PI-038 - APPLICATION OF MODELING AND SIMULATION TO EXTRAPOLATE THERAPEUTIC BUROSUMAB DOSING REGIMENS FOR SUBJECTS WITH PEDIATRIC TUMOR-INDUCED OSTEOMALCIA.

M. Mascelli¹, D. Marsteller¹, K. Mehta¹, M. Hruska¹, N. Gosselin², L. Sid-Otmane²; ¹Kyowa Kirin Co., Ltd., Princeton, NJ, USA, ²Certara, Montreal, Quebec, Canada.

Background: Tumor induced osteomalacia (TIO) is a rare disease caused by tumor overexpression of fibroblast growth factor 23 (FGF23) and results in hypophosphatemia (HPO). Burosumab is a human monoclonal antibody that binds FGF23 and increases serum phosphate (Pi). It is approved in the EU for adult and pediatric (ped) patients aged >1year with either X-linked HPO or TIO. The objectives of these analyses were to determine the burosumab dose regimens for ped TIO patients.

Methods: Pop PK and PK/PD models were developed with data from 27 adults with TIO and 279 patients (212 adults and 94 ped) with XLH. Longitudinal simulations were conducted to predict doses providing Pi for ped TIO sub > the lower limit of normal (LLN). A virtual population was simulated for ped patients that were sub-stratified by baseline serum FGF23 quartiles (bFGF23Q) observed in the adult TIO studies (range: 84.5 to 2694 pg/mL).

Results: The predicted PK/PD relationships support a burosumab starting dose of 0.4 mg/kg and 0.3 mg/kg for TIO ped and adolescent patients, respectively, up to maximum dose of 2 mg/kg Q2W. Burosumab 0.4 mg/kg Q2W was predicted to maintain Pi > LLN at trough levels (Cminss), and low risk of hyperphosphatemia (HPE; ≤ 0.4%) at maximum concentration (Cmaxss) in ped patients within the lowest two bFGF23Q. A high number (~ 96%) of adolescent patients were predicted to achieve Pi >LLN at Cminss, with the 0.3 mg/kg Q2W dose of burosumab, with a low risk of HPE (~4%) at Cmaxss. For all ped TIO patients in the 2 highest bFGF23Q, burosumab doses up to 2.0 mg/kg Q2W were predicted to provide Pi > LLN in a majority of sub at Cminss.

Conclusion: The analyses exemplify the use of modeling & simulation to extrapolate efficacious doses of burosumab in a rare ped disease and supported the approval of TIO doses for ped patients in the EU.