DAURISMO™ Nonclinical Toxicology

(glasdegib)

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

Carcinogenicity studies have not been performed with glasdegib.

Glasdegib was not mutagenic in vitro in the bacterial reverse mutation (Ames) assay and was not clastogenic in the in vitro chromosome aberration assay in human lymphocytes. Glasdegib was not clastogenic or aneugenic in the rat micronucleus assay.

Based on nonclinical safety findings, glasdegib has the potential to impair reproductive function in males. Men should seek advice on effective fertility preservation before treatment. In repeat-dose toxicity studies in rats, findings observed in the male reproductive tract included adverse testicular changes with glasdegib at doses ≥50 mg/kg/day, and consisted of minimal to severe hypospermatogenesis characterized by partial to complete loss of spermatogonia, spermatocytes and spermatids and testicular degeneration. Hypospermatogenesis did not recover whereas testicular degeneration did recover. The dose at which testicular effects were observed in male rats was identified as 50 mg/kg/day with corresponding systemic exposures that were approximately 6.6-times (based on AUC) those associated with the observed human exposure at the 100 mg once-daily dose.

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Nonclinical Toxicology

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

Carcinogenicity studies have not been performed with glasdegib.

Glasdegib was not mutagenic in vitro in the bacterial reverse mutation (Ames) assay and was not clastogenic in the in vitro chromosome aberration assay in human lymphocytes. Glasdegib was not clastogenic or aneugenic in the rat micronucleus assay.

Based on nonclinical safety findings, glasdegib has the potential to impair reproductive function in males. Men should seek advice on effective fertility preservation before treatment. In repeat-dose toxicity studies in rats, findings observed in the male reproductive tract included adverse testicular changes with glasdegib at doses ≥50 mg/kg/day, and consisted of minimal to severe hypospermatogenesis characterized by partial to complete loss of spermatogonia, spermatocytes and spermatids and testicular degeneration. Hypospermatogenesis did not recover whereas testicular degeneration did recover. The dose at which testicular effects were observed in male rats was identified as 50 mg/kg/day with corresponding systemic exposures that were approximately 6.6-times (based on AUC) those associated with the observed human exposure at the 100 mg once-daily dose.

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