Burosumab Improves Biochemical, Skeletal, and Clinical Features of Tumor-Induced Osteomalacia Syndrome

Abstract

Tumor-induced Osteomalacia (TIO) is a rare condition in which excess FGF23 produced by a tumor leads to renal phosphate wasting, impaired 1,25(OH)2D synthesis, osteomalacia, fractures, weakness, fatigue, and decreased mobility. In an ongoing open-label Phase 2 study (NCT02304367), 17 adults with TIO or cutaneous skeletal hypophosphatemia syndrome (CSHS) were enrolled and received burosumab, a fully human monoclonal antibody against FGF23. Key endpoints were changes in serum phosphorus and osteomalacia as assessed from trans-iliac crest bone biopsies. This report excludes 3/17 subjects who did not have TIO: 2 subjects diagnosed with X-linked hypophosphatemia post-enrollment and 1 subject with CSHS. Serum phosphorus increased from baseline (BL; 1.60 mg/dL) and was maintained after titration, from Week (W) 22 (2.85 mg/dL, dosing cycle midpoint) to W144 (2.56 mg/dL, dosing cycle endpoint, p<0.0001). Serum TmP/GFR and 1,25(OH)2D also increased with burosumab. Eleven subjects underwent paired bone biopsies at BL and W48. Osteoid volume/bone volume decreased from a mean ± SE of 17.6% ± 5.9% at BL to 12.1% ± 4.7% at W48 (p=0.086). Mean ± SE osteoid thickness decreased from 16.5 ± 3.6 µm to 11.3 ± 2.8 µm (p<0.05). Using imputation (Dempster et al. 2012), mineralization lag time decreased from a mean ± SE of 1598 ± 420 days to 1032 ± 712 days (p=0.41). Osteoid surface/bone surface showed no change from BL (mean ± SE BL: 57% ± 9%, W48: 57% ± 7%). Of 249 areas identified with increased uptake on bone scan at BL, 68 (27%) and 81 (33%) were fully healed at W96 and W144, respectively; 56 (23%) and 32 (13%) were partially healed at W96 and W144, respectively. Mean (SD) Global Fatigue Score decreased from 5.6 (2.5) at BL to 3.5 (3.0) at W48, and to 3.8 (2.2) at W144 (both p<0.01). All 3 domains of the Brief Pain Inventory decreased with burosumab (W144 Pain Severity and Pain Interference p<0.05), indicating reduced pain. The SF-36 mean (SD) physical component summary score increased from 33 (10) at BL to 39 (10) at W48 (p<0.05) and to 41 (12) at W144 (p<0.01), indicating improved physical functioning. The mean (SD) number of sit-to-stand repetitions, an assessment of proximal muscle function, increased from 6.7 (4.2) at BL to 8.5 (4.2) at W48 (n=10; p<0.01). All subjects had ≥1 adverse event (AE). Two subjects discontinued: 1 to undergo chemotherapy to treat an AE of neoplasm progression and 1 failed to meet serum phosphorus dosing criteria and therefore received minimal burosumab dosing. There were 16 serious AEs in 7 subjects, all unrelated to drug. Of the 6 subjects with a serious AE of tumor progression/compression, 5 had a history of tumor progression prior to enrollment. There was 1 death, considered unrelated to treatment. In adults with TIO Syndrome, burosumab was associated with improvements in phosphate metabolism, osteomalacia, skeletal metabolism/fracture healing, physical functioning, fatigue, pain, and quality of life.