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Takeda Presents Additional Data from the EXAMINE Cardiovascular Safety Outcomes Trial at the American College of Cardiology’s 63rd Annual Scientific Session

March 27, 2014

Sub-analyses Investigate the Effects of alogliptin on Cardiovascular Mortality Rates and Hospitalization for Heart Failure in Type 2 Diabetes Patients with Recent Acute Coronary Syndrome

Washington, DC, March 27, 2014 and Osaka, Japan, March 28, 2014 – Takeda Pharmaceutical Company Limited (Takeda) will present sub-analyses from the global EXAMINE (EXamination of CArdiovascular OutcoMes: AlogliptIN vs. Standard of CarE in Patients with Type 2 Diabetes Mellitus and Acute Coronary Syndrome) cardiovascular (CV) safety outcomes trial in a poster session at the American College of Cardiology’s (ACC) 63rd Annual Scientific Session in Washington, DC. These sub-analyses specifically investigated the effects of the dipeptidyl peptidase-4 inhibitor (DPP-4i) alogliptin on rates of CV mortality and hospitalization for heart failure (HF).

Alogliptin is the first and only DPP-4i to demonstrate CV safety outcomes in Type 2 diabetes patients with recent acute coronary syndrome (ACS). Heart disease, or cardiovascular disease (CVD), is the leading cause of morbidity and mortality in patients with Type 2 diabetes, and is responsible for between 50 and 80 percent of deaths in people with diabetes.

Findings from the sub-analysis, “Cardiovascular mortality in patients with type 2 diabetes and recent acute coronary syndrome from the EXAMINE Trial,” demonstrated no effect on rates of CV mortality [hazard ratio (HR)=0.85, 95% confidence interval (CI): 0.66, 1.10] in patients with Type 2 diabetes and recent ACS with alogliptin, compared to placebo (n=112, 4.1% and n=130, 4.9%, respectively). There was also no increase in sudden cardiac death with alogliptin (n=59, 2.2%) versus placebo (n=73, 2.7%) [HR=0.80, 95% CI: 0.57, 1.12].

The other sub-analysis, “Alogliptin in patients with type 2 diabetes after acute coronary syndromes: Heart failure outcomes and cardiovascular safety in heart failure patients,” demonstrated that in patients with Type 2 diabetes and recent ACS, the pre-specified composite CV outcome of first occurrence of all-cause mortality, nonfatal MI and stroke, urgent revascularization due to unstable angina, and hospitalization for HF was similar for alogliptin compared with placebo [HR=0.98, 95% CI, 0.86-1.12]. Within this composite endpoint, hospitalized HF occurred in 3.1 percent of patients on alogliptin versus 2.9 percent on placebo [HR=1.07, 95% CI, 0.79-1.46]. Additionally, alogliptin neither induced new onset HF nor worsened HF outcomes in patients with a history of HF and / or with markers for HF (elevated NT-pro-BNP levels).

“Cardiovascular events are very common in patients with Type 2 diabetes, so it is important that diabetes treatments adequately manage glucose levels in these patients without adversely affecting cardiovascular outcomes, such as hospitalized heart failure and cardiac death,” said William B. White, MD, FASH, FAHA, FACP, principal investigator of the EXAMINE trial and abstract author. “Based on data presented, alogliptin showed no difference from placebo on rates of cardiovascular mortality and hospitalized heart failure in this high risk population of patients with Type 2 diabetes.”

Results from EXAMINE, a global, large, randomized, double-blind, placebo-controlled clinical trial, were published in the New England Journal of Medicine in September 2013. The trial was designed to evaluate CV safety following treatment with alogliptin in addition to standard of care, versus placebo in addition to standard of care, in patients with Type 2 diabetes and a recent ACS. The EXAMINE trial’s primary composite endpoint of non-inferiority compared to placebo in addition to standard of care was met, showing no increase in CV risk in a Type 2 diabetes patient population at high risk for CV events, including CV death, nonfatal myocardial infarction and nonfatal stroke.

“Takeda is committed to working with key investigators to continue analyzing and publishing relevant findings from the EXAMINE trial,” said Ajay Ahuja, MD, vice president, Global Medical Affairs, Takeda. “Findings from such sub-analyses provide further important information about alogliptin for this patient population.”

About the EXAMINE Trial
EXAMINE randomized 5,380 patients in 49 countries with Type 2 diabetes with an ACS within the previous 15-90 days. The EXAMINE primary endpoint of non-inferiority compared to placebo in addition to standard of care was met, showing no increase in CV risk in a Type 2 diabetes patient population at high risk for CV events based on the primary composite endpoint of CV death, nonfatal myocardial infarction and nonfatal stroke. The primary endpoint occurred at similar rates in the alogliptin and placebo groups (in 11.3% of patients vs. 11.8% of patients during a median follow-up period of 18 months; HR, 0.96; upper boundary of the one-sided repeated CI, 1.16).

