Alogliptin and Pioglitazone (Page 9 of 11)

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

Alogliptin and Pioglitazone

No carcinogenicity, mutagenicity or impairment of fertility studies have been conducted with alogliptin and pioglitazone tablets. The following data are based on findings in studies performed with alogliptin or pioglitazone individually.

Alogliptin

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).

Pioglitazone

A two year carcinogenicity study was conducted in male and female rats at oral doses up to 63 mg/kg (approximately 14 times the MRHD of 45 mg based on mg/m2). Drug-induced tumors were not observed in any organ except for the urinary bladder. Benign and/or malignant transitional cell neoplasms were observed in male rats at 4 mg/kg and above (approximately equal to the MRHD based on mg/m2). A two year carcinogenicity study was conducted in male and female mice at oral doses up to 100 mg/kg (approximately 11 times the MRHD based on mg/m2). No drug-induced tumors were observed in any organ.

Pioglitazone was not mutagenic in a battery of genetic toxicology studies, including the Ames bacterial assay, a mammalian cell forward gene mutation assay (CHO/HPRT and AS52/XPRT), an in vitro cytogenetics assay using CHL cells, an unscheduled DNA synthesis assay and an in vivo micronucleus assay.

No adverse effects upon fertility were observed in male and female rats at oral doses up to 40 mg/kg pioglitazone daily prior to and throughout mating and gestation (approximately nine times the MRHD based on mg/m2).

13.2 Animal Toxicology and/or Pharmacology

Pioglitazone

Heart enlargement has been observed in mice (100 mg/kg), rats (4 mg/kg and above) and dogs (3 mg/kg) treated orally with pioglitazone (approximately 11, one, and two times the MRHD for mice, rats and dogs, respectively, based on mg/m2). In a one year rat study, drug-related early death due to apparent heart dysfunction occurred at an oral dose of 160 mg/kg (approximately 35 times the MRHD based on mg/m2). Heart enlargement was seen in a 13 week study in monkeys at oral doses of 8.9 mg/kg and above (approximately four times the MRHD based on mg/m2), but not in a 52 week study at oral doses up to 32 mg/kg (approximately 13 times the MRHD based on mg/m2).

14 CLINICAL STUDIES

The coadministration of alogliptin and pioglitazone has been studied in patients with type 2 diabetes inadequately controlled on either diet and exercise alone or on metformin alone.

There have been no clinical efficacy studies conducted with alogliptin and pioglitazone tablets; however, bioequivalence of alogliptin and pioglitazone tablets with coadministered alogliptin and pioglitazone tablets was demonstrated, and efficacy of the combination of alogliptin and pioglitazone has been demonstrated in four Phase 3 efficacy studies.

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

Alogliptin and Pioglitazone Coadministration in Patients with Type 2 Diabetes Inadequately Controlled on Diet and Exercise

In a 26 week, double-blind, active-controlled study, a total of 655 patients inadequately controlled on diet and exercise alone (mean baseline A1C=8.8%) were randomized to receive alogliptin 25 mg alone, pioglitazone 30 mg alone, alogliptin 12.5 mg with pioglitazone 30 mg or alogliptin 25 mg with pioglitazone 30 mg once daily. Coadministration of alogliptin 25 mg with pioglitazone 30 mg resulted in statistically significant improvements from baseline in A1C and FPG compared to either alogliptin 25 mg alone or to pioglitazone 30 mg alone (Table 10). Coadministration of alogliptin 25 mg with pioglitazone 30 mg once daily resulted in statistically significant reductions in fasting plasma glucose (FPG) starting from Week 2 through Week 26 compared to either alogliptin 25 mg or pioglitazone 30 mg alone. A total of 3% of patients receiving alogliptin 25 mg coadministered with pioglitazone 30 mg, 11% of those receiving alogliptin 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 when coadministered with pioglitazone.

