Nonclinical Profile of PF-06952229 (MDV6058), a Novel TGFßRI/Activin Like Kinase 5 (ALK-5) Inhibitor Supports Clinical Evaluation in Cancer.

ABSTRACT

The development of TGFßR inhibitors (TGFßRi) as new medicines have been affected by cardiac valvulopathy and arteriopathy toxicity findings in nonclinical toxicology studies. PF-06952229 (MDV6058) selected using rational drug design is a potent and selective TGFßRI inhibitor (TGFßRIi) with a relatively clean off-target selectivity profile and good pharmacokinetic properties across species. PF-06952229 inhibited clinically translatable phospho-SMAD2 biomarker ({greater than or equal to}60%) in human and cynomolgus monkey peripheral blood mononuclear cells, as well as in mouse and rat splenocytes. Using an optimized, intermittent dosing schedule (7 day-on, 7-off/cycle; five cycles), PF-06952229 demonstrated efficacy in a 63-day syngeneic MC38 colon carcinoma mouse model. In the pivotal repeat dose toxicity studies (rat and cynomolgus monkey), PF-06952229 on an intermittent dosing schedule (5 day-on, 5-off/cycle; five cycles, 28 doses) showed no cardiac-related adverse findings. However, new toxicity findings related to PF-06952229 included reversible hepatocellular (hepatocyte necrosis with corresponding clinically monitorable transaminase increases) and lung (hemorrhage with mixed cell inflammation) findings at {greater than or equal to} targeted projected clinical efficacious exposures. Furthermore, partially reversible cartilage hypertrophy (trachea and femur in rat; femur in monkey), and partially to fully reversible, clinically monitorable decreases in serum phosphorus and urinary phosphate, at {greater than or equal to} projected clinically efficacious exposures were observed. Given the integral role of TGFß in endochondral bone formation, cartilage findings in toxicity studies have been observed with other TGFßRi class of compounds. The favorable cumulative profile of PF-06952229 in biochemical, pharmacodynamic, pharmacokinetic and nonclinical studies, allowed for its evaluation in cancer patients using the intermittent dosing schedule (7-on/7-off) and careful protocol-defined monitoring. Significance Statement Only a few TGFßRi have progressed for clinical evaluation due to adverse cardiac findings in pivotal nonclinical toxicity studies. Potential translation of such findings in patients are of major concern. Using a carefully optimized intermittent dosing schedule PF-06952229 has demonstrated impressive pharmacological efficacy in the syngeneic MC38 colon carcinoma mouse model. Additionally, a nonclinical toxicology package without cardiovascular liabilities and generally monitorable toxicity profile has been completed. The compound presents an acceptable ICHS9 compliant profile for the intended-to-treat cancer patients.