ONGLYZA (Page 6 of 14)

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

Carcinogenesis

Carcinogenicity was evaluated in 2-year studies conducted in CD-1 mice and Sprague-Dawley rats. Saxagliptin did not increase the incidence of tumors in mice dosed orally at 50, 250, and 600 mg/kg up to 870-times (males) and 1165-times (females) the 5 mg/day clinical dose, based on AUC. Saxagliptin did not increase the incidence of tumors in rats dosed orally at 25, 75, 150, and 300 mg/kg up to 355-times (males) and 2217-times (females) the 5 mg/day clinical dose, based on AUC.

Mutagenesis

Saxagliptin was not mutagenic or clastogenic in a battery of genotoxicity tests (Ames bacterial mutagenesis, human and rat lymphocyte cytogenetics, rat bone marrow micronucleus and DNA repair assays). The active metabolite of saxagliptin was not mutagenic in an Ames bacterial assay.

Impairment of Fertility

Saxagliptin administered to rats had no effect on fertility or the ability to maintain a litter at exposures up to 603-times and 776-times the 5 mg clinical dose in males and females, based on AUC.

13.2 Animal Toxicology and/or Pharmacology

Saxagliptin produced adverse skin changes in the extremities of cynomolgus monkeys (scabs and/or ulceration of tail, digits, scrotum, and/or nose). Skin lesions were reversible within exposure approximately 20-times the 5 mg clinical dose, but in some cases were irreversible and necrotizing at higher exposures. Adverse skin changes were not observed at exposures similar to (1- to 3-times) the 5 mg clinical dose. Clinical correlates to skin lesions in monkeys have not been observed in human clinical trials of saxagliptin.

14 CLINICAL STUDIES

14.1 Glycemic Efficacy Trials

ONGLYZA has been studied as monotherapy and in combination with metformin, glyburide, and thiazolidinedione (pioglitazone and rosiglitazone) therapy.

A total of 4148 patients with type 2 diabetes mellitus were randomized in six, double-blind, controlled clinical trials conducted to evaluate the safety and glycemic efficacy of ONGLYZA. A total of 3021 patients in these trials were treated with ONGLYZA. In these trials, the mean age was 54 years, and 71% of patients were Caucasian, 16% were Asian, 4% were black, and 9% were of other racial groups. An additional 423 patients, including 315 who received ONGLYZA, participated in a placebo-controlled, dose-ranging study of 6 to 12 weeks in duration.

In these six, double-blind trials, ONGLYZA was evaluated at doses of 2.5 mg and 5 mg once daily. Three of these trials also evaluated an ONGLYZA dose of 10 mg daily. The 10 mg daily dose of ONGLYZA did not provide greater efficacy than the 5 mg daily dose. The 10 mg dosage is not an approved dosage. Treatment with ONGLYZA 5 mg and 2.5 mg doses produced clinically relevant and statistically significant improvements in A1C, fasting plasma glucose (FPG), and 2-hour postprandial glucose (PPG) following a standard oral glucose tolerance test (OGTT), compared to control. Reductions in A1C were seen across subgroups including gender, age, race, and baseline BMI.

ONGLYZA was not associated with significant changes from baseline in body weight or fasting serum lipids compared to placebo.

ONGLYZA has also been evaluated in five additional trials in patients with type 2 diabetes: an active-controlled trial comparing add-on therapy with ONGLYZA to glipizide in 858 patients inadequately controlled on metformin alone, a trial comparing ONGLYZA to placebo in 455 patients inadequately controlled on insulin alone or on insulin in combination with metformin, a trial comparing ONGLYZA to placebo in 257 patients inadequately controlled on metformin plus a sulfonylurea, a trial comparing ONGLYZA to placebo in 315 patients inadequately controlled on dapagliflozin and metformin, and a trial comparing ONGLYZA to placebo in 170 patients with type 2 diabetes and moderate or severe renal impairment or ESRD.

