Burosumab, a fully human monoclonal antibody against fibroblast growth factor 23 (FGF23), may restore phosphorus homeostasis and improve mineralization defect in in patients with X-linked hypophosphatemia (XLH), according to study results published in the Journal of Bone & Mineral Research.
Loss-of-function mutations in the PHEX gene (phosphate-regulating endopeptidase homolog, X-linked) cause XLH, a rare disease associated with increased FGF23 levels, chronic hypophosphatemia, and impaired production of 1,25-dihydroxyvitamin D. Burosumab was approved for the treatment of XLH, with studies reporting improved fracture healing and increased serum phosphorus levels and bone remodeling markers.
An ongoing open-label phase 3 single-group multicenter trial (ClinicalTrials.gov Identifier: NCT02537431) is investigating the efficacy of burosumab in improving osteomalacia in adults with XLH. The goal of the current study was to assess the effect of burosumab on histomorphometric indices of osteomalacia in adults with XLH.
Burosumab 1.0 mg/kg was administered subcutaneously every 4 weeks for at least 96 weeks. Transiliac crest bone biopsies were obtained at baseline and week 48 and qualitatively analyzed in real time to determine whether osteomalacia was present. After week 48, all patients continued treatment for an additional 48-week extension period. The current study focuses on the first 48 weeks of treatment.
The study cohort included adults aged 18 to 65 years with a diagnosis of XLH and a PHEX mutation or a serum intact FGF23 >30 pg/mL. Further, patients had a fasting serum phosphorus and renal tubular reabsorption of phosphate <2.5 mg/dL and significant skeletal pain.
The primary endpoint was the percentage change from baseline to week 48 in osteoid volume/bone volume. In addition, the researchers assessed serum phosphorus, markers of bone turnover, fracture/pseudofracture healing, and drug safety.
Of 25 patients who were screened for the study, 14 enrolled and 13 completed the first 48 weeks of the trial, including 11 who underwent paired bone biopsies.
After 48 weeks of treatment, there was a significant improvement in all osteomalacia-related histomorphometric measures, including a decrease in osteoid volume/bone volume from 26.1%±12.4% at baseline to 11.9%±6.6% at week 48 (percentage change, -54%; P <.0001). Osteoid thickness decreased from 17.2±4.1 µm at baseline to 11.6±3.1 µm at week 48 (percentage change, -32%; P <.0001). Osteoid surface/bone surface also decreased from 92%±3% at baseline to 68%±14% at week 48 (percentage change, -26%; P =.0002).
When averaged across the midpoint of the dose intervals through week 24, the mean serum phosphorus concentration was above the lower limit of normal in 13 participants (mean concentration, 3.3±0.4 mg/dL), with a mean increase of 1.1 mg/dL from baseline. This increase in serum phosphorus was maintained through week 48 when measured at the end of the dose cycle between weeks 24 and 48.
At week 48, there was also evidence of increased bone remodeling markers, with a least squares mean increase of 77% (P <.0001) in procollagen type 1 N-terminal propeptide (P1NP) and of 36% (P <.0001) in C-terminal telopeptide of type 1 collagen (CTX).
Most patients (n=10; 71%) experienced at least 1 burosumab-related adverse event, most commonly urticaria, pain, or reaction at the injection site; abdominal pain; or asthenia. Two patients experienced serious adverse events, including paresthesia and migraine (both grade 3); neither was considered related to burosumab, and both resolved. No deaths or incidents of hyperphosphatemia occurred.
The study was limited by its small sample size, lack of control group, and relatively short treatment period, which does not address whether longer treatment duration confers greater improvement in osteomalacia measures.
“Given its proven efficacy, better safety profile and sound therapeutic rational, burosumab, represents an appealing therapeutic option for symptomatic adults with XLH,” concluded the investigators.
Disclosure: This clinical trial was supported by Ultragenyx Pharmaceutical Inc. and Kyowa Hakko Kirin International plc. Please see the original reference for a full list of authors’ disclosures.
Insogna KL, Rauch F, Kamenický P, et al. Burosumab improved histomorphometric measures of osteomalacia in adults with X-Linked Hypophosphatemia: a phase 3, single-arm, international trial [published online August 1, 2019]. J Bone Miner Res. doi:10.1002/jbmr.3843