Steglujan ertugliflozin and sitagliptin 5 mg; 100 mg Tablet, Film Coated — NDC 0006-5367-09 (Billing 00006-5367-09)

12 CLINICAL PHARMACOLOGY

12.1Mechanism of Action STEGLUJAN STEGLUJAN combines two antihyperglycemic agents with complementary mechanisms of action to improve glycemic control in patients with type 2 diabetes mellitus: ertugliflozin, a SGLT2 inhibitor, and sitagliptin, a DPP-4 inhibitor. Ertugliflozin SGLT2 is the predominant transporter responsible for reabsorption of glucose from the glomerular filtrate back into the circulation. Ertugliflozin is an inhibitor of SGLT2.

By inhibiting SGLT2, ertugliflozin reduces renal reabsorption of filtered glucose and lowers the renal threshold for glucose, and thereby increases urinary glucose excretion. Sitagliptin Sitagliptin is a DPP-4 inhibitor, which is believed to exert its actions in patients with type 2 diabetes mellitus by slowing the inactivation of incretin hormones. Concentrations of the active intact hormones are increased by sitagliptin, thereby increasing and prolonging the action of these hormones.

Incretin hormones, including glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP), are released by the intestine throughout the day, and levels are increased in response to a meal. These hormones are rapidly inactivated by the enzyme, DPP-4. The incretins are part of an endogenous system involved in the physiologic regulation of glucose homeostasis.

When blood glucose concentrations are normal or elevated, GLP-1 and GIP increase insulin synthesis and release from pancreatic beta cells by intracellular signaling pathways involving cyclic AMP. GLP-1 also lowers glucagon secretion from pancreatic alpha cells, leading to reduced hepatic glucose production. By increasing and prolonging active incretin levels, sitagliptin increases insulin release and decreases glucagon levels in the circulation in a glucose-dependent manner.

Sitagliptin demonstrates selectivity for DPP-4 and does not inhibit DPP-8 or DPP-9 activity in vitro at concentrations approximating those from therapeutic doses.

12.2Pharmacodynamics Ertugliflozin Urinary Glucose Excretion and Urinary Volume Dose-dependent increases in the amount of glucose excreted in urine were observed in healthy subjects and in patients with type 2 diabetes mellitus following single- and multiple-dose administration of ertugliflozin. Dose-response modeling indicates that ertugliflozin 5 mg and 15 mg result in near maximal urinary glucose excretion (UGE). Enhanced UGE is maintained after multiple-dose administration.

UGE with ertugliflozin also results in increases in urinary volume. Cardiac Electrophysiology The effect of ertugliflozin on QTc interval was evaluated in a Phase 1 randomized, placebo- and positive-controlled 3-period crossover study in 42 healthy subjects. At 6.7 times the therapeutic exposures with maximum recommended dose, ertugliflozin does not prolong QTc to any clinically relevant extent.

Sitagliptin General In patients with type 2 diabetes mellitus, administration of sitagliptin led to inhibition of DPP-4 enzyme activity for a 24-hour period. After an oral glucose load or a meal, this DPP-4 inhibition resulted in a 2- to 3-fold increase in circulating levels of active GLP-1 and GIP, decreased glucagon concentrations, and increased responsiveness of insulin release to glucose, resulting in higher C-peptide and insulin concentrations. The rise in insulin with the decrease in glucagon was associated with lower fasting glucose concentrations and reduced glucose excursion following an oral glucose load or a meal.

In a two-day study in healthy subjects, sitagliptin alone increased active GLP-1 concentrations, whereas metformin alone increased active and total GLP-1 concentrations to similar extents. Coadministration of sitagliptin and metformin had an additive effect on active GLP-1 concentrations. Sitagliptin, but not metformin, increased active GIP concentrations.

It is unclear how these findings relate to changes in glycemic control in patients with type 2 diabetes mellitus. In studies with… [Excerpted — this section continues on DailyMed.]

12.1Mechanism of Action STEGLUJAN STEGLUJAN combines two antihyperglycemic agents with complementary mechanisms of action to improve glycemic control in patients with type 2 diabetes mellitus: ertugliflozin, a SGLT2 inhibitor, and sitagliptin, a DPP-4 inhibitor. Ertugliflozin SGLT2 is the predominant transporter responsible for reabsorption of glucose from the glomerular filtrate back into the circulation. Ertugliflozin is an inhibitor of SGLT2.

By inhibiting SGLT2, ertugliflozin reduces renal reabsorption of filtered glucose and lowers the renal threshold for glucose, and thereby increases urinary glucose excretion. Sitagliptin Sitagliptin is a DPP-4 inhibitor, which is believed to exert its actions in patients with type 2 diabetes mellitus by slowing the inactivation of incretin hormones. Concentrations of the active intact hormones are increased by sitagliptin, thereby increasing and prolonging the action of these hormones.

