Synjardy XR (Page 7 of 11)

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

SYNJARDY or SYNJARDY XR

No carcinogenicity, mutagenicity, or impairment of fertility studies have been conducted with the combination of empagliflozin and metformin HCl. General toxicity studies in rats up to 13 weeks were performed with the combined components. These studies indicated that no additive toxicity is caused by the combination of empagliflozin and metformin.

Empagliflozin

Carcinogenesis was evaluated in 2-year studies conducted in CD-1 mice and Wistar rats. Empagliflozin did not increase the incidence of tumors in female rats dosed at 100, 300, or 700 mg/kg/day (up to 72 times the exposure from the maximum clinical dose of 25 mg). In male rats, hemangiomas of the mesenteric lymph node were increased significantly at 700 mg/kg/day or approximately 42 times the exposure from a 25 mg clinical dose. Empagliflozin did not increase the incidence of tumors in female mice dosed at 100, 300, or 1,000 mg/kg/day (up to 62 times the exposure from a 25 mg clinical dose). Renal tubule adenomas and carcinomas were observed in male mice at 1,000 mg/kg/day, which is approximately 45 times the exposure of the maximum clinical dose of 25 mg. These tumors may be associated with a metabolic pathway predominantly present in the male mouse kidney.

Empagliflozin was not mutagenic or clastogenic with or without metabolic activation in the in vitro Ames bacterial mutagenicity assay, the in vitro L5178Y tk+/- mouse lymphoma cell assay, and an in vivo micronucleus assay in rats.

Empagliflozin had no effects on mating, fertility or early embryonic development in treated male or female rats up to the high dose of 700 mg/kg/day (approximately 155 times the 25 mg clinical dose in males and females, respectively).

Metformin HCl

Long-term carcinogenicity studies have been performed in rats (dosing duration of 104 weeks) and mice (dosing duration of 91 weeks) at doses up to and including 900 mg/kg/day and 1,500 mg/kg/day, respectively. These doses are both approximately 4 times the maximum recommended human daily dose of 2,000 mg/kg/day based on body surface area comparisons. No evidence of carcinogenicity with metformin was found in either male or female mice. Similarly, there was no tumorigenic potential observed with metformin in male rats. There was, however, an increased incidence of benign stromal uterine polyps in female rats treated with 900 mg/kg/day.

There was no evidence of a mutagenic potential of metformin in the following in vitro tests: Ames test (Salmonella typhimurium), gene mutation test (mouse lymphoma cells), or chromosomal aberrations test (human lymphocytes). Results in the in vivo mouse micronucleus test were also negative.

Fertility of male or female rats was unaffected by metformin when administered at doses as high as 600 mg/kg/day, which is approximately 2 times the MRHD based on body surface area comparisons.

14 CLINICAL STUDIES

14.1 Glycemic Control Trials in Adults with Type 2 Diabetes Mellitus

In adult patients with type 2 diabetes mellitus, treatment with empagliflozin and metformin produced clinically and statistically significant improvements in HbA1c compared to placebo and metformin. Reductions in HbA1c were observed across subgroups including age, sex, race, and baseline BMI.

Empagliflozin Add-On Combination Therapy with Metformin in Adult Patients with Type 2 Diabetes Mellitus

A total of 637 patients with type 2 diabetes mellitus participated in a double-blind, placebo-controlled trial to evaluate the efficacy of empagliflozin in combination with metformin.

Patients with type 2 diabetes mellitus inadequately controlled on at least 1,500 mg of metformin HCl per day entered an open-label 2-week placebo run-in. At the end of the run-in period, patients who remained inadequately controlled and had an HbA1c between 7% and 10% were randomized to placebo, empagliflozin 10 mg, or empagliflozin 25 mg.

At Week 24, treatment with empagliflozin 10 mg or 25 mg daily provided statistically significant reductions in HbA1c (p-value <0.0001), FPG, and body weight compared with placebo (see Table 7).

Table 7 Results at Week 24 From a Placebo-Controlled Trial for Empagliflozin used in Combination with Metformin
Empagliflozin 10 mgN=217 Empagliflozin 25 mgN=213 PlaceboN=207
a Modified intent-to-treat population. Last observation on trial (LOCF) was used to impute missing data at Week 24. At Week 24, 9.7%, 14.1%, and 24.6% was imputed for patients randomized to empagliflozin 10 mg, empagliflozin 25 mg, and placebo, respectively.
b ANCOVA p-value <0.0001 (HbA1c: ANCOVA model includes baseline HbA1c, treatment, renal function, and region. Body weight and FPG: same model used as for HbA1c but additionally including baseline body weight/baseline FPG, respectively.)
c FPG (mg/dL); for empagliflozin 10 mg, n=216, for empagliflozin 25 mg, n=213, and for placebo, n=207
HbA1c (%)a
Baseline (mean) 7.9 7.9 7.9
Change from baseline (adjusted mean) -0.7 -0.8 -0.1
Difference from placebo + metformin (adjusted mean) (95% CI) -0.6b (-0.7, -0.4) -0.6b (-0.8, -0.5)
Patients [n (%)] achieving HbA1c <7% 75 (38%) 74 (39%) 23 (13%)
FPG (mg/dL)c
Baseline (mean) 155 149 156
Change from baseline (adjusted mean) -20 -22 6
Difference from placebo + metformin (adjusted mean) -26 -29
Body Weight
Baseline mean in kg 82 82 80
% change from baseline (adjusted mean) -2.5 -2.9 -0.5
Difference from placebo (adjusted mean) (95% CI) -2.0b (-2.6, -1.4) -2.5b (-3.1, -1.9)

