be a phase 2, open-label, single-arm study to evaluate the safety and efficacy of burosumab to normalize serum phosphate levels in subjects with fibrous dysplasia (FD) and fibroblast growth factor 23 (FGF23)-mediated hypophosphatemia.

Objectives:

Primary Objective:

-Evaluate the efficacy of burosumab to normalize serum phosphate levels in subjects with FD and FGF23-mediated hypophosphatemia at 48 weeks.

Secondary Objectives:

* Evaluate the efficacy of burosumab to normalize serum phosphate levels in subjects with FD and FGF23-mediated hypophosphatemia at 24 weeks.
* Evaluate the safety and tolerability of burosumab in patients with FD.
* Evaluate the effect of burosumab on increasing serum phosphate and additional mineral markers.
* Evaluate the impact of burosumab on FD lesion activity.
* Evaluate the effect of burosumab on functional parameters.
* Evaluate the effect of burosumab on pain and health-related quality of life.

Endpoints:

Primary Endpoint:

-The proportion of subjects achieving serum phosphate levels within the target range (Z-score -1 to +2) at Week 48.

Secondary Endpoints:

* Proportion of subjects achieving serum phosphate levels within the target range (Z-score -1 to +2) at Week 24.
* Adverse events and clinical safety laboratory tests for up to 4 weeks after the final burosumab dose (48 weeks for adult subjects, 50 weeks for pediatric subjects).
* Change and percent change from baseline to post-baseline visits in serum phosphate, serum 1,25(OH)2D, ratio of renal tubular maximum reabsorption rate of phosphate to glomerular filtration rate (TmP/GFR).
* Change in FD lesion activity using 18F-NaF PET/CT total lesion activity from baseline to 48 weeks
* Change and percent change in serum bone turnover markers, including procollagen 1 N-terminal propeptide (P1NP), beta crosslaps C-telopeptides (CTX), osteocalcin, and bone-specific alkaline phosphatase from baseline to 48 weeks.
* Change in FD lesion histology and cell proliferation as assessed by minimally invasive bone biopsies from baseline to 48 weeks (adults with capacity to consent only) from baseline to 48 weeks
* Skeletal changes assessed on skeletal survey at baseline and 48 weeks
* Change from baseline to 48 weeks in:

  * Muscle strength
  * Range-of-motion
  * Walking speed (9-minute walk)

Change from baseline to 48 weeks in patient reported outcomes measures:

* SF36: adults
* SF10: children
* PROMIS Pain Intensity: Pediatric and Parent Proxy version 1.0, Adult version 2.0
* PROMIS Pain Interference: Pediatric and Parent Proxy v 2.0, Adult v 1.1
* PROMIS Mobility: Pediatric and Parent Proxy version 2.0, Adult Mobility Lower Extremity v 1.0
* PROMIS Fatigue: Pediatric and Parent Proxy v 2.0, Adult FACIT 13a v1.0
* Activities of Daily Living Questions: adults and children

Eligibility Criteria:
* INCLUSION CRITERIA:

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

* Confirmed diagnosis of fibrous dysplasia
* Serum phosphate \<10th percentile for age and sex, AND intact serum FGF23 \>=30 pg/mL
* Age \>=1 year
* Provision of signed and dated informed consent/assent form
* Stated willingness of subject or Legally Authorized Representative (LAR) to comply with all study procedures and availability for the duration of the study
* For females of reproductive potential: agreement to use highly effective contraception for during study participation. Highly effective contraception methods include:

  * Total abstinence (when this is in line with the preferred and usual lifestyle of the participant). Periodic abstinence (e.g., calendar, ovulation, symptothermal, postovulation methods) and withdrawal are not acceptable methods of contraception
  * Female sterilization (have had surgical bilateral oophorectomy with or without hysterectomy) or tubal ligation at least six weeks before taking study treatment.
  * Male sterilization (at least 6 months prior to screening). For female participants on the study the vasectomized male partner should be the sole partner for that participant.
  * Combination of the following (a+b or a+c, or b+c):

    * Use of oral, injected or implanted hormonal methods of contraception or other forms of hormonal contraception that have comparable efficacy (failure rate \<1%), for example hormone vaginal ring or transdermal hormone contraception
    * Placement of an intrauterine device (IUD) or intrauterine system (IUS)
    * Barrier methods of contraception: Condom or Occlusive cap (diaphragm or cervical/vault caps) with spermicidal foam/gel/film/cream/vaginal suppository
* For males of reproductive potential: use of condoms or other methods described above to ensure effective contraception with partner
* Minimum body weight of 7.5 kilograms

EXCLUSION CRITERIA:

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

* Pregnancy or lactation
* Known allergic reactions to burosumab or drug component
* Treatment with another investigational drug within 30 days of screening
* Treatment with burosumab within 30 days of screening
* Have any condition which in the opinion of the PI could present a concern for subject safety or difficulty with data interpretation
* Severe renal impairment or end stage renal disease, defined as: pediatric patients with estimated glomerular filtration rate (eGFR) 15 mL/min/1.73m2 to 29 mL/min/1.73m2 or end stage renal disease (eGFR \< 15 mL/min/1.73m2), adult patients with creatinine clearance (CLcr) 15 mL/min to 29 mL/min or end stage renal disease (CLcr \< 15 mL/min)