Non-clinical safety evaluation and risk assessment to human of aleglitazar, a dual PPAR α/γ agonist, and its major human metabolite

•Publication of overall non-clinical safety profile incl. major human metabolite.•Summarizes data from over 50 toxicology studies conducted over more than 10 years.•High major metabolite exposure in human - not in animal toxicity studies.•Occurrence of hair loss/thinning in chronic monkey toxicity study.•Describes risk assessment that supported long-term Phase 3 clinical trials.

The non-clinical safety profile of aleglitazar, a peroxisome proliferator activated receptor alpha/gamma agonist, and its major human metabolite M6 was studied in a complete package consisting of drug metabolism and pharmacokinetics characterization, safety pharmacology, genotoxicity, repeat dose toxicity, reproductive toxicity and carcinogenicity studies. These studies identified the following main targets similar to other PPAR agonists: red blood cell parameters, liver, heart, kidney, ovaries, testes, bone marrow, adipose tissue, and fluid accumulation. Additionally, and in the 12-month monkey study only, an increased incidence of generalized hair loss/thinning was observed in all groups including controls. In the rat carcinogenicity study there was no statistically significant increase in tumors. In the mouse carcinogenicity study, there was an increased incidence of angiomatous tumors and there were three males with gallbladder adenoma. No relevant compound-related effects were observed in safety pharmacology, genotoxicity, and a 28-day immunotoxicity rat study. Effects observed in reproductive toxicity studies were similar to those known for other PPARγ agonists. Separate studies with the human metabolite M6 did not reveal findings that would prevent human dosing. Overall, the results from the non-clinical safety studies conducted with aleglitazar and the human metabolite M6 were considered to support the clinical Phase 3 program.