Investigations on the Relationship Between Ovarian, Endocrine, and Renal Findings in Nonclinical Safety Studies of the γ-Secretase Inhibitor Avagacestat

Frank J Simutis; Thomas P Sanderson; Gary D Pilcher; Michael J Graziano

doi:10.1093/toxsci/kfz129

Investigations on the Relationship Between Ovarian, Endocrine, and Renal Findings in Nonclinical Safety Studies of the γ-Secretase Inhibitor Avagacestat

Toxicol Sci. 2019 Sep 1;171(1):98-116. doi: 10.1093/toxsci/kfz129.

Authors

Frank J Simutis¹, Thomas P Sanderson¹, Gary D Pilcher¹, Michael J Graziano¹

Affiliation

¹ Drug Safety Evaluation, Research and Development, Bristol-Myers Squibb Company, New Brunswick, New Jersey 08903.

PMID: 31165171
DOI: 10.1093/toxsci/kfz129

Abstract

Avagacestat, a gamma (γ)-secretase inhibitor that was in development for treatment of Alzheimer's disease, produced ovarian granulosa-thecal cell tumors in rats and dogs and a glomerulopathy with profound proteinuria in female rats. This report describes the results of follow-up investigative studies, including the use of ovariectomized (OVX) rats, to further characterize these findings and determine their mechanism(s). Ovarian proliferative changes in rats likely resulted from: (1) inhibition of Notch signaling pathways regulating ovarian follicular differentiation/development, characterized microscopically as altered ovarian cyclicity and/or ovarian follicular degeneration; (2) subsequent disruption of the hypothalamic-pituitary-ovarian axis due to ovarian atrophy with decreases in serum estrogen and progesterone (as low as 0.45× and 0.21× controls, respectively); and (3) chronic gonadotropin stimulation and pituitary hypertrophy/hyperplasia in response to the absence of negative feedback. Gonadotropin stimulation in rats was confirmed by increases in serum follicle-stimulating hormone (up to 7.75× controls) and luteinizing hormone (up to 5.84×). A similar nongenotoxic mechanism was likely responsible for the ovarian findings in dogs although changes in serum hormone levels were not detected. The dose- and time-dependent glomerulopathy with progression to chronic progressive nephropathy in female rats appears to be a direct effect of avagacestat and was not ameliorated with coadministration of 17β-estradiol or an antihypertensive (enalapril) and was not present in control OVX rats. In contrast, adrenocortical hypertrophy in female rats was considered secondary to ovarian changes based on the absence of this finding in avagacestat-treated OVX rats and no increase in adrenocorticotropic hormone staining in the pituitary.

Keywords: avagacestat; gamma (γ)-secretase inhibitor; glomerulopathy; granulosa-thecal cell tumor; ovariectomized rats; subchronic/chronic toxicity.