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

“Sebetralstat was not mutagenic or clastogenic in the following assays: in vitro bacterial reverse mutation assay (Ames test), in vitro chromosomal aberration assay in mouse lymphoma cells, and in vivo rat micronucleus assay.”

“A statement regarding carcinogenicity has been implemented in SmPC in section 5.3. to reflect the lack of carcinogenicity based on a 26-week study in rasH2-Tg transgenic mice and a 104-week study in rats.”

“In an embryo-fetal development (EFD) study in pregnant rats, administration of sebetralstat during the period of organogenesis caused increased incidence of malformations in offspring, specifically cleft palate and incomplete interventricular septum of the heart, at 60 times the exposure at the maximum recommended human dose (MRHD) of 1,200 mg sebetralstat.”

“an in vitro study on hERG channels demonstrated the absence of inhibition > 30% of these channels at a concentration of 30 µM. This concentration allows a safety margin > 50. When NHP was exposed to doses up to 300 mg/kg, no effect was observed on heart rate, BP and ECG parameters, QTc prolongation and other waveform morphologies.”

“Sebetralstat was negative for mutagenic or clastogenic potential in the following assays: in vitro bacterial reverse mutation assay (Ames test), in vitro L5178Y gene mutation assay, and the in vivo micronucleus assay (bone marrow) in male and female Wistar Han rats.”

“Sebetralstat was negative for mutagenic or clastogenic potential in the following assays: in vitro bacterial reverse mutation assay (Ames test), in vitro L5178Y gene mutation assay, and the in vivo micronucleus assay (bone marrow) in male and female Wistar Han rats.”

“Sebetralstat was negative for mutagenic or clastogenic potential in the following assays: in vitro bacterial reverse mutation assay (Ames test), in vitro L5178Y gene mutation assay, and the in vivo micronucleus assay (bone marrow) in male and female Wistar Han rats.”

“A statement regarding carcinogenicity has been implemented in SmPC in section 5.3. to reflect the lack of carcinogenicity based on a 26-week study in rasH2-Tg transgenic mice and a 104-week study in rats.”

“While the NDA includes appropriate preapproval nonclinical and clinical pharmacology studies, a post-marketing requirement will be issued to complete an ongoing 2-year carcinogenicity study in rats receiving sebetralstat.”

“With regard to the cardiovascular system, an in vitro study on hERG channels demonstrated the absence of inhibition > 30% of these channels at a concentration of 30 µM. This concentration allows a safety margin > 50. When NHP was exposed to doses up to 300 mg/kg, no effect was observed on heart rate, BP and ECG parameters, QTc prolongation and other waveform morphologies.”