Givlaari: which tox species, and why?

“In addition to being pharmacologically active in humans, based on the nonclinical data described below, givosiran is also pharmacologically active in both rats and monkeys but is not pharmacologically active in rabbits.”

“This parent duplex, with complete sequence homology to human and monkey ALAS1, and is therefore expected to be pharmacologically active in each of the indicated species.”

“Pharmacodynamics measurement on GD 22 indicated that givosiran did not reduce hepatic ALAS1 transcript levels in pregnant rabbits at any dose level, confirming that givosiran is not pharmacologically active in rabbits.”

“In the repeat-dose toxicity studies conducted in rats and monkeys, the rat was identified as the most sensitive species to givosiran-related effects, with the liver being identified as the primary target organ of toxicity in both the rat and monkey.”

“Maximal exposure was low in pregnant rats (maximally 1.7x human exposure based on AUC) and slightly higher in rabbits (maximally 5x human exposure).”

“There was no evidence of carcinogenicity in the 26-week conducted in f Tg-rasH2 mice. A longer, 2-year carcinogenicity study in Sprague Dawley rats (AS1-GLP18-007), currently ongoing, will be submitted upon its completion.”

“In addition to being pharmacologically active in humans, based on the nonclinical data described below, givosiran is also pharmacologically active in both rats and monkeys but is not pharmacologically active in rabbits.”