A Randomized, Double-Blind, Placebo-Controlled, Phase 3 Trial Evaluating the Efficacy of Burosumab, an Anti-FGF23 Antibody, in Adults With X-Linked Hypophosphatemia: Week 24 Primary Analysis

Abstract

In X-linked hypophosphatemia (XLH), inherited loss-of-function mutations in the PHEX gene cause excess circulating levels of fibroblast growth factor 23 (FGF23), leading to lifelong renal phosphate wasting and hypophosphatemia. Adults with XLH present with chronic musculoskeletal pain and stiffness, short stature, lower limb deformities, fractures, and pseudofractures due to osteomalacia, accelerated osteoarthritis, dental abscesses, and enthesopathy. Burosumab, a fully human monoclonal antibody, binds and inhibits FGF23 to correct hypophosphatemia. This report summarizes results from a double-blind, placebo-controlled, phase 3 trial of burosumab in symptomatic adults with XLH. Participants with hypophosphatemia and pain were assigned 1:1 to burosumab 1 mg/kg (n ¼ 68) or placebo (n ¼ 66) subcutaneously every 4 weeks (Q4W) and were comparable at baseline. Across midpoints of dosing intervals, 94.1% of burosumab-treated participants attained mean serum phosphate concentration above the lower limit of normal compared with 7.6% of those receiving placebo (p < 0.001). Burosumab significantly reduced the Western Ontario and the McMaster Universities Osteoarthritis Index (WOMAC) stiffness subscale compared with placebo (least squares [LS] mean AE standard error [SE] difference, -8.1 AE 3.24; p ¼ 0.012). Reductions in WOMAC physical function subscale (-4.9 AE 2.48; p ¼ 0.048) and Brief Pain Inventory worst pain (-0.5 AE 0.28; p ¼ 0.092) did not achieve statistical significance after Hochberg multiplicity adjustment. At week 24, 43.1% (burosumab) and 7.7% (placebo) of baseline active fractures were fully healed; the odds of healed fracture in the burosumab group was 16.8-fold greater than that in the placebo group (p < 0.001). Biochemical markers of bone formation and resorption increased significantly from baseline with burosumab treatment compared 1383with placebo. The safety profile of burosumab was similar to placebo. There were no treatment-related serious adverse events or meaningful changes from baseline in serum or urine calcium, intact parathyroid hormone, or nephrocalcinosis. These data support the conclusion that burosumab is a novel therapeutic addressing an important medical need in adults with XLH.

FGF23, Hypophosphatemia, and Emerging Treatments

“…Similar peak and trough effects occur during repeated dosing. However, with long‐term repeated dosing, the magnitude of that peak in 1,25(OH) 2 D lessens, while the peak effect on phosphate generally persists . This 1,25(OH) 2 D effect suggests that vitamin D activation is being suppressed in the pretreatment state by high FGF23 concentrations but that the cellular machinery is in place to support a rapid switch to producing 1,25(OH) 2 D. This is consistent with studies in the XLH mouse model indicating that despite high FGF23, the gene expression for the enzyme 1‐alpha hydroxylase is actually increased compared with normal mice, but the expression of the protein itself and its enzyme activity are lower than normal due to posttranscriptional or posttranslational effects .…”

“…During this burosumab trial, improvements were also demonstrated in patient‐reported outcomes including physical functioning and stiffness scores using the Western Ontario and McMaster Osteoarthritis Index (WOMAC) scale . These improvements were generally supported by improvements in patient‐reported outcomes and functional outcomes in subsequent trials in children and adults …”

“…Severe dental disease is present in more than half of patients with XLH and is associated with abnormally mineralized dentin and cementum . Enthesopathy and osteoarthritis may severely limit range of motion and contribute to pain in patients with XLH . The occurrence of spinal stenosis and its consequences in these patients is an under‐recognized issue, impairing quality of life.…”

“…The occurrence of spinal stenosis and its consequences in these patients is an under‐recognized issue, impairing quality of life. Patients may also have bone pain from osteomalacia itself, along with poorly healing chronic pseudofractures in up to half of adults . Muscle weakness is also present to some degree in many patients …”

“…Interestingly restless legs syndrome was described in 17.9% of adults in the first multidose trial, though the mechanism is uncertain. In the randomized phase 3 trial, restless legs syndrome occurred in 11.8% of burosumab‐treated subjects but still occurred in 7.6% of placebo subjects, suggesting this may be an unrecognized complication of XLH …”