Senior Manager, Clinical Pharmacology Bicycle Therapeutics, United States
Disclosure(s):
Andy Tse: No relevant disclosure to display
Objectives: BT7480 is a novel, fully synthetic Bicycle tumor-targeted immune cell agonist (Bicycle TICA®) molecule comprised of three bicyclic peptides, one targeting Nectin-4 and two agonist binders of CD137. Nectin-4 is highly expressed in multiple cancers, and CD137 is expressed on T and natural killer cells. Targeting by Nectin-4 binding and agonism of CD137 by BT7480 is hypothesized to result in a tumor-localized costimulatory signal leading to enhanced antitumor activity. BT7480 is currently being evaluated in a phase 1/2 study (NCT05163041) alone or in combination with nivolumab in patients with advanced solid tumors. Dose escalation started at 0.002 mg/kg weekly (QW) and continued through 3.5 mg/kg QW monotherapy as of 12 Feb 2024. This analysis aimed to identify an optimal dose range for further development of BT7480 based on cross-linking (BT7480 binding to CD137+ T cells and Nectin-4+ tumor cells simultaneously) and CD137 and Nectin-4 receptor occupancy (RO) projected from a fit-for-purpose QSP model.
Methods: A pharmacokinetic (PK) and a target binding model were built to simulate BT7480 cross-linking in vitro and in patients with solid tumors. The model was parameterized with biophysical properties of BT7480 and the targets (CD137 and Nectin-4) using internal and literature data, and calibrated with in vitro RO, bioactivity, and clinical PK/pharmacodynamic (PD) data. Subsequently, simulations were performed for various dosing regimens to identify the optimal dose range for further development.
Results: The model adequately characterized the clinical PK/PD and in vitro PD data. Simulations of total max cross-linking demonstrated a plateau within the dose range of 0.6 to 3.5 mg/kg, supporting this dose range to be further tested in the clinic. This is in line with preliminary efficacy and PD data from the clinical study, which also suggested 0.6 to 3.5 mg/kg to be a pharmacologically active range for further investigation. Within this dose range, simulated tumor CD137 RO reached a plateau, while tumor Nectin-4 RO continued to increase.
Conclusions: The fit-for-purpose QSP model serves as an integrated approach to leverage preclinical and clinical PK/PD data under a mechanistic framework to facilitate optimal dose range identification for further BT7480 clinical development.
