BMS-986260

Small‐molecule inhibitors of transforming growth factor beta receptor 1 (TGFβRI) have a history of significant class‐based toxicities (eg, cardiac valvulopathy) in preclinical species that have limited their development as new medicines. Nevertheless, some TGFβRI inhibitors have entered into clinical trials using intermittent‐dosing schedules and exposure limits in an attempt to avoid these toxicities. This report describes the toxicity profile of the small‐molecule TGFβRI inhibitor, BMS‐986260, in rats and dogs. Daily oral dosing for 10 days resulted in valvulopathy and/or aortic pathology at systemic exposures that would have been targeted clinically, preventing further development with this dosing schedule. These toxicities were not observed in either species in 1‐month studies using the same doses on an intermittent‐dosing schedule of 3 days on and 4 days off (QDx3 once weekly). Subsequently, 3‐month studies were conducted (QDx3 once weekly), and while there were no cardiovascular findings in dogs, valvulopathy and mortality occurred early in rats. The only difference compared to the 1‐month study was that the rats in the 3‐month study were 2 weeks younger at the start of dosing. Therefore, a follow‐up 1‐month study was conducted to evaluate whether the age of rats influences sensitivity to target‐mediated toxicity. Using the same dosing schedule and similar doses as in the 3‐month study, there was no difference in the toxicity of BMS‐986260 in young (8 weeks) or adult (8 months) rats. In summary, an intermittent‐dosing schedule mitigated target‐based cardiovascular toxicity in dogs but did not prevent valvulopathy in rats, and thus the development of BMS‐986260 was terminated.

Novel imidazole-based TGFβR1 inhibitors were identified and optimized for potency, selectivity, and pharmacokinetic and physicochemical characteristics. Herein, we report the discovery, optimization, and evaluation of a potent, selective, and orally bioavailable TGFβR1 inhibitor, 10 (BMS-986260). This compound demonstrated functional activity in multiple TGFβ-dependent cellular assays, excellent kinome selectivity, favorable pharmacokinetic properties, and curative in vivo efficacy in combination with anti-PD-1 antibody in murine colorectal cancer (CRC) models. Since daily dosing of TGFβR1 inhibitors is known to cause class-based cardiovascular (CV) toxicities in preclinical species, a dosing holiday schedule in the anti-PD-1 combination efficacy studies was explored. An intermittent dosing regimen of 3 days on and 4 days off allowed mitigation of CV toxicities in one month dog and rat toxicology studies and also provided similar efficacy as once daily dosing.