Alogliptin (Page 4 of 8)

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

Rats were administered oral doses of 75, 400 and 800 mg/kg alogliptin for two years. No drug-related tumors were observed up to 75 mg/kg or approximately 32 times the maximum recommended clinical dose of 25 mg, based on area under the plasma concentration curve (AUC) exposure. At higher doses (approximately 308 times the maximum recommended clinical dose of 25 mg), a combination of thyroid C-cell adenomas and carcinomas increased in male but not female rats. No drug-related tumors were observed in mice after administration of 50, 150 or 300 mg/kg alogliptin for two years, or up to approximately 51 times the maximum recommended clinical dose of 25 mg, based on AUC exposure.

Alogliptin was not mutagenic or clastogenic, with and without metabolic activation, in the Ames test with S. typhimurium and E. coli or the cytogenetic assay in mouse lymphoma cells. Alogliptin was negative in the in vivo mouse micronucleus study.

In a fertility study in rats, alogliptin had no adverse effects on early embryonic development, mating or fertility at doses up to 500 mg/kg, or approximately 172 times the clinical dose based on plasma drug exposure (AUC).

14 CLINICAL STUDIES

Alogliptin tablets have been studied as monotherapy and in combination with metformin, a sulfonylurea, a thiazolidinedione (either alone or in combination with metformin or a sulfonylurea) and insulin (either alone or in combination with metformin).

A total of 14,053 patients with type 2 diabetes were randomized in 11 double-blind, placebo- or active-controlled clinical safety and efficacy studies conducted to evaluate the effects of alogliptin tablets on glycemic control. The racial distribution of patients exposed to study medication was 70% Caucasian, 17% Asian, 6% Black and 7% other racial groups. The ethnic distribution was 30% Hispanic. Patients had an overall mean age of 57 years (range 21 to 91 years).

In patients with type 2 diabetes, treatment with alogliptin tablets produced clinically meaningful and statistically significant improvements in hemoglobin A1c (A1C) compared to placebo. As is typical for trials of agents to treat type 2 diabetes, the mean reduction in A1C with alogliptin tablets appears to be related to the degree of A1C elevation at baseline.

Alogliptin tablets had similar changes from baseline in serum lipids compared to placebo.

14.1 Patients with Inadequate Glycemic Control on Diet and Exercise

A total of 1768 patients with type 2 diabetes participated in three double-blind studies to evaluate the efficacy and safety of alogliptin tablets in patients with inadequate glycemic control on diet and exercise. All three studies had a four week, single-blind, placebo run-in period followed by a 26 week randomized treatment period. Patients who failed to meet prespecified hyperglycemic goals during the 26 week treatment periods received glycemic rescue therapy.

In a 26 week, double-blind, placebo-controlled study, a total of 329 patients (mean baseline A1C = 8%) were randomized to receive alogliptin tablets 12.5 mg, alogliptin tablets 25 mg or placebo once daily. Treatment with alogliptin tablets 25 mg resulted in statistically significant improvements from baseline in A1C and fasting plasma glucose (FPG) compared to placebo at Week 26 (Table 3). A total of 8% of patients receiving alogliptin tablets 25 mg and 30% of those receiving placebo required glycemic rescue therapy.

Improvements in A1C were not affected by gender, age or baseline body mass index (BMI).

The mean change in body weight with alogliptin tablets was similar to placebo.

Table 3. Glycemic Parameters at Week 26 in a Placebo-Controlled Monotherapy Study of Alogliptin Tablets *
Alogliptin Tablets25 mg Placebo
*
Intent-to-treat population using last observation on study
Least squares means adjusted for treatment, baseline value, geographic region and duration of diabetes
p<0.01 compared to placebo
A1C (%) N=128 N=63
Baseline (mean) 7.9 8.0
Change from baseline (adjusted mean ) -0.6 0
Difference from placebo (adjusted mean with 95% confidence interval) -0.6 (-0.8, -0.3) ˗
% of patients (n/N) achieving A1C ≤7% 44% (58/131) 23% (15/64)
FPG (mg/dL) N=129 N=64
Baseline (mean) 172 173
Change from baseline (adjusted mean ) -16 11
Difference from placebo (adjusted mean with 95% confidence interval) -28 (-40, -15) ˗

In a 26 week, double-blind, active-controlled study, a total of 655 patients (mean baseline A1C = 8.8%) were randomized to receive alogliptin tablets 25 mg alone, pioglitazone 30 mg alone, alogliptin tablets 12.5 mg with pioglitazone 30 mg or alogliptin tablets 25 mg with pioglitazone 30 mg once daily. Coadministration of alogliptin tablets 25 mg with pioglitazone 30 mg resulted in statistically significant improvements from baseline in A1C and FPG compared to alogliptin tablets 25 mg alone and to pioglitazone 30 mg alone (Table 4). A total of 3% of patients receiving alogliptin tablets 25 mg coadministered with pioglitazone 30 mg, 11% of those receiving alogliptin tablets 25 mg alone and 6% of those receiving pioglitazone 30 mg alone required glycemic rescue.

Improvements in A1C were not affected by gender, age or baseline BMI.

The mean increase in body weight was similar between pioglitazone alone and alogliptin tablets when coadministered with pioglitazone.