Table 10. Glycemic Parameters at Week 26 in a Coadministration Study of Alogliptin and Pioglitazone in Patients Inadequately Controlled on Diet and Exercise *
Alogliptin25 mg Pioglitazone30 mg Alogliptin 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 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 -1.2 -1.7
Difference from alogliptin 25 mg (adjusted mean with 95% confidence interval) -0.8 (-1, -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 25 mg (adjusted mean with 95% confidence interval) -25 (-34, -15)
Difference from pioglitazone 30 mg (adjusted mean with 95% confidence interval) -13 (-22, -4)

Alogliptin and Pioglitazone Coadministration in Patients with Type 2 Diabetes Inadequately Controlled on Metformin Alone

In the second 26 week, double-blind, placebo-controlled study, a total of 1554 patients already on metformin (mean baseline A1C=8.5%) were randomized to one of 12 double-blind treatment groups: placebo; 12.5 mg or 25 mg of alogliptin alone; 15 mg, 30 mg or 45 mg of pioglitazone alone; or 12.5 mg or 25 mg of alogliptin in combination with 15 mg, 30 mg or 45 mg of pioglitazone. Patients were maintained on a stable dose of metformin (median dose=1700 mg) during the treatment period. Coadministration of alogliptin and pioglitazone provided statistically significant improvements in A1C and FPG compared to placebo, to alogliptin alone, or to pioglitazone alone when added to background metformin therapy (Table 11, Figure 3). A total of 4%, 5% or 2% of patients receiving alogliptin 25 mg with 15 mg, 30 mg or 45 mg pioglitazone, 33% of patients receiving placebo, 13% of patients receiving alogliptin 25 mg, and 10%, 15% or 9% of patients receiving pioglitazone 15 mg, 30 mg or 45 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 when coadministered with pioglitazone.

Table 11. Glycemic Parameters at Week 26 for Alogliptin and Pioglitazone Alone and in Combination in Patients with Type 2 Diabetes *
PlaceboAlogliptin25 mgPioglitazone15 mgPioglitazone30 mgPioglitazone45 mgAlogliptin 25 mg + Pioglitazone 15 mgAlogliptin 25 mg + Pioglitazone 30 mgAlogliptin 25 mg + Pioglitazone 45 mg
*
Intent-to-treat population using last observation carried forward
Least squares means adjusted for treatment, geographic region metformin dose and baseline value
p≤0.01 when compared to pioglitazone and alogliptin alone
A1C (%) N=126N=123N=127N=123N=126N=127N=124N=126
Baseline (mean)8.58.68.58.58.58.58.58.6
Change from baseline (adjusted mean with 95% confidence interval)-0.1-0.9-0.8-0.9-1-1.3-1.4-1.6
Difference from pioglitazone (adjusted mean with 95% confidence interval)-0.5 (-0.7, -0.3)-0.5 (-0.7, -0.3)-0.6 (-0.8, -0.4)
Difference from alogliptin (adjusted mean with 95% confidence interval)-0.4 (-0.6, -0.1)-0.5 (-0.7, -0.3)-0.7 (-0.9, -0.5)
Patients (%) achieving A1C ≤7%6%(8/129)27%(35/129)26%(33/129)30%(38/129)36%(47/129)55%(71/130)53%(69/130)60%(78/130)
FPG (mg/dL) N=129N=126N=127N=125N=129N=130N=126N=127
Baseline (mean)177184177175181179179178
Change from baseline (adjusted mean with 95% confidence interval)7-19-24-29-32-38-42-53
Difference from pioglitazone (adjusted mean with 95% confidence interval)-14 (-24, -5)-13 (-23, -3)-20 (-30, -11)
Difference from alogliptin (adjusted mean with 95% confidence interval)-19 (-29, -10)-23 (-33, -13)-34 (-44, -24)

Figure 3. Change from Baseline in A1C at Week 26 with Alogliptin and Pioglitazone Alone and Alogliptin in Combination with Pioglitazone when Added to Metformin

Figure 3
(click image for full-size original)

Alogliptin Add-On Therapy in Patients with Type 2 Diabetes Inadequately Controlled on Metformin in Combination with Pioglitazone

In a 52 week, active-comparator study, a total of 803 patients inadequately controlled (mean baseline A1C = 8.2%) on a current regimen of pioglitazone 30 mg and metformin at least 1500 mg per day or at the maximum tolerated dose were randomized to either receive the addition of alogliptin 25 mg or the titration of pioglitazone 30 mg to 45 mg following a four week, single-blind, placebo run-in period. Patients were maintained on a stable dose of metformin (median dose=1700 mg). Patients who failed to meet prespecified hyperglycemic goals during the 52 week treatment period received glycemic rescue therapy.