Incretin hormones, including glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP), are released by the intestine throughout the day, and levels are increased in response to a meal. These hormones are rapidly inactivated by the enzyme, DPP-4. The incretins are part of an endogenous system involved in the physiologic regulation of glucose homeostasis.

When blood glucose concentrations are normal or elevated, GLP-1 and GIP increase insulin synthesis and release from pancreatic beta cells by intracellular signaling pathways involving cyclic AMP. GLP-1 also lowers glucagon secretion from pancreatic alpha cells, leading to reduced hepatic glucose production. By increasing and prolonging active incretin levels, sitagliptin increases insulin release and decreases glucagon levels in the circulation in a glucose-dependent manner.

Sitagliptin demonstrates selectivity for DPP-4 and does not inhibit DPP-8 or DPP-9 activity in vitro at concentrations approximating those from therapeutic doses.

12.3Pharmacokinetics General Introduction Ertugliflozin The pharmacokinetics of ertugliflozin are similar in healthy subjects and patients with type 2 diabetes mellitus. The steady state mean plasma AUC and C max were 398 ng∙hr/mL and 81.3 ng/mL, respectively, with 5 mg ertugliflozin once daily treatment, and 1,193 ng∙hr/mL and 268 ng/mL, respectively, with 15 mg ertugliflozin once daily treatment. Steady-state is reached after 4 to 6 days of once-daily dosing with ertugliflozin.

Ertugliflozin does not exhibit time-dependent pharmacokinetics and accumulates in plasma up to 10-40% following multiple dosing. Sitagliptin The pharmacokinetics of sitagliptin have been extensively characterized in healthy subjects and patients with type 2 diabetes mellitus. After oral administration of a 100-mg dose to healthy subjects, sitagliptin was rapidly absorbed, with peak plasma concentrations (median T max ) occurring 1 to 4 hours postdose.

Plasma AUC of sitagliptin increased in a dose proportional manner. Following a single oral 100-mg dose to healthy volunteers, mean plasma AUC of sitagliptin was 8.52 μM∙hr, C max was 950 nM, and apparent terminal half-life (t 1/2 ) was 12.4 hours. Plasma AUC of sitagliptin increased approximately 14% following 100-mg doses at steady state compared to the first dose.

The intra subject and inter subject coefficients of variation for sitagliptin AUC were small (5.8% and 15.1%). The pharmacokinetics of sitagliptin was generally similar in healthy subjects and in patients with type 2 diabetes mellitus. Absorption STEGLUJAN The effects of a high-fat meal on the pharmacokinetics of ertugliflozin and sitagliptin when administered as STEGLUJAN tablets are comparable to those reported for the individual tablets.

Administration of STEGLUJAN with food decreased ertugliflozin C max by 29% and had no meaningful effect on ertugliflozin AUC inf , and on sitagliptin AUC inf and C max . Ertugliflozin Following single-dose oral administration of 5 mg and 15 mg of ertugliflozin, peak plasma concentrations of ertugliflozin occur at 1 hour postdose (median T max ) under fasted conditions. Plasma C max and AUC of ertugliflozin increase in a dose-proportional manner following single doses from 0.5 mg (0.1 times the lowest recommended dose) to 300 mg (20 times the highest recommended dose) and following multiple doses from 1 mg (0.2 times the lowest recommended dose) to 100 mg (6.7 times the highest recommended dose).

The absolute oral bioavailability of ertugliflozin following administration of a 15 mg dose is approximately 100%. Effect of Food Administration of ertugliflozin with a high-fat and high-calorie meal decreases ertugliflozin C max by 29% and prolongs T max by 1 hour, but does not alter AUC as compared with the fasted state. The observed effect of food on ertugliflozin pharmacokinetics is not considered clinically relevant, and ertugliflozin may be administered with or without food.

In Phase 3 clinical trials, ertugliflozin was administered without regard to meals. Sitagliptin The absolute bioavailability of sitagliptin is approximately 87%. Because coadministration of a high fat meal with sitagliptin had no effect on the pharmacokinetics, sitagliptin may be administered with or without food.

Distribution Ertugliflozin The mean steady-state volume of distribution of ertugliflozin following an intravenous dose is

85.5L. Plasma protein binding of ertugliflozin is 93.6% and is independent of ertugliflozin plasma concentrations. Plasma protein binding is not meaningfully altered in patients with renal or hepatic impairment.

The blood-to-plasma concentration ratio of ertugliflozin is 0.66. Sitagliptin The mean volume of distribution at steady state following a single 100-mg intravenous dose of sitagliptin to healthy subjects is approximately 198 L. The fraction of sitagliptin reversibly bound to plasma proteins is low (38%).

