TY - JOUR
T1 - Burosumab for the Treatment of Tumor-Induced Osteomalacia
AU - Jan de Beur, Suzanne M.
AU - Miller, Paul D.
AU - Weber, Thomas J.
AU - Peacock, Munro
AU - Insogna, Karl
AU - Kumar, Rajiv
AU - Rauch, Frank
AU - Luca, Diana
AU - Cimms, Tricia
AU - Roberts, Mary Scott
AU - San Martin, Javier
AU - Carpenter, Thomas O.
N1 - Funding Information:
Authors’ roles: SMJdB, DL, TC, MSR, and JSM participated in study design. SMJdB, PDM, TJW, MP, KI, RK, FR, and TC participated in collection of data. DL, TC, and MSR participated in data analysis. All authors participated in data interpretation, reviewing the manuscript, and approval of the final version. Principal investigators and the sponsors, Ultragenyx Pharmaceuticals Inc. and Kyowa Kirin Co., Ltd., designed the study. The sponsor and investigators collected, analyzed, and interpreted the data. Authors vouch for the completeness and accuracy of the data. This article was written by the authors with medical writing support from the sponsor. All authors had access to the data and decided to publish this manuscript. Data sharing: Because of the rarity of TIO and the small number of subjects in this trial, individual patient data will not be shared in order to safeguard patient privacy, consistent with the data sharing policy listed on Ultragenyx.com. The study protocol and statistical analysis plan for this study will be available on the relevant clinical trial registry websites with the tabulated results.
Funding Information:
SMJdB received grants, personal fees, and non‐financial support from Ultragenyx and grants from Mereo. PDM received grants and participated in a scientific advisory board for Ultragenyx, Amgen, and Radius Health; received grants from Elxion; and is an employee of Colorado Center for Bone Research. TJW received grants and personal fees from Ultragenyx. MP received grants from Ultragenyx. KI received grants, personal fees, and other fees from Ultragenyx. RK has nothing to disclose. FR's lab performed analyses for Ultragenyx on a fee‐for‐service basis, and FR received personal fees from Mereo and Novartis and grants from PreciThera. DL and TC are employees and stockholders of Ultragenyx. MSR is an employee of Ultragenyx. JSM was an employee of Ultragenyx at the time the study was conducted, is an employee and shareholder of Arrowhead, and has a pending patent with Ultragenyx. TOC received grants and personal fees from Ultragenyx and personal fees from Kyowa Kirin and Inozyme. This study was sponsored and funded by Ultragenyx Pharmaceutical Inc. in partnership with Kyowa Kirin International plc. Medical writing support was provided by Catherine Woods (Ultragenyx) and Kerri Hebard‐Massey (Ultragenyx).
Publisher Copyright:
© 2020 The Authors. Journal of Bone and Mineral Research published by American Society for Bone and Mineral Research.
PY - 2021/4
Y1 - 2021/4
N2 - Tumor-induced osteomalacia (TIO) is caused by phosphaturic mesenchymal tumors producing fibroblast growth factor 23 (FGF23) and is characterized by impaired phosphate metabolism, skeletal health, and quality of life. UX023T-CL201 is an ongoing, open-label, phase 2 study investigating the safety and efficacy of burosumab, a fully human monoclonal antibody that inhibits FGF23, in adults with TIO or cutaneous skeletal hypophosphatemia syndrome (CSHS). Key endpoints were changes in serum phosphorus and osteomalacia assessed by transiliac bone biopsies at week 48. This report focuses on 14 patients with TIO, excluding two diagnosed with X-linked hypophosphatemia post-enrollment and one with CSHS. Serum phosphorus increased from baseline (0.52 mmol/L) and was maintained after dose titration from week 22 (0.91 mmol/L) to week 144 (0.82 mmol/L, p < 0.0001). Most measures of osteomalacia were improved at week 48: osteoid volume/bone, osteoid thickness, and mineralization lag time decreased; osteoid surface/bone surface showed no change. Of 249 fractures/pseudofractures detected across 14 patients at baseline, 33% were fully healed and 13% were partially healed at week 144. Patients reported a reduction in pain and fatigue and an increase in physical health. Two patients discontinued: one to treat an adverse event (AE) of neoplasm progression and one failed to meet dosing criteria (receiving minimal burosumab). Sixteen serious AEs occurred in seven patients, and there was one death; all serious AEs were considered unrelated to treatment. Nine patients had 16 treatment-related AEs; all were mild to moderate in severity. In adults with TIO, burosumab exhibited an acceptable safety profile and was associated with improvements in phosphate metabolism and osteomalacia.
AB - Tumor-induced osteomalacia (TIO) is caused by phosphaturic mesenchymal tumors producing fibroblast growth factor 23 (FGF23) and is characterized by impaired phosphate metabolism, skeletal health, and quality of life. UX023T-CL201 is an ongoing, open-label, phase 2 study investigating the safety and efficacy of burosumab, a fully human monoclonal antibody that inhibits FGF23, in adults with TIO or cutaneous skeletal hypophosphatemia syndrome (CSHS). Key endpoints were changes in serum phosphorus and osteomalacia assessed by transiliac bone biopsies at week 48. This report focuses on 14 patients with TIO, excluding two diagnosed with X-linked hypophosphatemia post-enrollment and one with CSHS. Serum phosphorus increased from baseline (0.52 mmol/L) and was maintained after dose titration from week 22 (0.91 mmol/L) to week 144 (0.82 mmol/L, p < 0.0001). Most measures of osteomalacia were improved at week 48: osteoid volume/bone, osteoid thickness, and mineralization lag time decreased; osteoid surface/bone surface showed no change. Of 249 fractures/pseudofractures detected across 14 patients at baseline, 33% were fully healed and 13% were partially healed at week 144. Patients reported a reduction in pain and fatigue and an increase in physical health. Two patients discontinued: one to treat an adverse event (AE) of neoplasm progression and one failed to meet dosing criteria (receiving minimal burosumab). Sixteen serious AEs occurred in seven patients, and there was one death; all serious AEs were considered unrelated to treatment. Nine patients had 16 treatment-related AEs; all were mild to moderate in severity. In adults with TIO, burosumab exhibited an acceptable safety profile and was associated with improvements in phosphate metabolism and osteomalacia.
KW - BONE HISTOMORPHOMETRY
KW - CLINICAL TRIALS
KW - OSTEOMALACIA AND RICKETS
KW - PTH/VIT D/FGF23
KW - TUMOR-INDUCED BONE DISEASE
UR - http://www.scopus.com/inward/record.url?scp=85099275545&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85099275545&partnerID=8YFLogxK
U2 - 10.1002/jbmr.4233
DO - 10.1002/jbmr.4233
M3 - Article
C2 - 33338281
AN - SCOPUS:85099275545
SN - 0884-0431
VL - 36
SP - 627
EP - 635
JO - Journal of Bone and Mineral Research
JF - Journal of Bone and Mineral Research
IS - 4
ER -