Deerfield, Ill., April 14, 2015 and Osaka, Japan, April 15, 2015 – Takeda Pharmaceuticals U.S.A. Inc. and Takeda Pharmaceutical Company Limited ("Takeda") today announced that members of the Endocrinologic and Metabolic Drugs Advisory Committee (EMDAC) of the United States (U.S.) Food and Drug Administration (FDA) convened to review one of the first cardiovascular (CV) outcomes trials (CVOT) in patients with Type 2 diabetes, EXAMINE (EXamination of CArdiovascular OutcoMes: AlogliptIN vs. Standard of CarE in Patients with Type 2 Diabetes Mellitus and Acute Coronary Syndrome). The Committee voted that, based on the data presented, the results of EXAMINE demonstrate that the use of alogliptin in patients with Type 2 diabetes has an acceptable CV risk profile. All 16 voting members of the Committee supported this recommendation. In addition, 13 out of 16 Committee members voted that safety information from the EXAMINE study should be added to the alogliptin labeling and the other three members voted for no change to the labeling.
"Patients with diabetes are at an increased risk of cardiac related comorbidities such as heart disease and stroke, as well as hospitalized heart failure and cardiac death," said William B. White, MD, Professor, Calhoun Cardiology Center, University of Connecticut School of Medicine, Farmington, Connecticut, U.S., on behalf of the EXAMINE Steering Committee and Investigators. "Today's Advisory Committee recommendation provides important information about alogliptin that may be useful for prescribing physicians as they consider appropriate treatment options for patients with Type 2 diabetes."
EXAMINE, a large, randomized, double-blind, placebo-controlled outcomes study, was completed as a result of the U.S. FDA 2008 Guidance, titled "Guidance for Industry: Diabetes Mellitus – Evaluating Cardiovascular Risk in New Antidiabetic Therapies to Treat Type 2 Diabetes," for all Type 2 diabetes treatments under development since the issuance of the guidance. The EXAMINE 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 who were at high risk for major adverse cardiovascular events (MACE) due to recent acute coronary syndrome (ACS). The trial's primary objective was to evaluate non-inferiority of CV risk based on a primary composite endpoint of CV death, nonfatal myocardial infarction (MI) and nonfatal stroke.
"Takeda is pleased with the recommendation of the Committee and we remain confident in alogliptin as an important treatment option for patients living with Type 2 diabetes," said Robert Jackson, MD, MBA, Vice President, Global Medical Head, CVM-Respiratory Therapy, Takeda Pharmaceuticals International.
"Today's outcome reinforces that the global EXAMINE trial met the FDA postmarketing guidance requirements. The trial is important as it assesses cardiovascular safety in patients known to be at a high risk for cardiovascular disease."
Patient safety is a top priority for Takeda, and we remain committed to ongoing clinical research to understand and investigate potential safety concerns. Alogliptin has been studied as a monotherapy and in combination with metformin, a sulfonylurea (SU), a thiazolidinedione (TZD), and insulin in a comprehensive global clinical program comprising more than 50 clinical studies involving approximately 1,000 healthy adult patients and more than 17,000 adult patients with Type 2 diabetes.
The FDA also asked the Committee to discuss whether additional alogliptin studies are needed and to make any recommendations regarding the evaluation of the risk-benefit profile for alogliptin. In addition to discussing EXAMINE's pre-specified primary CV outcome data, the Committee discussed other study analyses including heart failure, study data by geographic region, and other data including renal safety findings.
The outcome of the Advisory Committee meeting is non-binding and will be taken into consideration by the FDA.
Alogliptin is the first dipeptidyl peptidase-4 inhibitors (DPP-4i) to report out results on CV safety outcomes in Type 2 diabetes patients who are at high risk due to recent ACS. Heart disease, or cardiovascular disease (CVD), is a commonly occurring comorbid condition in patients living with Type 2 diabetes.[i]
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 MI and nonfatal stroke. The primary endpoint occurred at similar rates in the alogliptin (n=305) and placebo (n=316) groups (in 11.3 percent of patients vs. 11.8 percent of patients during a median follow-up period of 18 months; hazard ratio (HR), 0.96; upper boundary of the one-sided repeated CI, 1.16).
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 (glucagon-like peptide-1) and GIP (glucose-dependent insulinotropic peptide). 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.
Takeda launched alogliptin in Japan in 2010. Since that time alogliptin has been launched in a variety of markets across the globe including the U.S. in 2013, as well as Italy, Austria, the United Kingdom, China, Mexico and South Korea. Diabetes prevalence continues to grow worldwide, with more than 382 million people impacted by diabetes.1 As the disease becomes increasingly prevalent, Takeda remains focused on expanding access of alogliptin, especially in emerging markets like Brazil, India and Russia.
About NESINA, KAZANO and OSENI
NESINA is a DPP-4i for the treatment of type 2 diabetes in adults as an adjunct to diet and exercise. DPP-4is 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.
KAZANO is an FDC therapy which combines alogliptin and metformin HCl in a single tablet for the treatment of type 2 diabetes in adults as an adjunct to diet and exercise. Metformin HCl is a biguanide, a widely used anti-diabetes medication that acts primarily by reducing the amount of glucose produced by the liver.
OSENI is an FDC therapy which combines alogliptin and pioglitazone in a single tablet, for the treatment of type 2 diabetes in adults as an adjunct to diet and exercise. Pioglitazone is a TZD that decreases insulin resistance, a condition in which the body does not efficiently use the insulin it produces to control blood glucose levels, and is approved in adults for the treatment of type 2 diabetes as an adjunct to diet and exercise. An NDA for alogliptin and pioglitazone was approved in July 2011 by the Japanese Ministry of Health, Labour and Welfare for the treatment of type 2 diabetes, and the therapy is currently available under the brand name LIOVEL in Japan.
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
WARNING: CONGESTIVE HEART FAILURE—for OSENI
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.
WARNING: LACTIC ACIDOSIS—for KAZANO
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 infarction, 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 hepatic impairment.
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.
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%).
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 Pharmaceuticals U.S.A., Inc.
Takeda Pharmaceuticals U.S.A., Inc., located in Deerfield, Ill., is the U.S. marketing and sales organization of Takeda Pharmaceutical Company Limited, Osaka, Japan. The company has a commercial presence covering more than 70 countries, with particular strength in Asia, North America, Europe and fast-growing emerging markets including Latin America, Russia-CIS and China. Areas of focus include cardiovascular and metabolic, oncology, respiratory and immunology, central nervous system, general medicine, and vaccines. 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 striving towards better health for people worldwide through leading innovation in medicine. Through strategic acquisitions, Takeda has been transforming itself, broadening its therapeutic expertise and geographic outreach. Additional information about Takeda Pharmaceuticals U.S.A., Inc. is available through its website, www.takeda.us.
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.