At Week 24, the systolic blood pressure was statistically significantly reduced compared to placebo by -4.1 mmHg (placebo-corrected, p-value <0.0001) for empagliflozin 10 mg and -4.8 mmHg (placebo-corrected, p-value <0.0001) for empagliflozin 25 mg.

Empagliflozin Initial Combination Therapy with Metformin

A total of 1,364 patients with type 2 diabetes mellitus participated in a double-blind, randomized, active-controlled trial to evaluate the efficacy of empagliflozin in combination with metformin as initial therapy compared to the corresponding individual components.

Treatment-naïve patients with inadequately controlled type 2 diabetes mellitus entered an open-label placebo run-in for 2 weeks. At the end of the run-in period, patients who remained inadequately controlled and had an HbA1c between 7% and 10.5% were randomized to one of 8 active-treatment arms: empagliflozin 10 mg or 25 mg; metformin HCl 1,000 mg, or 2,000 mg; empagliflozin 10 mg in combination with 1,000 mg or 2,000 mg metformin HCl; or empagliflozin 25 mg in combination with 1,000 mg or 2,000 mg metformin HCl.

At Week 24, initial therapy of empagliflozin in combination with metformin provided statistically significant reductions in HbA1c (p-value <0.01) compared to the individual components (see Table 8).

Table 8 Glycemic Parameters at 24 Weeks in a Trial Comparing Empagliflozin and Metformin to the Individual Components as Initial Therapy
Empagliflozin 10 mg + Metformin 1,000 mga N=161 Empagliflozin 10 mg + Metformin 2,000 mga N=167 Empagliflozin 25 mg + Metformin 1,000 mga N=165 Empagliflozin 25 mg + Metformin 2,000 mga N=169 Empagliflozin 10 mgN=169 Empagliflozin 25 mgN=163 Metformin 1,000 mga N=167 Metformin 2,000 mga N=162
a Metformin HCl total daily dose, administered in two equally divided doses per day.
b p-value ≤0.0062 (modified intent-to-treat population [observed case] MMRM model included treatment, renal function, region, visit, visit by treatment interaction, and baseline HbA1c).
c p-value ≤0.0056 (modified intent-to-treat population [observed case] MMRM model included treatment, renal function, region, visit, visit by treatment interaction, and baseline HbA1c).
HbA1c (%)
Baseline (mean) 8.7 8.7 8.8 8.7 8.6 8.9 8.7 8.6
Change from baseline(adjusted mean) -2.0 -2.1 -1.9 -2.1 -1.4 -1.4 -1.2 -1.8
Comparison vs empagliflozin(adjusted mean)(95% CI) -0.6b (-0.9, -0.4) -0.7b (-1.0, -0.5) -0.6c (-0.8, -0.3) -0.7c (-1.0, -0.5)
Comparison vs metformin(adjusted mean)(95% CI) -0.8b (-1.0, -0.6) -0.3b (-0.6, -0.1) -0.8c (-1.0, -0.5) -0.3c (-0.6, -0.1)
Patients [n (%)] achieving HbA1c <7% 96 (63%) 112 (70%) 91 (57%) 111 (68%) 69 (43%) 51 (32%) 63 (38%) 92 (58%)

Empagliflozin Add-On Combination Therapy with Metformin and Sulfonylurea

A total of 666 patients with type 2 diabetes mellitus participated in a double-blind, placebo-controlled trial to evaluate the efficacy of empagliflozin in combination with metformin plus a sulfonylurea.

Patients with inadequately controlled type 2 diabetes mellitus on at least 1,500 mg per day of metformin HCl and on a sulfonylurea, entered a 2-week open-label placebo run-in. At the end of the run-in, patients who remained inadequately controlled and had an HbA1c between 7% and 10% were randomized to placebo, empagliflozin 10 mg, or empagliflozin 25 mg.

Treatment with empagliflozin 10 mg or 25 mg daily provided statistically significant reductions in HbA1c (p-value <0.0001), FPG, and body weight compared with placebo (see Table 9).

