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

“Olezarsen was not mutagenic in vitro or in vivo.”

“Carcinogenicity studies were not conducted with olezarsen, but lifetime carcinogenicity studies were conducted for the active unconjugated ASO, volanesorsen, in both mice and rats.”

“The Agency agreed that embryofetal development and pre-/postnatal development evaluations conducted with the unconjugated active ASO component of olezarsen in mice and/or rabbits were adequate to support a marketing application.”

“Other than a transient increase in heart rate at the highest dose at 360 minutes, there were no effects on cardiovascular, respiratory, or central nervous system functioning observed.”

“Overall, this test concluded that olezarsen does not possess mutagenic potential in bacterial systems.”

“Consequently, olezarsen was considered negative for clastogenicity, meaning it did not cause chromosomal damage in CHL cells up to the highest concentration tested.”

“For genotoxicity, the studies conducted did not show any mutagenic or clastogenic potential, with negative results in the Ames test, chromosome aberration assay, and in vivo micronucleus assay.”

“Carcinogenicity studies were not conducted with olezarsen, but lifetime carcinogenicity studies were conducted for the active unconjugated ASO, volanesorsen, in both mice and rats.”

“they determined that no additional carcinogenicity studies were required for olezarsen, and that the data from volanesorsen’s carcinogenicity studies were sufficient to support olezarsen.”

“At concentrations of 30 and 300 µM, minimal reductions (<2%) in hERG current were noted. The IC50 was considered >300µM (greater than 1000 times the human exposure).”