Non-Clinical Safety Evaluation and Risk Assessment of Aleglitazar, a Dual PPAR α/γ Agonist, and Its Major Human Metabolite

The non-clinical safety evaluation of aleglitazar, a dual PPAR α/γ agonist, and its major human metabolite M6 included comprehensive studies on drug metabolism, pharmacokinetics, safety pharmacology, genotoxicity, repeat dose toxicity, reproductive toxicity, and carcinogenicity. Key findings included effects on red blood cell parameters, liver, heart, kidney, reproductive organs, bone marrow, adipose tissue, and fluid accumulation, consistent with other PPAR agonists. Notably, a 12-month monkey study observed generalized hair loss/thinning across all groups. Carcinogenicity studies showed no significant tumor increase in rats, but mice had a higher incidence of angiomatous tumors and some gallbladder adenomas. No significant effects were found in safety pharmacology, genotoxicity, and immunotoxicity studies. Reproductive toxicity effects were similar to other PPARγ agonists. The human metabolite M6 did not show adverse findings that would hinder human dosing. Overall, the non-clinical safety data supported the progression to clinical Phase 3 trials.