13 NONCLINICAL TOXICOLOGY 

 

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

 

Carcinogenesis 

 

Carcinogenicity was eva luated in CD-1 mice and Sprague-Dawley rats. In the mouse study, ertugliflozin was administered by oral gavage at doses of 5, 15, and 40 mg/kg/day for up to 97 weeks in males and 102 weeks in females. There were no ertugliflozin-related neoplastic findings at doses up to 40 mg/kg/day (approximately 50 times human exposure at the maximum recommended human dose [MRHD] of 15 mg/day based on AUC). In the rat study, ertugliflozin was administered by oral gavage at doses of 1.5, 5, and 15 mg/kg/day for up to 92 weeks in females and 104 weeks in males. Ertugliflozin-related neoplastic findings included an increased incidence of adrenal medullary pheochromocytoma (PCC) in male rats at 15 mg/kg/day. Although the molecular mechanism remains unknown, this finding may be related to carbohydrate malabsorption leading to altered calcium homeostasis, which has been associated with PCC development in rats and has unclear relevancy to human risk. The no-observed-effect level (NOEL) for neoplasia was 5 mg/kg/day (approximately 16 times human exposure at the MRHD of 15 mg/day, based on AUC).

Mutagenesis 

 

Ertugliflozin was not mutagenic or clastogenic with or without metabolic activation in the microbial reverse mutation, in vitro cytogenetic (human lymphocytes), and in vivo rat micronucleus assays.

Impairment of Fertility 

 

In the rat fertility and embryonic development study, male and female rats were administered ertugliflozin at 5, 25, and 250 mg/kg/day. No effects on fertility were observed at 250 mg/kg/day (approximately 480 and 570 times male and female human exposures, respectively, at the MRHD of 15 mg/day based on AUC comparison).

 

14 CLINICAL STUDIES 

 

14.1 Overview of Clinical Studies in Patients with Type 2 Diabetes Mellitus

 

The efficacy and safety of STEGLATRO have been studied in 7 multicenter, randomized, double-blind, placebo- or active comparator-controlled, clinical studies involving 4,863 patients with type 2 diabetes mellitus. These studies included White, Hispanic, Black, Asian, and other racial and ethnic groups, and patients with an average age of approximately 57.8 years.

 

STEGLATRO has been studied as monotherapy and in combination with metformin and/or a dipeptidyl peptidase 4 (DPP-4) inhibitor. STEGLATRO has also been studied in combination with antidiabetic medications, including insulin and a sulfonylurea, in patients with type 2 diabetes mellitus with moderate renal impairment.

 

In patients with type 2 diabetes mellitus treatment with STEGLATRO reduced hemoglobin A1c (HbA1c) compared to placebo. 

 

In patients with type 2 diabetes mellitus treated with STEGLATRO, the reduction in HbA1c was generally similar across subgroups defined by age, sex, race, geographic region, baseline body mass index (BMI), and duration of type 2 diabetes mellitus. In patients with type 2 diabetes mellitus and moderate renal impairment, treatment with STEGLATRO did not result in a reduction in HbA1c compared to placebo.

 

14.2 Clinical Study of Monotherapy Use of STEGLATRO in Patients with Type 2 Diabetes Mellitus