Elimination Metabolism Ertugliflozin Metabolism is the primary clearance mechanism for ertuglifl… [Excerpted — this section continues on DailyMed.]

12.2Pharmacodynamics Ertugliflozin Urinary Glucose Excretion and Urinary Volume Dose-dependent increases in the amount of glucose excreted in urine were observed in healthy subjects and in patients with type 2 diabetes mellitus following single- and multiple-dose administration of ertugliflozin. Dose-response modeling indicates that ertugliflozin 5 mg and 15 mg result in near maximal urinary glucose excretion (UGE). Enhanced UGE is maintained after multiple-dose administration.

UGE with ertugliflozin also results in increases in urinary volume. Cardiac Electrophysiology The effect of ertugliflozin on QTc interval was evaluated in a Phase 1 randomized, placebo- and positive-controlled 3-period crossover study in 42 healthy subjects. At 6.7 times the therapeutic exposures with maximum recommended dose, ertugliflozin does not prolong QTc to any clinically relevant extent.

Sitagliptin General In patients with type 2 diabetes mellitus, administration of sitagliptin led to inhibition of DPP-4 enzyme activity for a 24-hour period. After an oral glucose load or a meal, this DPP-4 inhibition resulted in a 2- to 3-fold increase in circulating levels of active GLP-1 and GIP, decreased glucagon concentrations, and increased responsiveness of insulin release to glucose, resulting in higher C-peptide and insulin concentrations. The rise in insulin with the decrease in glucagon was associated with lower fasting glucose concentrations and reduced glucose excursion following an oral glucose load or a meal.

In a two-day study in healthy subjects, sitagliptin alone increased active GLP-1 concentrations, whereas metformin alone increased active and total GLP-1 concentrations to similar extents. Coadministration of sitagliptin and metformin had an additive effect on active GLP-1 concentrations. Sitagliptin, but not metformin, increased active GIP concentrations.

It is unclear how these findings relate to changes in glycemic control in patients with type 2 diabetes mellitus. In studies with healthy subjects, sitagliptin did not lower blood glucose or cause hypoglycemia. Cardiac Electrophysiology In a randomized, placebo controlled crossover study, 79 healthy subjects were administered a single oral dose of sitagliptin 100 mg, sitagliptin 800 mg (8 times the recommended dose), and placebo.

At the recommended dose of 100 mg, there was no effect on the QTc interval obtained at the peak plasma concentration, or at any other time during the study. Following the 800 mg dose, the maximum increase in the placebo corrected mean change in QTc from baseline was observed at 3 hours postdose and was 8.0 msec. This increase is not considered to be clinically significant.

At the 800 mg dose, peak sitagliptin plasma concentrations were approximately 11 times higher than the peak concentrations following a 100-mg dose. In patients with type 2 diabetes mellitus administered sitagliptin 100 mg (N=81) or sitagliptin 200 mg (N=63) daily, there were no meaningful changes in QTc interval based on ECG data obtained at the time of expected peak plasma concentration.

14 CLINICAL STUDIES

14.1Glycemic Control Trials in Patients with Type 2 Diabetes Mellitus The efficacy and safety of ertugliflozin in combination with sitagliptin have been studied in 3 multi-center, randomized, double-blind, placebo- and active comparator-controlled, clinical studies involving 1,985 patients with type 2 diabetes mellitus. These studies included White, Hispanic or Latino, Black or African American, Asian, and other racial and ethnic groups, and patients with an age range of 21 to 85 years. In patients with type 2 diabetes mellitus, treatment with ertugliflozin in combination with sitagliptin reduced HbA1c compared to placebo or active comparator.

In patients with type 2 diabetes mellitus treated with ertugliflozin in combination with sitagliptin, the change in HbA1c was generally similar across subgroups defined by age, sex, and race. In Combination with Sitagliptin versus Ertugliflozin Alone and Sitagliptin Alone, as Add-on to Metformin HCl A total of 1,233 patients with type 2 diabetes mellitus with inadequate glycemic control (HbA1c between 7.5% and 11%) on metformin HCl monotherapy (≥1,500 mg/day for ≥8 weeks) participated in a randomized, double-blind, 26-week, active controlled study (NCT02099110) to evaluate the efficacy and safety of ertugliflozin 5 mg or 15 mg administered orally in combination with sitagliptin 100 mg compared to the individual components.

Patients were randomized to one of five treatment arms: ertugliflozin 5 mg, ertugliflozin 15 mg, sitagliptin 100 mg, ertugliflozin 5 mg + sitagliptin 100 mg, or ertugliflozin 15 mg + sitagliptin 100 mg. At Week 26, ertugliflozin 5 mg or 15 mg + sitagliptin 100 mg provided statistically significantly greater reductions in HbA1c compared to the individual components. More patients achieved an HbA1c < 7% on the combination as compared to the individual components (see Table 6 and Figure 3 ).