Monotherapy

A total of 766 patients with type 2 diabetes inadequately controlled on diet and exercise (A1C ≥7% to ≤10%) participated in two 24-week, double-blind, placebo-controlled trials evaluating the efficacy and safety of ONGLYZA monotherapy.

In the first trial, following a 2-week single-blind diet, exercise, and placebo lead-in period, 401 patients were randomized to 2.5 mg, 5 mg, or 10 mg of ONGLYZA or placebo. The 10 mg dosage is not an approved dosage. Patients who failed to meet specific glycemic goals during the study were treated with metformin rescue therapy, added on to placebo or ONGLYZA. Efficacy was evaluated at the last measurement prior to rescue therapy for patients needing rescue. Dose titration of ONGLYZA was not permitted.

Treatment with ONGLYZA 2.5 mg and 5 mg daily provided significant improvements in A1C, FPG, and PPG compared to placebo (Table 4). The percentage of patients who discontinued for lack of glycemic control or who were rescued for meeting prespecified glycemic criteria was 16% in the ONGLYZA 2.5 mg treatment group, 20% in the ONGLYZA 5 mg treatment group, and 26% in the placebo group.

Table 4: Glycemic Parameters at Week 24 in a Placebo-Controlled Study of ONGLYZA Monotherapy in Patients with Type 2 Diabetes *

* Intent-to-treat population using last observation on study or last observation prior to metformin rescue therapy for patients needing rescue. † Least squares mean adjusted for baseline value. ‡ p-value <0.0001 compared to placebo. § p-value <0.05 compared to placebo. ¶ Significance was not tested for the 2-hour PPG for the 2.5 mg dose of ONGLYZA.
Efficacy Parameter	ONGLYZA 2.5 mg N=102	ONGLYZA 5 mg N=106	Placebo N=95
Hemoglobin A1C (%)	N=100	N=103	N=92
Baseline (mean)	7.9	8.0	7.9
Change from baseline (adjusted mean †)	−0.4	−0.5	+0.2
Difference from placebo (adjusted mean †)	−0.6‡	−0.6‡
95% Confidence Interval	(−0.9, −0.3)	(−0.9, −0.4)
Percent of patients achieving A1C <7%	35% (35/100)	38%§ (39/103)	24% (22/92)
Fasting Plasma Glucose (mg/dL)	N=101	N=105	N=92
Baseline (mean)	178	171	172
Change from baseline (adjusted mean †)	−15	−9	+6
Difference from placebo (adjusted mean †)	−21§	−15§
95% Confidence Interval	(−31, −10)	(−25, −4)
2-hour Postprandial Glucose (mg/dL)	N=78	N=84	N=71
Baseline (mean)	279	278	283
Change from baseline (adjusted mean †)	−45	−43	−6
Difference from placebo (adjusted mean †)	−39¶	−37§
95% Confidence Interval	(−61, −16)	(−59, −15)

A second 24-week monotherapy trial was conducted to assess a range of dosing regimens for ONGLYZA. Treatment-naive patients with inadequately controlled diabetes (A1C ≥7% to ≤10%) underwent a 2-week, single-blind diet, exercise, and placebo lead-in period. A total of 365 patients were randomized to 2.5 mg every morning, 5 mg every morning, 2.5 mg with possible titration to 5 mg every morning, or 5 mg every evening of ONGLYZA, or placebo. Patients who failed to meet specific glycemic goals during the study were treated with metformin rescue therapy added on to placebo or ONGLYZA; the number of patients randomized per treatment group ranged from 71 to 74.

Treatment with either ONGLYZA 5 mg every morning or 5 mg every evening provided significant improvements in A1C versus placebo (mean placebo-corrected reductions of −0.4% and −0.3%, respectively). Treatment with ONGLYZA 2.5 mg every morning also provided significant improvement in A1C versus placebo (mean placebo-corrected reduction of −0.4%).