Lupkynis: genotox, carcinogenicity and repro: done or skipped?

“Mix-ISA247 (approximately 50: 50 cis-trans mixture) was negative for genetic toxicity in the in vitro bacteria reverse mutation assay (Ames) test, a chromosomal aberration test with CHO cells, and an in vivo micronucleus assay in rats after single oral doses up to 2000 mg/kg.”

“Two-year studies were conducted in rats and mice. In the rat study, there were no voclosporin-related neoplasms in either males or females. In the mouse study, females had a significant increase in voclosporin-related malignant lymphomas at the high dose of 30 mg/kg/day”

“Mix-ISA247 caused a decrease in litter size and numbers of viable pups and an increase in resorptions (both early and late) at 25 mg/kg/day in the embryofetal development study in rats.”

“Cardiovascular studies in conscious cynomolgus monkeys found a that voclosporin, mix-ISA247 or cis-enhance ISA247 at a high dose of 200 mg/kg increased the QTc interval. There was also a signal for QTc prolongation from the hERG assay and Purkinje fiber electrophysiology assay.”

“Voclosporin was negative for mutagenic potential in the in vitro bacteria reverse mutation assay (Ames) test.”

“Voclosporin was not mutagenic in a bacterial reverse mutation assay (Ames) or in a vitro chromosomal aberration assay using CHO cells.”

“An isomer mix (Mix-ISA247), used in early development, showed no genotoxic potential in an in vivo micronucleus assay with bone marrow smears.”

“Two long term studies with voclosporin were performed in mice and rats. Planned to be 2-year studies, both had to be early terminated due to decreased survival.”

“Two-year studies were conducted in rats and mice.”

“The hERG assay showed IC50 values of 23, 72, and 43 µM for mix-ISA247, cis-ISA247, and voclosporin, respectively.”