(W-122) Dual Target-Mediated Drug Disposition Model to Guide the Selection of Starting Dose and Escalation in FTIH Trials for Volrustomig (MEDI5752), a Monovalent Bispecific Antibody Targeting PD-1 and CTLA-4

Zoey Tang, PhD – Associate Director, AstraZeneca; Xuyang Song, PhD – Director, AstraZeneca; Diansong Zhou, PhD – Senior Director, AstraZeneca; Amal Ayyoub, PhD – Director, AstraZeneca; Steven Eck, PhD – Director, AstraZeneca; Yariv Mazor, PhD – Executive Director, AstraZeneca; Simon Dovedi, PhD – Head of IO Discovery, AstraZeneca; Ikbel Achour, PhD – Global Head IO Bispecific Franchise, AstraZeneca; Deepa S. Subramaniam, M.D., M.Sc. – Executive Medical Director, AstraZeneca; Dan Freeman, PhD – VP Projects Early Oncology, AstraZeneca; Anis Khan, PhD – Senior Director, AstraZeneca; Song Ren, PhD – Senior Director, AstraZeneca; Megan Gibbs, Ph.D., BscPharm, FCP – Vice President, AstraZeneca; Alex Phipps, PhD – Senior Director, AstraZeneca

Objectives: Volrustomig (MEDI5752) is a monovalent bispecific antibody (DuetMab) with an Fc-domain engineered to reduce effector function, targeting two clinically validated negative T cell regulators, Programmed death 1 (PD-1) and cytotoxic T-lymphocyte-associated protein-4 (CTLA-4). The bispecific antibody has been designed to suppress the PD-1 pathway and provide enhanced CTLA4 inhibition in the context of PD1 expression, such as PD1+/CTLA4+ activated T cells. Our goal was to develop and validate a dual TMDD model by incorporating the cell binding data to predict a safe starting dose and clinical efficacious exposure in humans for the First-Time-In-Human (FTIH) study.

Methods: The dual TMDD model included human monoclonal antibody (mAb) PK, PD-1 and CTLA-4 receptor occupancy (RO) on different T cell populations including PD-1- (non-activated) and PD-1+ (activated T cells / Tumour infiltrating Lymphocytes (TIL)). The in vitro cell binding data, including antibody affinity and antigen density, were incorporated into the model to predict human exposure and extent of volrustomig for PD-1 and CTLA-4 RO on both resting and activated T cell populations in the periphery and TILs. By integrating the comprehensive data into the model, a safe starting dose and escalation scheme for FTIH trial were determined based on toxicology and pharmacology considerations. The model predictions were later confirmed with clinical PK and RO data from the Phase 1 study (NCT03530397).

Results: The dual TMDD model adequately predicted the observed in vitro cell based binding data and human PKPD. Model-predicted EC50 values (6.5 and 30 nM respectively) were consistent with the observed EC50 values for CTLA-4 and PD-1 (4.07 nM and 84.9 nM, respectively) in functional cell-based assay for volrustomig. Based on the predicted human PK and RO, the MABEL-based starting human dose of 2.25 mg Q3W was proposed by identifying the dose needed to keep Cmax concentration below the EC20 values for CTLA-4 occupancy on PD-1-/CTLA-4 + single positive cells. The starting dose was predicted to show a safety margin of 1025-fold compared to the cynomolgus monkey AUC at the highest non-severely toxic dose (HNSTD) level. Predicted human PK profiles were in good agreement with clinical PK data.

Conclusions: This model predicts that a flat dose of 2.25 Q3W volrustomig is a safe starting dose in FTIH study. The model can be used generally for design, optimization and human dose prediction of similar class of bispecific antibodies.

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