Nonclinical Profile of PF-06952229 (MDV6058), a Novel TGFβRI/Activin Like Kinase 5 Inhibitor Supports Clinical Evaluation in Cancer
The development of transforming growth factor β receptor inhibitors (TGFβRi) as potential therapeutic agents has faced significant challenges, primarily due to concerns about cardiac valvulopathy and arteriopathy toxicity identified in nonclinical toxicology studies. PF-06952229 (also known as MDV6058), a potent and selective TGFβRI inhibitor, was developed using rational drug design and features a relatively clean off-target selectivity profile, as well as favorable pharmacokinetic properties across multiple species. PF-06952229 has shown effective inhibition of the phospho-SMAD2 biomarker (≥60%) in human and cynomolgus monkey peripheral blood mononuclear cells, as well as in mouse and rat splenocytes, making it a promising candidate for clinical translation.
In preclinical studies, PF-06952229 demonstrated significant efficacy when administered using an optimized intermittent dosing schedule (7 days on/7 days off per cycle, for 5 cycles) in a 63-day syngeneic MC38 colon carcinoma mouse model. This dosing regimen provided effective therapeutic results, further supporting the compound’s potential for clinical application. During pivotal repeat-dose toxicity studies conducted in rats and cynomolgus monkeys, PF-06952229, when dosed intermittently on a 5-day on/5-day off cycle for a total of 28 doses, did not show any cardiac-related adverse effects, which is a major advantage over other TGFβRi agents that have encountered cardiovascular concerns.
However, new toxicity findings were observed with PF-06952229, primarily related to hepatocellular toxicity (evidenced by hepatocyte necrosis and corresponding clinically measurable increases in transaminases) and lung toxicity (characterized by hemorrhage with mixed cell inflammation) at or above the projected clinical efficacious exposures. Additionally, toxicity related to cartilage hypertrophy (seen in the trachea and femur of rats, and femur of monkeys) was noted, although these changes were partially reversible. Furthermore, reductions in serum phosphorus and urinary phosphate levels, which were partially to fully reversible, were also detected at doses corresponding to projected clinical efficacious exposures.
Given that TGFβ plays an essential role in endochondral bone formation, cartilage-related findings are not unique to PF-06952229 and have been observed with other TGFβRi compounds in clinical development. Despite these findings, the overall pharmacological profile of PF-06952229 in terms of its biochemical, pharmacodynamic, pharmacokinetic, and nonclinical toxicology properties remains favorable. The compound’s nonclinical toxicology data, which lack cardiovascular liabilities and have a generally manageable toxicity profile, support its further evaluation in cancer patients under an intermittent dosing regimen (7 days on/7 days off) with careful monitoring as defined in the treatment protocol.