Table 6: Results at Week 26 from a Factorial Study with Ertugliflozin and Sitagliptin as Add-on Combination Therapy with Metformin HCl Compared to Individual Components Alone N includes all randomized and treated patients with a baseline measurement of the outcome variable. At Week 26 the primary HbA1c endpoint was missing for 13%, 10%, 11%, 11%, and 12% of patients and during the trial rescue medication was initiated by 6%, 6%, 3%, 2%, and 0% of patients randomized to sitagliptin, ertugliflozin 5 mg, ertugliflozin 15 mg, ertugliflozin 5 mg + sitagliptin, and ertugliflozin 15 mg + sitagliptin, respectively.

Missing Week 26 measurements were imputed using multiple imputation with a mean equal to the baseline value of the patient. Results included measurements collected after initiation of rescue medication. For those subjects who did not receive rescue medication and had values measured at 26 weeks, the mean change from baseline for HbA1c was -1.1%, -1.1%, -1.1%, -1.5% and -1.6% for sitagliptin, ertugliflozin 5 mg, ertugliflozin 15 mg, ertugliflozin 5 mg + sitagliptin, and ertugliflozin 15 mg + sitagliptin, respectively.

Sitagliptin 100 mg Ertugliflozin 5 mg Ertugliflozin 15 mg Ertugliflozin 5 mg +Sitagliptin 100 mg Ertugliflozin 15 mg + Sitagliptin 100 mg HbA1c (%) N = 242 N = 244 N = 247 N = 237 N = 241 Baseline (mean) 8.5 8.6 8.6 8.6

8.6Change from baseline (LS mean Intent-to-treat analysis using ANCOVA adjusted for baseline value and baseline eGFR. ) -1.0 -1.0 -1.0 -1.4 -1.4 Difference from Sitagliptin -0.4 p<0.001 compared to control group. (-0.6, -0.2) -0.4 (-0.5, -0.2) Ertugliflozin 5 mg -0.4 (-0.5, -0.2) Ertugliflozin 15 mg -0.4 (-0.6, -0.2) (LS mean , 95% CI) Patients [N (%)] with HbA1c <7% 93 (38.5) 72 (29.3) 83 (33.7) 126 (53.3) 123 (50.9) FPG (mg/dL) N = 246 N = 250 N = 247 N = 240 N = 241 Baseline (mean) 177.4 184.1 179.5 183.8 177.2 Change from baseline (LS mean ) -24.3 -34.0 -34.6 -41.1 -44.3 Difference from Sitagliptin -16.8 (-23.2, -10.4) -20.0 (-26.4, -13.6) Ertugliflozin 5 mg -7.0 p<0.03 compared to control group.

(-13.3, -0.7) Ertugliflozin 15… [Excerpted — this section continues on DailyMed.]

13 NONCLINICAL TOXICOLOGY

13.1Carcinogenesis, Mutagenesis, Impairment of Fertility Carcinogenesis Ertugliflozin Carcinogenicity was evaluated 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 relevance 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). Sitagliptin A two year carcinogenicity study was conducted in male and female rats given oral doses of sitagliptin of 50, 150, and 500 mg/kg/day. There was an increased incidence of combined liver adenoma/carcinoma in males and females and of liver carcinoma in females at 500 mg/kg.

This dose results in exposures approximately 60 times the human exposure at the maximum recommended daily adult human dose (MRHD) of 100 mg/day based on AUC comparisons. Liver tumors were not observed at 150 mg/kg, approximately 20 times the human exposure at the MRHD. A two year carcinogenicity study was conducted in male and female mice given oral doses of sitagliptin of 50, 125, 250, and 500 mg/kg/day.

There was no increase in the incidence of tumors in any organ up to 500 mg/kg, approximately 70 times human exposure at the MRHD. Mutagenesis Ertugliflozin 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. Sitagliptin Sitagliptin was not mutagenic or clastogenic with or without metabolic activation in the Ames bacterial mutagenicity assay, a Chinese hamster ovary (CHO) chromosome aberration assay, an in vitro cytogenetics assay in CHO, an in vitro rat hepatocyte DNA alkaline elution assay, and an in vivo micronucleus assay.

Impairment of Fertility Ertugliflozin 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). Sitagliptin In rat fertility studies with oral gavage doses of 125, 250, and 1,000 mg/kg, males were treated for 4 weeks prior to mating, during mating, up to scheduled termination (approximately 8 weeks total) and females were treated 2 weeks prior to mating through gestation day 7.

No adverse effect on fertility was observed at 125 mg/kg (approximately 12 times human exposure at the MRHD of 100 mg/day based on AUC comparisons). At higher doses, nondose-related increased resorptions in females were observed (approximately 25 and 100 times human exposure at the MRHD based on AUC comparison).