MDM2 inhibitors block the interaction between the Tumor Protein p53 (TP53) and MDM2, its key negative regulator, and represent a new therapeutic concept for cancer therapy. MDM2 inhibitors are designed to restore p53 activity in TP53 wild-type tumors. Several MDM2 inhibitors are currently being evaluated in early clinical development with mainly daily dosing regimens. However, recent clinical data suggest myelosuppression as an on-target, dose-limiting toxicity for this class of inhibitors. Particularly thrombocytopenia could limit the clinical utility of MDM2 inhibitors. Hence there is a need to mitigate these side effects and to improve the therapeutic window. One approach is less frequent dosing to allow bone marrow recovery while still maintaining efficacious exposure levels and clinical activity. Here we present pharmacokinetic data on BI 907828, a novel and potent MDM2 inhibitor with optimized drug-like properties. Due to its high permeability, good physiological solubility and low systemic clearance, the compound shows a high bioavailability in mice, rats, dogs and minipigs. BI 907828 is not absorption-limited, even at multiples of the efficacious dose, and shows a reliable, dose-linear PK with low variability in AUC and Cmax across species. Based on a good PK-PD correlation with efficacy in preclinical models and a robust human PK prediction based on in vivo PK data across species, a low human efficacious dose is predicted. The PK properties of BI 907828 enable a variety of different clinical dosing schedules with the potential to improve the therapeutic index with respect to on-target safety. In summary, BI 907828 is a novel, potent, orally available MDM2 inhibitor with excellent PK properties and low estimated human dose suitable for high-dose intermittent dose schedules in the clinic.

Citation Format: Joerg Rinnenthal, Dorothea Rudolph, Sophia Blake, Andreas Gollner, Andreas Wernitznig, Ulrike Weyer-Czernilofsky, Christian Haslinger, Pilar Garin-Chesa, Jürgen Moll, Norbert Kraut, Darryl McConnell, Jens Quant. BI 907828: A highly potent MDM2 inhibitor with low human dose estimation, designed for high-dose intermittent schedules in the clinic [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 4865.