Home
|
Inbox
|
Search
|
View Abstract
PK and PK/PD Modeling to Inform Dosing Optimization for Pamrevlumab in Idiopathic Pulmonary Fibrosis (IPF)
Description
.abstract img { width:300px !important; height:auto; display:block; text-align:center; margin-top:10px } .abstract { overflow-x:scroll } .abstract table { width:100%; display:block; border:hidden; border-collapse: collapse; margin-top:10px } .abstract td, th { border-top: 1px solid #ddd; padding: 4px 8px; } .abstract tbody tr:nth-child(even) td { background-color: #efefef; } .abstract a { overflow-wrap: break-word; word-wrap: break-word; }
A1640 - PK and PK/PD Modeling to Inform Dosing Optimization for Pamrevlumab in Idiopathic Pulmonary Fibrosis (IPF)
Author Block: E. Gorina1, J. Chou1, T. Sekayan1, S. Porter1, P. Yu1, E. Kouchakji1, M. Zager2, H. Li2, R. Wada2; 1FibroGen, San Francisco, CA, United States, 2Certara, Princeton, NJ, United States.
Pamrevlumab is a fully human mAb against connective tissue growth factor (CTGF) under development in several fibrotic indications. In a phase 2 study in IPF, the average decline in FVC % of predicted (FVCpp) in pamrevlumab treated patients was 4.3% less than placebo (60% relative difference), with a dosing regimen of 30 mg/kg every 3 weeks over 48 weeks. Given the good tolerability of pamrevlumab to date, with no identified maximum tolerated dose, the evaluation of its PK in relation to its efficacy and safety outcomes can be used to optimize dosing. Previously we demonstrated in a pancreatic cancer trial that trough plasma exposures of pamrevlumab greater than 150 mcg/mL resulted in improved overall survival results. PK data from four pamrevlumab clinical trials (N=217) using various therapeutic regimens were analyzed and a PK model was fitted to simulate various dosing regimen hypothesis in an exposure-response (E-R) context and assessed against both efficacy and safety outcomes in IPF Phase 2 studies. These included lung function outcomes (FVC and FVCpp) as well as safety outcomes (AEs, SAEs and Infusion-associated AEs). E-R analysis using trough plasma levels (Cmin) of pamrevlumab shows improved FVC and FVCpp outcomes with increased exposure in a statistically significant manner (p=0.016 for FVC; p=0.031 for FVCpp). Lung function outcomes in IPF subjects meeting the target product profile are observed above a threshold of 200 mcg/mL Cmin concentration. This exposure level was only achieved in 24% of Phase 2 IPF subjects. After simulation, the PK model predicts that 80% of subjects would reach the 200 mcg/mL Cmin level by increasing the frequency of administration to q2w without modifying the nominal 30mg/kg dose. Analysis of the incidence and type of AEs showed no increment in key AEs with increased exposure, supporting the preservation of good tolerability with higher or more frequent dosing. The current simulation analysis and PK/PD data supports an increased pamrevlumab dosing regimen (i.e. 30-35mg/kg q2w) that may deliver improved efficacy over that observed during Phase 2 studies without compromising on tolerability. A regimen of pamrevlumab at 35mg/kg q2w is already being used in a Duchenne muscular dystrophy study.
Author Block: E. Gorina1, J. Chou1, T. Sekayan1, S. Porter1, P. Yu1, E. Kouchakji1, M. Zager2, H. Li2, R. Wada2; 1FibroGen, San Francisco, CA, United States, 2Certara, Princeton, NJ, United States.
Pamrevlumab is a fully human mAb against connective tissue growth factor (CTGF) under development in several fibrotic indications. In a phase 2 study in IPF, the average decline in FVC % of predicted (FVCpp) in pamrevlumab treated patients was 4.3% less than placebo (60% relative difference), with a dosing regimen of 30 mg/kg every 3 weeks over 48 weeks. Given the good tolerability of pamrevlumab to date, with no identified maximum tolerated dose, the evaluation of its PK in relation to its efficacy and safety outcomes can be used to optimize dosing. Previously we demonstrated in a pancreatic cancer trial that trough plasma exposures of pamrevlumab greater than 150 mcg/mL resulted in improved overall survival results. PK data from four pamrevlumab clinical trials (N=217) using various therapeutic regimens were analyzed and a PK model was fitted to simulate various dosing regimen hypothesis in an exposure-response (E-R) context and assessed against both efficacy and safety outcomes in IPF Phase 2 studies. These included lung function outcomes (FVC and FVCpp) as well as safety outcomes (AEs, SAEs and Infusion-associated AEs). E-R analysis using trough plasma levels (Cmin) of pamrevlumab shows improved FVC and FVCpp outcomes with increased exposure in a statistically significant manner (p=0.016 for FVC; p=0.031 for FVCpp). Lung function outcomes in IPF subjects meeting the target product profile are observed above a threshold of 200 mcg/mL Cmin concentration. This exposure level was only achieved in 24% of Phase 2 IPF subjects. After simulation, the PK model predicts that 80% of subjects would reach the 200 mcg/mL Cmin level by increasing the frequency of administration to q2w without modifying the nominal 30mg/kg dose. Analysis of the incidence and type of AEs showed no increment in key AEs with increased exposure, supporting the preservation of good tolerability with higher or more frequent dosing. The current simulation analysis and PK/PD data supports an increased pamrevlumab dosing regimen (i.e. 30-35mg/kg q2w) that may deliver improved efficacy over that observed during Phase 2 studies without compromising on tolerability. A regimen of pamrevlumab at 35mg/kg q2w is already being used in a Duchenne muscular dystrophy study.
|
Home
|
Inbox
|
Search
|