Abstract
ABSTRACTPatients with tumor‐induced osteomalacia (TIO), an acquired paraneoplastic condition characterized by osteomalacia due to hypophosphatemia, exhibit a similar clinical picture to those with X‐linked hypophosphatemic rickets/osteomalacia (XLH). The human monoclonal anti‐fibroblast growth factor 23 (FGF23) antibody burosumab (KRN23) increases serum phosphate and improves bone turnover, fracture healing, pain, and physical function in XLH patients by inhibiting circulating FGF23; thus, burosumab is expected to be an effective treatment for TIO. We report here an interim analysis of a multicenter, open‐label, intraindividual dose‐adjustment study of burosumab (0.3 to 2.0 mg/kg every 4 weeks) in Japanese and Korean TIO patients. The primary endpoint was the fasting serum phosphate level at each visit. Key secondary endpoints were changes over time in bone biomarkers, pharmacodynamic markers, bone histomorphometric parameters, motor function, and patient‐reported outcomes. Safety was assessed based on treatment‐emergent adverse events (TEAEs). Thirteen patients received burosumab treatment, of whom 4 underwent bone biopsy. The mean dose after week 112 was approximately 1.0 mg/kg. After the first burosumab administration, mean serum phosphate levels increased and remained above the lower limit of normal and in the normal range from weeks 14 to 112. Bone biomarkers initially increased, reaching maximum values at week 16 or 24, and then gradually decreased. After burosumab treatment, patients were able to walk further (evaluated by the 6‐minute walk test), reported decreased pain levels, and showed a tendency toward healing of baseline fractures and pseudofractures. Two patients discontinued, one each due to disease progression and consent withdrawal. Burosumab was generally well tolerated, with no treatment‐related TEAEs of grade ≥3 and no treatment‐related serious AEs. In conclusion, the interim results of this first study of burosumab to treat TIO patients indicate that this drug has the potential to provide clinical benefit for patients with unresectable tumors. The full study results are eagerly anticipated. © 2020 The Authors. Journal of Bone and Mineral Research published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research (ASBMR)..
Highlights
Burosumab (KRN23) is a fully human monoclonal antibody targeted against fibroblast growth factor 23 (FGF23).(13) Burosumab has shown efficacy in the treatment of X-linked hypophosphatemic rickets/osteomalacia (XLH) patients, increasing serum phosphate[14] and improving bone histomorphometric measures and fracture healing.[15,16] 24 weeks of burosumab treatment was associated with improvements in pain, physical function, and stiffness compared with placebo-treated patients with XLH.[15]. Burosumab was approved in the United States, Canada, and the European Union for the treatment of XLH in 2018(13,17,18) and in Japan for FGF23-related hypophosphatemic rickets and osteomalacia in 2019.(19)
Most of the patients had been previously treated with active vitamin D and/or inorganic phosphate, the interim study results showed that serum phosphate levels increased after burosumab administration
69.2% of patients achieved mean peak serum phosphate levels above the LLN and 46.2% of patients achieved mean trough levels above the LLN; the distance walked in the 6MWT increased after the start of burosumab administration; worst pain scores decreased; and the number of fractures and pseudofractures was reduced
Summary
Unlike the genetic disease XLH, TIO is an acquired paraneoplastic condition in which the tumor produces excessive levels of FGF23,(2,4,7) and the time between onset of symptoms to diagnosis can be lengthy, taking up to 20 years.[10] The causative tumors in TIO are typically benign, characterized by small size and slow growth and can occur at various sites;(11) they may be difficult to identify and diagnose with standard imaging techniques.[7,11] For tumor lesions that can be identified and are accessible, surgical complete resection is the first treatment choice.[2,4] After complete resection, blood FGF23 levels decrease markedly and immediately, and biochemical parameters commonly resolve within days or weeks.[12] If the tumor cannot be identified or resected, patients are treated with oral inorganic phosphate and/or active vitamin D preparations.[4,7] the efficacy of these treatments can be suboptimal, and there are safety concerns associated with them, including renal insufficiency and secondary hyperparathyroidism.[4,7]. We conducted a phase 2 open-label trial, which is the first clinical study in TIO patients to evaluate the efficacy and safety of burosumab in this patient population
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