No abstract

Activation of p53 by blocking p53-Mdm2 interaction using small-molecule inhibitors is being pursued as a promising cancer therapeutic strategy in p53 wild-type tumors. Here, we report the identification of NVP-HDM201, a novel, highly potent and selective inhibitor of the p53-Mdm2 interaction, with optimized drug-like properties allowing a versatile use with regard to route of administration, dose and scheduling. We determined the pharmacokinetics, pharmacodynamics and efficacy relationship of NVP-HDM201 with various dosing schedules in xenograft bearing mouse and rat models. NVP-HDM201 administered either daily at a low dose or once at a high dose revealed a differentiated engagement of the p53 molecular response. In contrast to the daily low dose treatment regimen, the single high dose NVP-HDM201 regimen resulted in a rapid and dramatic induction of p53-dependent PUMA expression and apoptosis. This was consistent with the finding that a single high dose NVP-HDM201 treatment, administered orally or intravenously, resulted in a robust and sustained tumor regression. Overall, both daily and once every 3 weeks dosing regimen showed comparable long term efficacy in preclinical studies. The ongoing clinical trial is currently designed to compare both dosing regimens with regard to efficacy and tolerability. Citation Format: Stéphane Ferretti, Ramona Rebmann, Marjorie Berger, Francesca Santacroce, Geneviève Albrecht, Kerstin Pollehn, Dario Sterker, Markus Wartmann, Andreas Hueber, Marion Wiesmann, Michael R. Jensen, Francesco Hofmann, William R. Sellers, Philipp Holzer, Sébastien Jeay. Insights into the mechanism of action of NVP-HDM201, a differentiated and versatile Next-Generation small-molecule inhibitor of Mdm2, under evaluation in phase I clinical trials. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 1224.

Although functional inactivation of the tumor suppressor p53 is a frequent genetic event, half of all human tumors express wild-type p53. Stabilization of p53 by antagonizing its negative regulator mouse double minute 2 (Mdm2) leads to selective induction of the p53 pathway, thus offering a promising therapeutic opportunity. NVP-CGM097 binds in the p53 pocket on the surface of Mdm2 and effectively disrupts the interaction between p53 and Mdm2. The aim of this study was to determine the pharmacokinetic (PK), pharmacodynamic (PD) and efficacy profile of this novel p53-Mdm2 inhibitor in mouse models of human cancer. During the medicinal chemistry discovery efforts, the compound series was optimized for oral administration. The selected compound, NVP-CGM097, was well absorbed in mice where the maximum plasma concentration (Tmax) was observed about 3 hours post dose followed by a prolonged absorption phase. PD effects were determined by measuring the expression levels of p53 target genes including p21, PUMA and Mdm2 in tumors. The expression levels of p53 target genes correlated with the concentrations of NVP-CGM097 demonstrating a good PK/PD relationship. Optimal treatment schedules were investigated in the Mdm2-amplified, p53 wild-type osteosarcoma xenograft model SJSA-1. Interestingly, various schedules were highly efficacious at well-tolerated dose levels. Tumor regression was observed when NVP-CGM097 was administered in schedules ranging from daily to twice per week with no adverse effects. Following dose optimization studies, potent anti-tumor efficacy was observed in a range of p53 wild-type expressing xenograft models including Mdm2 non-amplified orthotopic AML as well as well-differentiated (WDLPS) and dedifferentiated (DDLPS) liposarcomas. Overall, we demonstrate that the novel p53-Mdm2 inhibitor NVP-CGM097 has a good PK profile and affects PD markers in human tumors leading to tumor regression at well-tolerated dose levels. These data strongly support clinical development of NVP-CGM097. Citation Format: Stéphane Ferretti, Marjorie Berger, Ramona Rebmann, Francesca Santacroce, Dario Sterker, Michael Jensen, Keiichi Masuya, Sébastien Jeay. NVP-CGM097: a novel p53-Mdm2 inhibitor exhibiting potent antitumor activity in mouse models of human cancer. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 4638. doi:10.1158/1538-7445.AM2014-4638