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

“The in vitro Ames assay and in vivo mouse micronucleus assays were negative. Although an in vitro chromosomal aberration assay was positive, a clastogenic response was only evident at cytotoxic concentrations (mitotic index ≥50%).”

“Carcinogenicity assessment in two rodent species is considered necessary as a post marketing requirement.”

“Administration of daily oral doses of palovarotene to pregnant rats during the period of organogenesis resulted in multiple fetal external, visceral, and skeletal malformations at ≥0.25 mg/kg/day (below clinical exposures), consistent with the pattern of retinoid-mediated embryopathy.”

“Based on safety pharmacology studies conducted to assess the potential for cardiovascular, neurobehavioral, gastrointestinal and urinary effects, palovarotene did not appear to pose any”

“The in vitro Ames assay and in vivo mouse micronucleus assays were negative.”

“Although an in vitro chromosomal aberration assay was positive, a clastogenic response was only evident at cytotoxic concentrations (mitotic index ≥50%).”

“The in vitro Ames assay and in vivo mouse micronucleus assays were negative.”

“Dedicated rodent carcinogenicity studies to assess the carcinogenic potential of palovarotene have not been conducted; instead, the Applicant assessed the carcinogenic potential of palovarotene using a weight of evidence (WoE) approach outlined in an amendment to International Council for Harmonization S1B(R1).”

“Therefore, rodent carcinogenicity studies in two species to assesses the carcinogenic potential from long-term oral exposure to palovarotene are being recommended as post marketing requirements.”

“Palovarotene significant reduced inward and outward K+ currents, with IC50 of 7.2μM (~2985 ng/mL), which results in wide safety margin (>30-fold between hERG IC50 and the free Cmax at the MRHD).”