In the alogliptin group, 71.4 percent of patients received 25 mg, 25.7 percent received 12.5 mg, and 2.9 percent received 6.25 mg daily. Alogliptin doses were adjusted according to renal function: estimated glomerular filtration rate (eGFR) by the Modification of Diet in Renal Disease formula ≥ 60 ml/min/1.73 m2, 25 mg daily; < 60 ml/min/1.73 m2 but ≥ 30 ml/min/1.73 m2, 12.5 mg daily; and < 30 ml/min/1.73 m2, 6.25 mg daily. Premature discontinuation of the study drug was similar in the alogliptin and placebo groups (20.9% of patients vs. 22.6%). The median duration of exposure to study drug was 533 days (interquartile range, 280 to 751 days). By the end of the study, the mean change from baseline in HbA1c was -0.33 percent and 0.03 percent in the alogliptin and placebo groups, respectively, and the least square means difference in HbA1c between alogliptin and placebo was -0.36 percent (95% CI, -0.43, -0.28, p<0.001). In the analysis of the components of the primary endpoint, the hazard ratios were consistent with the overall result. Hazard ratios for death from any cause and CV death were consistent with the primary composite endpoint.

Takeda conducted the global EXAMINE trial in accordance with the United States (U.S.) Food and Drug Administration’s (FDA) 2008 Guidance, titled “Guidance for Industry: Diabetes Mellitus – Evaluating Cardiovascular Risk in New Antidiabetic Therapies to Treat Type 2 Diabetes,” for all new Type 2 diabetes treatments.

About Alogliptin
Alogliptin is a DPP-4i for the treatment of Type 2 diabetes in adults as an adjunct to diet and exercise. DPP-4is are designed to slow the inactivation of incretin hormones GLP-1 and GIP. As a result, an increased amount of active incretins enables the pancreas to secrete insulin in a glucose-dependent manner, thereby assisting in the management of blood glucose levels.

Alogliptin is approved as a monotherapy and also in fixed-dose combination (FDC) with pioglitazone and metformin HCl for the treatment of Type 2 diabetes in adults as adjuncts to diet and exercise. These therapies are not for treatment of Type 1 diabetes or diabetic ketoacidosis.

Alogliptin is available in many markets across Australia, China, Europe, Japan, Mexico, South Korea and the U.S.

Indications in the U.S.
Indications for NESINA (alogliptin) 6.25 mg, 12.5 mg, and 25 mg Tablets; KAZANO (alogliptin and metformin HCl) 12.5 mg/500 mg and 12.5 mg/1000 mg Tablets; and OSENI (alogliptin and pioglitazone) 25 mg/15 mg, 25 mg/30 mg, 25 mg/45 mg, 12.5 mg/15 mg, 12.5 mg/30 mg, and 12.5 mg/45 mg Tablets

NESINA, KAZANO, and OSENI are indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus.

NESINA, KAZANO, and OSENI are not for treatment of type 1 diabetes or diabetic ketoacidosis.

Important Safety Information in the U.S.
Thiazolidinediones, including pioglitazone, which is a component of OSENI, cause or exacerbate congestive heart failure in some patients. After initiation of OSENI, and after dose increases, monitor patients carefully for signs and symptoms of heart failure (e.g., excessive, rapid weight gain, dyspnea, and/or edema). If heart failure develops, it should be managed according to current standards of care and discontinuation or dose reduction of pioglitazone in OSENI must be considered. OSENI is not recommended in patients with symptomatic heart failure. Initiation of OSENI in patients with established New York Heart Association (NYHA) Class III or IV heart failure is contraindicated.

Lactic acidosis is a rare, but serious complication that can occur due to metformin accumulation. The risk increases with conditions such as sepsis, dehydration, excess alcohol intake, hepatic impairment, renal impairment, and acute congestive heart failure. The onset is often subtle, accompanied only by nonspecific symptoms such as malaise, myalgias, respiratory distress, increasing somnolence, and nonspecific abdominal distress. Laboratory abnormalities include low pH, increased anion gap, and elevated blood lactate. If acidosis is suspected, KAZANO should be discontinued and the patient hospitalized immediately.

NESINA, KAZANO, and OSENI are contraindicated in patients with a history of serious hypersensitivity reaction to any of the components of these products, such as anaphylaxis, angioedema, or severe cutaneous adverse reactions. KAZANO is contraindicated in patients with renal impairment (e.g., serum creatinine levels ≥1.5 mg/dL for men, ≥1.4 mg/dL for women or abnormal creatinine clearance), which may also result from conditions such as cardiovascular collapse (shock), acute myocardial infarctions, and septicemia. KAZANO is contraindicated in patients with acute or chronic metabolic acidosis, including diabetic ketoacidosis. Do not initiate OSENI in patients with established NYHA Class III or IV heart failure.

Warnings and Precautions—for KAZANO
Lactic acidosis: Warn against excessive alcohol intake. KAZANO is not recommended in hepatic impairment and is contraindicated in renal impairment. Ensure normal renal function before initiating and at least annually thereafter. Temporarily discontinue in patients undergoing radiologic studies with intravascular iodinated contrast materials or any surgical procedures necessitating restricted intake of food and fluids. Lactic acidosis due to metformin accumulation during therapy is fatal in approximately 50% of cases. The risk increases in patients with renal impairment, congestive heart failure requiring drug treatment, and with increasing age.