In combination with pioglitazone and metformin, alogliptin 25 mg was shown to be statistically superior in lowering A1C and FPG compared with the titration of pioglitazone from 30 mg to 45 mg at Week 26 and Week 52 (Table 12, results shown only for Week 52). A total of 11% of patients who were receiving alogliptin 25 mg in combination with pioglitazone 30 mg and metformin and 22% of patients receiving a dose titration of pioglitazone from 30 mg to 45 mg in combination with metformin required glycemic rescue.

Improvements in A1C were not affected by gender, age, race or baseline BMI. The mean increase in body weight was similar in both treatment arms. Lipid effects were neutral.

Table 12. Glycemic Parameters at Week 52 in an Active-Controlled Study of Alogliptin as Add-On Combination Therapy to Metformin and Pioglitazone *
Alogliptin 25 mg + Pioglitazone 30 mg + Metformin Pioglitazone 45 mg + Metformin
*
Intent-to-treat population using last observation on study
Least squares means adjusted for treatment, baseline value, geographic region and baseline metformin dose
Noninferior and statistically superior to metformin plus pioglitazone at the 0.025 one-sided significance level
§
p<0.001 compared to pioglitazone 45 mg + metformin
A1C (%) N=397 N=394
Baseline (mean) 8.2 8.1
Change from Baseline (adjusted mean ) -0.7 -0.3
Difference from Pioglitazone 45 mg + Metformin (adjusted mean with 95% confidence interval) -0.4 (-0.5, -0.3)
% of Patients (n/N) achieving A1C ≤7% 33% (134/404)§ 21% (85/399)
FPG (mg/dL) N=399 N=396
Baseline (mean) 162 162
Change from Baseline (adjusted mean ) -15 -4
Difference from Pioglitazone 45 mg + Metformin (adjusted mean with 95% confidence interval) -11§ (-16, -6) ˗

Alogliptin Add-On Therapy to a Thiazolidinedione

A 26 week, placebo-controlled study, was conducted to evaluate the efficacy and safety of alogliptin as add-on therapy to pioglitazone in patients with type 2 diabetes. A total of 493 patients inadequately controlled on a thiazolidinedione alone or in combination with metformin or a sulfonylurea (mean baseline A1C=8%) were randomized to receive alogliptin 12.5 mg, alogliptin 25 mg or placebo. Patients were maintained on a stable dose of pioglitazone (median dose=30 mg) during the treatment period and those who were also previously treated on metformin (median dose=2000 mg) or sulfonylurea (median dose=10 mg) prior to randomization were maintained on the combination therapy during the treatment period. All patients entered into a four week, single-blind, placebo run-in period prior to randomization. Following randomization, all patients continued to receive instruction on diet and exercise. Patients who failed to meet prespecified hyperglycemic goals during the 26 week treatment period received glycemic rescue.

The addition of alogliptin 25 mg once daily to pioglitazone therapy resulted in significant improvements from baseline in A1C and FPG at Week 26 when compared to the addition of placebo (Table 13). A total of 9% of patients who were receiving alogliptin 25 mg and 12% of patients receiving placebo required glycemic rescue.

The improvement in A1C was not affected by gender, age, baseline BMI or baseline pioglitazone dose. The mean increase in body weight was similar between alogliptin and placebo when given in combination with pioglitazone. Lipid effects were neutral.

Table 13. Glycemic Parameters at Week 26 in a Placebo-Controlled Study of Alogliptin as Add-On Therapy to Pioglitazone *
Alogliptin 25 mg + Pioglitazone ± Metformin ± Sulfonylurea Placebo + Pioglitazone ± Metformin ± Sulfonylurea
*
Intent-to-treat population using last observation on study
Least squares means adjusted for treatment, baseline value, geographic region, baseline treatment regimen (pioglitazone, pioglitazone + metformin or pioglitazone + sulfonylurea) and baseline pioglitazone dose
p<0.01 compared to placebo
A1C (%) N=195 N=95
Baseline (mean) 8 8
Change from baseline (adjusted mean ) -0.8 -0.2
Difference from placebo (adjusted mean with 95% confidence interval) -0.6 (-0.8, -0.4)
% of patients (n/N) achieving A1C ≤7% 49%(98/199) 34%(33/97)
FPG (mg/dL) N=197 N=97
Baseline (mean) 170 172
Change from baseline (adjusted mean ) -20 -6
Difference from placebo (adjusted mean with 95% confidence interval) -14 (-23, -5)

