Modeling relationship of pharmacokinetics, in vitro potency, and α4β7 receptor occupancy with intestinal cell trafficking in a gut-homing mouse model of IBD with MORF-057

• Published in: The Journal of immunology (1950) Vol. 206; no. 1_Supplement; pp. 11 - 11.15
• Main Authors: Redhu, Naresh S., Hussain, Ali, Srinivasan, Sathish, Lee, Dooyoung, Bannister, Brianna, Blanco, Natalia, Bonesteel, Raegan, Camblin, Adam, Cappellucci, Laura, Cohen, Rhianna, Harrison, Bryce, Hahn, Kristopher N, Kim, Kwangsoo, Krumpoch, Megan, Lin, Fu-Yang, McManus, Kevin, McShea, Molly, Pondish, Jessica, Linde, Peter, Lugovskoy, Alex, Mangada, Maloy, Moy, Terence I., Sang, Allison, Gelais, Sarah St, Sullivan, Andrew, Troast, Dawn, Zhong, Cheng, Wang, Liangsu, Cui, Dan, Bursavich, Matthew G., Lippa, Blaise, Rogers, Bruce N., Ray, Adrian S., Wong, Jamie
• Format: Journal Article
• Language: English
• Published: 01.05.2021
• ISSN: 0022-1767; 1550-6606
• DOI: 10.4049/jimmunol.206.Supp.11.15

Abstract Objective: MORF-057 is an orally bioavailable, selective, and potent small molecule inhibitor of α4β7 integrin being developed for inflammatory bowel diseases (IBD) that is currently in phase 1 clinical testing. We have previously presented work that characterized its nonclinical pharmacologic profile. The current study integrates data to generate a pharmacokinetic (PK) and pharmacodynamic (PD) model of MORF-057. Methods: To determine in vivo potency, MORF-057 was tested in murine gut homing assays and the PD response was determined relative to the non-protein bound drug in mouse plasma. A cell adhesion assay (CAA) for α4β7 was refined to enable detection of picomolar-level sensitivity. Murine receptor occupancy (RO) assays for α4β7 and α4β1 were established under physiologic conditions, and MORF-057 was evaluated for its potency and selectivity in fresh mouse whole blood. These datasets were used to build and validate predictive models of PD response. Results: MORF-057 strongly inhibited the homing of α4β7hi cells to murine gut lymphoid tissues with an IC90 of 7.9 nM. MORF-057 showed high potency in CAA with an IC90 of 8.8 nM. Similarly, RO assays confirmed MORF-057 to be a highly potent inhibitor of α4β7 in mouse whole blood with an IC90 of 20.5 nM and over 1500-fold selectivity vs. α4β1. The predictive models built upon these datasets revealed a strong PK-PD relationship of α4β7 inhibitors in vivo. Conclusions: We observed consistently high potency of MORF-057 across multiple assay platforms. Integrated modeling based on these assays, particularly the RO assay, successfully predicted the PD response to MORF-057. These data begin to establish the relationship between PK, target engagement, and PD with MORF-057.