Contributions
Abstract: P1175
Type: Poster
Abstract Category: Therapy - disease modifying - 27 Neuroprotection and Repair
Background: MS is the most common inflammatory demyelinating CNS disease. Opicinumab is a first-in-class human monoclonal antibody directed against leucine-rich repeat and immunoglobulin domain-containing Nogo receptor-interacting protein-1 (LINGO-1). Antagonism of LINGO-1 with opicinumab may enhance remyelination and axonal protection. The dosing regimen of opicinumab in an upcoming phase IIb clinical trial is based on the population pharmacokinetic (popPK) analysis and simulations.
Objectives: To develop a popPK model and simulate opicinumab PK for various dosing regimens in support of a dose regimen to be used in phase IIb and future studies.
Methods: The combined plasma PK data set included two phase I studies (single ascending dose in healthy subjects and multiple ascending dose in patients with MS), and one phase II study (SYNERGY; dose-ranging plus interferon beta-1a in patients with MS). The computer program NONMEM (v.7.2.0) was used to conduct the popPK analyses. The final model was evaluated by diagnostic plots for goodness-of-fit, bootstrap and visual predictive check (VPC).
Results: A 2-compartment model adequately described opicinumab concentrations over doses ranging from 0.1 to 100 mg/kg, supporting dose linearity. The clearance (CL) of opicinumab is generally low (CL=0.0082 l/h), and the volume of distribution (V) is small, reflecting poor distribution outside the bloodstream (V1=3.01 l and V2=2.46 l). Body weight was the covariate on the PK parameters of CL, V1 and V2. Simulations of plasma concentrations at 3, 10, 30 and 100 mg/kg of opicinumab in SYNERGY by VPC showed good representation of opicinumab disposition. The simulations of 4-weekly dosing at 10 mg/kg and at 750 mg opicinumab showed the superimposed median serum concentrations, with average steady state concentrations above the half maximal effective concentration value. The exposure of 10 mg/kg and 750 mg appear to be comparable and the 750 mg dose shows relatively large variability based on its [5th, 95th] range of concentrations. The Cmax and area under concentration curve based on simulations of opicinumab at 3 and 30 mg/kg showed no overlap with [5th, 95th] the 10 mg/kg or 750 mg concentration ranges every 4 weeks.
Conclusions: Recommendations are made for 750 mg fixed dosing in future clinical studies, based upon the comparable exposures of 10 mg/kg and 750 mg, convenience, and the safety window of opicinumab.
Supported by: Biogen.
Disclosure: This study was supported by Biogen (Cambridge, MA, USA). Editorial support was provided by Excel Scientific Solutions (Horsham, UK): funding was provided by Biogen. L-HC, WY, and IN: employees of and hold stock/options in Biogen.
LX: Employee of Biogen during the completion of the work; may hold stock/options in Biogen. Current employee of Takeda, Cambridge, Massachusetts, US. There were no competing interests among the authors.
Abstract: P1175
Type: Poster
Abstract Category: Therapy - disease modifying - 27 Neuroprotection and Repair
Background: MS is the most common inflammatory demyelinating CNS disease. Opicinumab is a first-in-class human monoclonal antibody directed against leucine-rich repeat and immunoglobulin domain-containing Nogo receptor-interacting protein-1 (LINGO-1). Antagonism of LINGO-1 with opicinumab may enhance remyelination and axonal protection. The dosing regimen of opicinumab in an upcoming phase IIb clinical trial is based on the population pharmacokinetic (popPK) analysis and simulations.
Objectives: To develop a popPK model and simulate opicinumab PK for various dosing regimens in support of a dose regimen to be used in phase IIb and future studies.
Methods: The combined plasma PK data set included two phase I studies (single ascending dose in healthy subjects and multiple ascending dose in patients with MS), and one phase II study (SYNERGY; dose-ranging plus interferon beta-1a in patients with MS). The computer program NONMEM (v.7.2.0) was used to conduct the popPK analyses. The final model was evaluated by diagnostic plots for goodness-of-fit, bootstrap and visual predictive check (VPC).
Results: A 2-compartment model adequately described opicinumab concentrations over doses ranging from 0.1 to 100 mg/kg, supporting dose linearity. The clearance (CL) of opicinumab is generally low (CL=0.0082 l/h), and the volume of distribution (V) is small, reflecting poor distribution outside the bloodstream (V1=3.01 l and V2=2.46 l). Body weight was the covariate on the PK parameters of CL, V1 and V2. Simulations of plasma concentrations at 3, 10, 30 and 100 mg/kg of opicinumab in SYNERGY by VPC showed good representation of opicinumab disposition. The simulations of 4-weekly dosing at 10 mg/kg and at 750 mg opicinumab showed the superimposed median serum concentrations, with average steady state concentrations above the half maximal effective concentration value. The exposure of 10 mg/kg and 750 mg appear to be comparable and the 750 mg dose shows relatively large variability based on its [5th, 95th] range of concentrations. The Cmax and area under concentration curve based on simulations of opicinumab at 3 and 30 mg/kg showed no overlap with [5th, 95th] the 10 mg/kg or 750 mg concentration ranges every 4 weeks.
Conclusions: Recommendations are made for 750 mg fixed dosing in future clinical studies, based upon the comparable exposures of 10 mg/kg and 750 mg, convenience, and the safety window of opicinumab.
Supported by: Biogen.
Disclosure: This study was supported by Biogen (Cambridge, MA, USA). Editorial support was provided by Excel Scientific Solutions (Horsham, UK): funding was provided by Biogen. L-HC, WY, and IN: employees of and hold stock/options in Biogen.
LX: Employee of Biogen during the completion of the work; may hold stock/options in Biogen. Current employee of Takeda, Cambridge, Massachusetts, US. There were no competing interests among the authors.