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

“Inavolisib was not mutagenic in the bacterial reverse mutation (Ames) assay. Inavolisib was clastogenic in an in vitro human lymphocyte micronucleus assay. Inavolisib was not genotoxic in an in vivo rat bone marrow micronucleus test and did not induce DNA break in a liver comet assay.”

“Carcinogenicity studies were not conducted, nor warranted, with inavolisib to support the proposed indication in patients with advanced cancer in accordance with ICH S9 guidance.”

“Administration of inavolisib resulted in dose dependent effects on embryo-fetal development at ≥2 mg/kg ( ≥ 0.9 times the human exposure at the recommended dose of 9 mg/day based on AUC) that included decreases in fetal body weight and placental weight, post-implantation loss, lower fetal viability, fetal malformations”

“In a GLP-compliant single dose safety pharmacology study in telemetry instrumented Beagle dogs, inavolisib-related cardiovascular effects included generally dose-dependent, reversible decreases in heart rate, increases in arterial pressure and contractility, lengthening of PR and QT intervals (likely driven by the decreased heart rates), and minimally lengthened corrected QT (QTc) interval (+11 msec/+5%) at doses ≥ 0.3 mg/kg.”