Vitamin B12 deficiency: Metformin may lower Vitamin B12 levels. Monitor hematologic parameters annually.

Warnings and Precautions—for OSENI
Congestive heart failure: Fluid retention may occur and can exacerbate or lead to congestive heart failure. Combination use with insulin and use in congestive heart failure NYHA Class I and II may increase risk. Monitor patients for signs and symptoms.

Edema: Dose-related edema may occur. Use with caution in patients with edema.

Fractures: Increased incidence in female patients. Apply current standards of care for assessing and maintaining bone health.

Bladder cancer: Data suggest an increased risk of bladder cancer in pioglitazone users. Data also suggest that the risk increases with duration of use. Do not use OSENI in patients with active bladder cancer. Use caution when using in patients with a prior history of bladder cancer. Tell patients to promptly report any sign of hematuria or other symptoms such as dysuria or urinary urgency as these may be due to bladder cancer.

Macular edema: Macular edema has been reported in some patients taking pioglitazone. Recommend regular eye exams. Instruct patients to report any visual changes promptly.

Ovulation: Therapy with pioglitazone may result in ovulation in some premenopausal anovulatory women
Warnings and Precautions—for NESINA, KAZANO, and OSENI 
Acute pancreatitis: There have been postmarketing reports of acute pancreatitis. If pancreatitis is suspected, promptly discontinue NESINA, KAZANO, or OSENI.

Hypersensitivity: There have been postmarketing reports of serious hypersensitivity reactions in patients treated with alogliptin such as anaphylaxis, angioedema or severe cutaneous adverse reactions. In such cases, promptly discontinue NESINA, KAZANO, or OSENI, assess for other potential causes, institute appropriate monitoring and treatment, and initiate alternative treatment for diabetes. Use caution in a patient with a history of angioedema with another DPP-4i because it is unknown whether such patients will be predisposed to angioedema.

Hepatic effects: Postmarketing reports of hepatic failure, sometimes fatal. Causality cannot be excluded. Baseline liver test panel is recommended. If liver injury is detected, promptly interrupt NESINA, KAZANO, or OSENI and assess patient for probable cause, then treat cause if possible, to resolution or stabilization. Do not restart NESINA, KAZANO, or OSENI if liver injury is confirmed and no alternate etiology can be found. Use with caution in patients with liver disease.

Hypoglycemia: Insulin and insulin secretagogues are known to cause hypoglycemia. A lower dose of the insulin or insulin secretagogue may be required to minimize the risk when used in combination with NESINA, KAZANO, or OSENI.

Macrovascular outcomes: There have been no clinical studies establishing conclusive evidence of macrovascular risk reduction with NESINA, KAZANO, OSENI, or any other anti-diabetic drug.

Adverse Reactions

Most common adverse reactions (>4% of patients treated with NESINA 25 mg and more frequently than in patients who received placebo) were nasopharyngitis (4.4%), headache (4.2%), and upper respiratory tract infection (4.2%).

Most common adverse reactions (≥4% of patients treated with co-administration of alogliptin and metformin) were upper respiratory tract infection (8%), nasopharyngitis (6.8%), diarrhea (5.5%), hypertension (5.5%), headache (5.3%), back pain (4.3%), and urinary tract infection (4.2%).

Most common adverse reactions (≥4% of patients treated with co-administration of alogliptin and pioglitazone) were nasopharyngitis (4.9%), back pain (4.2%), and upper respiratory tract infection (4.1%).

Drug Interactions
Use of OSENI with CYP2C8 strong inhibitors (e.g., gemfibrozil) will, or inducers (e.g., rifampin) may, require dose adjustment.

Cationic drugs eliminated by renal tubular secretion should be used with caution if taken with KAZANO.

Please see accompanying Full Prescribing Information, including Medication Guide, for NESINA.

Please see accompanying Full Prescribing Information, including Medication Guide, for KAZANO.

Please see accompanying Full Prescribing Information, including Medication Guide, for OSENI.

About Takeda’s Diabetes Business
Takeda’s heritage in diabetes globally includes significant contributions towards scientific discovery and exchange, starting with the discovery of the thiazolidinedione (TZD) pioglitazone, the more recent developments of alogliptin and the fixed-dose combinations (FDC) alogliptin and pioglitazone, and alogliptin and metformin HCl. The company’s strong, diverse diabetes portfolio and available medications mark important milestones in Takeda’s ongoing commitment to advancing patient care and helping to meet the individual needs of this growing patient population.

About Takeda Pharmaceutical Company Limited
Located in Osaka, Japan, Takeda is a research-based global company with its main focus on pharmaceuticals. As the largest pharmaceutical company in Japan and one of the global leaders of the industry, Takeda is committed to strive towards better health for people worldwide through leading innovation in medicine.

Additional information about Takeda is available through its corporate website, www.takeda.com.

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Poster Session: Saturday, March 29, 2014, “Acute Coronary Syndromes: Comorbid Considerations” (2:45 – 3:30 p.m. CT)


Elissa J. Johnsen
Takeda Pharmaceuticals International, Inc.