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

“Bempedoic acid was not mutagenic in the Ames test. Increases in chromosome aberration were observed in human peripheral blood lymphocytes in vitro, but only in the presence of S9 and at a concentration associated with a level of cytotoxicity that approached or exceeded the maximum permissible.”

“In the 2-year rat carcinogenicity study, the incidences of hepatocellular adenomas, hepatocellular adenomas combined with carcinomas, thyroid follicular cell adenomas, follicular cell adenomas combined with carcinomas, and pancreas islet cell adenomas combined with carcinomas were statistical increased in male rats at 30 mg/kg/day.”

“The low safety margins identified from fertility, embryo-fetal and pre-and postnatal development studies conducted in rat (Table 47) are considered acceptable, because the adverse effects were only observed at maternally toxic doses.”

“In safety pharmacology studies, bempedoic acid administration was not associated with adverse effects on CNS, pulmonary, or cardiovascular function.”

“Bempedoic acid was negative for mutagenicity in an in vitro Ames assay and negative for clastogenicity in the vitro human lymphocyte chromosome aberration assay.”

“Positive: Clastogenic response was observed with metabolic activation at the highest concentration tested (1,000 μg/mL). However, this response was considered not biologically relevant since 1,000 μg/mL concentration cytotoxic (relative mitotic index = 58%).”

“Bempedoic acid was negative in both in vivo mouse micronucleus and in vivo rat bone marrow micronucleus/liver comet assay.”

“The carcinogenic potential of bempedoic acid was evaluated in a 2-year study in mice and rats.”

“the IND was put on Partial Clinical Hold on November 19, 2009, for clinical studies in excess of 6 months until draft repo1ts from completed 2-year rat and mouse carcinogenicity studies were submitted.”

“A statistically significant 5.4% inhibition of the hERG current was noted at 1,000μM, the highest concentration tested. IC50 was not calculated but was estimated to be >1,000μM (345 μg/mL), at least 15 times the human Cmax at the clinical dose of 180 mg.”