Cardiovascular Safety Trial

A randomized, double-blind, placebo-controlled cardiovascular outcomes trial (EXAMINE) was conducted to evaluate the cardiovascular risk of alogliptin. The trial compared the risk of major adverse cardiovascular events (MACE) between alogliptin (N=2701) and placebo (N=2679) when added to standard of care therapies for diabetes and atherosclerotic vascular disease (ASCVD). The trial was event driven and patients were followed until a sufficient number of primary outcome events accrued.

Eligible patients were adults with type 2 diabetes who had inadequate glycemic control at baseline (e.g., HbA1c >6.5%) and had been hospitalized for an acute coronary syndrome event (e.g., acute myocardial infarction or unstable angina requiring hospitalization) 15 to 90 days prior to randomization. The dose of alogliptin was based on estimated renal function at baseline per dosage and administration recommendations [see Dosage and Administration (2.2)]. The average time between an acute coronary syndrome event and randomization was approximately 48 days.

The mean age of the population was 61 years. Most patients were male (68%), Caucasian (73%), and were recruited from outside of the United States (86%). Asian and Black patients contributed 20% and 4% of the total population, respectively. At the time of randomization patients had a diagnosis of type 2 diabetes mellitus for approximately 9 years, 87% had a prior myocardial infarction and 14% were current smokers. Hypertension (83%) and renal impairment (27% with an eGFR ≤60 ml/min/1.73 m2) were prevalent co-morbid conditions. Use of medications to treat diabetes (e.g., metformin 73%, sulfonylurea 54%, insulin 41%), and ASCVD (e.g., statin 94%, aspirin 93%, renin-angiotensin system blocker 88%, beta-blocker 87%) was similar between patients randomized to alogliptin and placebo at baseline. During the trial, medications to treat diabetes and ASCVD could be adjusted to ensure care for these conditions adhered to standard of care recommendations set by local practice guidelines.

The primary endpoint in EXAMINE was the time to first occurrence of a MACE defined as the composite of cardiovascular death, nonfatal myocardial infarction (MI), or nonfatal stroke. The study was designed to exclude a pre-specified risk margin of 1.3 for the hazard ratio of MACE. The median exposure to study drug was 526 days and 95% of the patients were followed to study completion or death.

Table 14 shows the study results for the primary MACE composite endpoint and the contribution of each component to the primary MACE endpoint. The upper bound of the confidence interval was 1.16 and excluded a risk margin larger than 1.3.

Table 14. Patients with MACE in EXAMINE
Composite of first event of CV death, nonfatal MI or nonfatal stroke (MACE)AlogliptinPlaceboHazard Ratio
Number of Patients (%)Rate per 100 PY *Number of Patients (%)Rate per 100 PY *(98% CI)
N=2701N=2679
305 (11.3)7.6316 (11.8)7.90.96 (0.80, 1.16)
*
Patient Years (PY)
CV Death89 (3.3)2.2111 (4.1)2.8
Nonfatal MI187 (6.9)4.6173 (6.5)4.3
Nonfatal stroke29 (1.1)0.732 (1.2)0.8

The Kaplan-Meier based cumulative event probability is presented in Figure 4 for the time to first occurrence of the primary MACE composite endpoint by treatment arm. The curves for placebo and alogliptin overlap throughout the duration of the study. The observed incidence of MACE was highest within the first 60 days after randomization in both treatment arms (14.8 MACE per 100 PY), decreased from day 60 to the end of the first year (8.4 per 100 PY) and was lowest after one year of follow-up (5.2 per 100 PY).

Figure 4. Observed Cumulative Rate of MACE in EXAMINE
Figure 4
(click image for full-size original)

The rate of all cause death was similar between treatment arms with 153 (3.6 per 100 PY) recorded among patients randomized to alogliptin and 173 (4.1 per 100 PY) among patients randomized to placebo. A total of 112 deaths (2.9 per 100 PY) among patients on alogliptin and 130 among patients on placebo (3.5 per 100 PY) were adjudicated as cardiovascular deaths.

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