Table 9 Results at Week 24 from a Placebo-Controlled Trial for Empagliflozin in Combination with Metformin and Sulfonylurea
Empagliflozin 10 mgN=225 Empagliflozin 25 mg N=216 PlaceboN=225
a Modified intent-to-treat population. Last observation on trial (LOCF) was used to impute missing data at Week 24. At Week 24, 17.8%, 16.7%, and 25.3% was imputed for patients randomized to empagliflozin 10 mg, empagliflozin 25 mg, and placebo, respectively.
b ANCOVA p-value <0.0001 (HbA1c: ANCOVA model includes baseline HbA1c, treatment, renal function, and region. Body weight and FPG: same model used as for HbA1c but additionally including baseline body weight/baseline FPG, respectively.)
c FPG (mg/dL); for empagliflozin 10 mg, n=225, for empagliflozin 25 mg, n=215, for placebo, n=224
HbA1c (%)a
Baseline (mean) 8.1 8.1 8.2
Change from baseline (adjusted mean) -0.8 -0.8 -0.2
Difference from placebo (adjusted mean) (95% CI) -0.6b (-0.8, -0.5) -0.6b (-0.7, -0.4)
Patients [n (%)] achieving HbA1c <7% 55 (26%) 65 (32%) 20 (9%)
FPG (mg/dL)c
Baseline (mean) 151 156 152
Change from baseline (adjusted mean) -23 -23 6
Difference from placebo (adjusted mean) -29 -29
Body Weight
Baseline mean in kg 77 78 76
% change from baseline (adjusted mean) -2.9 -3.2 -0.5
Difference from placebo (adjusted mean) (95% CI) -2.4b (-3.0, -1.8) -2.7b (-3.3, -2.1)

Active-Controlled Trial vs Glimepiride in Combination with Metformin

The efficacy of empagliflozin was evaluated in a double-blind, glimepiride-controlled, trial in 1,545 patients with type 2 diabetes mellitus with insufficient glycemic control despite metformin therapy.

Patients with inadequate glycemic control and an HbA1c between 7% and 10% after a 2-week run-in period were randomized to glimepiride or empagliflozin 25 mg.

At Week 52, empagliflozin 25 mg and glimepiride lowered HbA1c and FPG (see Table 10, Figure 3). The difference in observed effect size between empagliflozin 25 mg and glimepiride excluded the pre-specified non-inferiority margin of 0.3%. The mean daily dosage of glimepiride was 2.7 mg and the maximal approved dosage in the United States is 8 mg per day.

Table 10 Results at Week 52 from an Active-Controlled Trial Comparing Empagliflozin to Glimepiride as Add-On Therapy in Patients Inadequately Controlled on Metformin
Empagliflozin 25 mgN=765GlimepirideN=780
a Modified intent-to-treat population. Last observation on trial (LOCF) was used to impute data missing at Week 52. At Week 52, data was imputed for 15.3% and 21.9% of patients randomized to empagliflozin 25 mg and glimepiride, respectively.
b Non-inferior, ANCOVA model p-value <0.0001 (HbA1c: ANCOVA model includes baseline HbA1c, treatment, renal function, and region)
c ANCOVA p-value <0.0001 (Body weight and FPG: same model used as for HbA1c but additionally including baseline body weight/baseline FPG, respectively.)
d FPG (mg/dL); for empagliflozin 25 mg, n=764, for glimepiride, n=779
HbA1c (%)a
Baseline (mean)7.97.9
Change from baseline (adjusted mean)-0.7-0.7
Difference from glimepiride (adjusted mean) (97.5% CI)-0.07b (-0.15, 0.01)
FPG (mg/dL)d
Baseline (mean)150150
Change from baseline (adjusted mean)-19-9
Difference from glimepiride (adjusted mean)-11
Body Weight
Baseline mean in kg82.583
% change from baseline (adjusted mean)-3.92.0
Difference from glimepiride (adjusted mean) (95% CI)-5.9c (-6.3, -5.5)

Figure 3 Adjusted mean HbA1c Change at Each Time Point (Completers) and at Week 52 (mITT Population) – LOCF

Figure 3
(click image for full-size original)

At Week 52, the adjusted mean change from baseline in systolic blood pressure was -3.6 mmHg, compared to 2.2 mmHg for glimepiride. The differences between treatment groups for systolic blood pressure was statistically significant (p-value <0.0001).

At Week 104, the adjusted mean change from baseline in HbA1c was -0.75% for empagliflozin 25 mg and -0.66% for glimepiride. The adjusted mean treatment difference was -0.09% with a 97.5% confidence interval of (-0.32%, 0.15%), excluding the pre-specified non-inferiority margin of 0.3%. The mean daily dosage of glimepiride was 2.7 mg and the maximal approved dosage in the United States is 8 mg per day. The Week 104 analysis included data with and without concomitant glycemic rescue medication, as well as off-treatment data. Missing data for patients not providing any information at the visit were imputed based on the observed off-treatment data. In this multiple imputation analysis, 13.9% of the data were imputed for empagliflozin 25 mg and 12.9% for glimepiride.

At Week 104, empagliflozin 25 mg daily resulted in a statistically significant difference in change from baseline for body weight compared to glimepiride (-3.1 kg for empagliflozin 25 mg vs. +1.3 kg for glimepiride; ANCOVA-LOCF, p-value <0.0001).

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