Interim Analysis of a Phase 2 Open-Label Trial Assessing Burosumab Efficacy and Safety in Patients With Tumor-Induced Osteomalacia

Abstract

Patients 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.

Effects of burosumab on osteocalcin and bone mineral density in patient with 15-year history of nonremission tumor-induced osteomalacia initially treated with conventional therapy: Case report

“…Thus, we consider that burosumab can be considered as a valid alternative for patients who have causative tumors that are difficult to resect surgically. Furthermore, in the present case, LS-BMD was noticeably improved after burosumab treatment, the same as in the recent report of Imanishi et al (2020) .…”

“…An unpublished open-label single-arm phase 2 trial conducted in the United States provided the only findings of burosumab for TIO until the recent study presented by Imanishi et al (2020) , which presented an interim analysis conducted as part of a multicenter open-label intra-individual dose-adjustment study of burosumab in Japanese and Korean patients with TIO (n = 13). During the course of that 96-week study, burosumab treatment was well tolerated and resulted in improved mean serum Pi, TmP/GFR, and serum 1,25(OH) 2 D. In addition, bone scan and bone histomorphometry findings related to osteomalacia assessed by paired bone biopsy samples showed evidence of improved bone quality and fracture healing over 48 weeks.…”

“…In December 2019, burosumab, a recombinant fully human IgG1 monoclonal antibody that inhibits FGF23 activity, was first covered by insurance in Japan before the rest of the world for treatment of FGF23-associated hypophosphatemic osteomalacia by TIO. Unfortunately, except for a case report presented in the United States ( Day et al, 2020 ) and an interim analysis of a phase 2 trial in Japan and Korea ( Imanishi et al, 2020 ), little is known about the precise effects of burosumab in patients with nonremission TIO encountered in daily clinical practice.…”

Burosumab for the Treatment of Tumor-Induced Osteomalacia

“…Benefits from burosumab treatment demonstrated in patients with TIO in this study were consistent with a case report of burosumab treatment in a patient with TIO, including normalization of serum phosphorus and improvement in pain and physical function, ( 24 ) and in an interim analysis of a phase 2 trial of burosumab in Japanese and Korean patients with TIO. ( 25 ) To our knowledge, these are the only other published studies of burosumab in TIO.…”

Tumor-Induced Osteomalacia: Treatment Progress Using Burosumab, an Anti-FGF23 Monoclonal Antibody

“…As the authors mention, last year, Imanishi and colleagues ( 6 ) detailed in JBMR the interim analysis, reflecting up to week 112 of their phase 2, open‐label study (NCT02722798) of 13 Japanese or Korean patients with TIO given burosumab similarly up to 2 mg/kg every 4 weeks. Their patients achieved mean fasting serum P levels within their slightly lower normal adult range of 2.4 to 4.3 mg/dL, and had radiological and histomorphometric improvements with reassuring treatment safety.…”