Table 4. Glycemic Parameters at Week 26 in an Active-Controlled Study of Alogliptin Tablets, Pioglitazone, and Alogliptin Tablets in Combination with Pioglitazone *
Alogliptin Tablets25 mg Pioglitazone30 mg Alogliptin Tablets 25 mg+ Pioglitazone 30 mg
*
Intent-to-treat population using last observation carried forward
Least squares means adjusted for treatment, geographic region and baseline value
p<0.01 compared to alogliptin tablets 25 mg or pioglitazone 30 mg
A1C (%) N=160 N=153 N=158
Baseline (mean) 8.8 8.8 8.8
Change from baseline (adjusted mean ) -1.0 -1.2 -1.7
Difference from alogliptin tablets 25 mg (adjusted mean with 95% confidence interval) ˗ ˗ -0.8 (-1.0, -0.5)
Difference from pioglitazone 30 mg (adjusted mean with 95% confidence interval) ˗ ˗ -0.6 (-0.8, -0.3)
% of Patients (n/N) achieving A1C ≤7% 24% (40/164) 34% (55/163) 63% (103/164)
FPG (mg/dL) N=162 N=157 N=162
Baseline (mean) 189 189 185
Change from baseline (adjusted mean ) -26 -37 -50
Difference from alogliptin tablets 25 mg (adjusted mean with 95% confidence interval) ˗ ˗ -24 (-34, -15)
Difference from pioglitazone 30 mg (adjusted mean with 95% confidence interval) ˗ ˗ -13 (-22, -4)

In a 26 week, double-blind, placebo-controlled study, a total of 784 patients inadequately controlled on diet and exercise alone (mean baseline A1C = 8.4%) were randomized to one of seven treatment groups: placebo; metformin HCl 500 mg or metformin HCl 1000 mg twice daily; alogliptin tablets 12.5 mg twice daily; alogliptin tablets 25 mg daily; or alogliptin tablets 12.5 mg in combination with metformin HCl 500 mg or metformin HCl 1000 mg twice daily. Both coadministration treatment arms (alogliptin tablets 12.5 mg + metformin HCl 500 mg and alogliptin tablets 12.5 mg + metformin HCl 1000 mg) resulted in statistically significant improvements in A1C and FPG when compared with their respective individual alogliptin and metformin component regimens (Table 5). Coadministration treatment arms demonstrated improvements in two hour postprandial glucose (PPG) compared to alogliptin tablets alone or metformin alone (Table 5). A total of 12.3% of patients receiving alogliptin tablets 12.5 mg + metformin HCl 500 mg, 2.6% of patients receiving alogliptin tablets 12.5 mg + metformin HCl 1000 mg, 17.3% of patients receiving alogliptin tablets 12.5 mg, 22.9% of patients receiving metformin HCl 500 mg, 10.8% of patients receiving metformin HCl 1000 mg and 38.7% of patients receiving placebo required glycemic rescue.

Improvements in A1C were not affected by gender, age, race or baseline BMI. The mean decrease in body weight was similar between metformin alone and alogliptin tablets when coadministered with metformin.

Table 5. Glycemic Parameters at Week 26 for Alogliptin Tablets and Metformin Alone and in Combination in Patients with Type 2 Diabetes
Placebo Alogliptin Tablets 12.5 mgTwice Daily Metformin HCl500 mgTwice Daily Metformin HCl1000 mgTwice Daily Alogliptin Tablets 12.5 mg + Metformin HCl500 mgTwice Daily Alogliptin Tablets 12.5 mg + Metformin HCl1000 mgTwice Daily
*
Intent-to-treat population using last observation on study prior to discontinuation of double-blind study medication or sulfonylurea rescue therapy for patients needing rescue
Least squares means adjusted for treatment, geographic region and baseline value
p<0.05 when compared to metformin and alogliptin tablets alone
§
Compared using logistic regression
Intent-to-treat population using data available at Week 26
A1C (%)* N=102 N=104 N=103 N=108 N=102 N=111
Baseline (mean) 8.5 8.4 8.5 8.4 8.5 8.4
Change from baseline (adjusted mean ) 0.1 -0.6 -0.7 -1.1 -1.2 -1.6
Difference from metformin (adjusted mean with 95% confidence interval) -0.6(-0.9, -0.3) -0.4(-0.7, -0.2)
Difference from Alogliptin Tablets (adjusted mean with 95% confidence interval) -0.7(-1.0, -0.4) -1.0(-1.3, -0.7)
% of Patients (n/N) achieving A1C <7%§ 4%(4/102) 20%(21/104) 27%(28/103) 34%(37/108) 47%(48/102) 59%(66/111)
FPG (mg/dL)* N=105 N=106 N=106 N=110 N=106 N=112
Baseline (mean) 187 177 180 181 176 185
Change from baseline (adjusted mean ) 12 -10 -12 -32 -32 -46
Difference from metformin (adjusted mean with 95% confidence interval) -20(-33, -8) -14(-26, -2)
Difference from Alogliptin Tablets (adjusted mean with 95% confidence interval) -22(-35, -10) -36(-49, -24)
2-Hour PPG (mg/dL) N=26 N=34 N=28 N=37 N=31 N=37
Baseline (mean) 263 272 247 266 261 268
Change from baseline (adjusted mean ) -21 -43 -49 -54 -68 -86
Difference from metformin (adjusted mean with 95% confidence interval) -19(-49, 11) -32(-58, -5)
Difference from Alogliptin Tablets (adjusted mean with 95% confidence interval) -25(-53, -3) -43(-70, -16)

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