Takeda Presents Additional Results from EXAMINE Cardiovascular Safety Outcomes Trial

Takeda Presents Additional Results from EXAMINE Cardiovascular Safety Outcomes Trial at the 49th Annual Meeting of the European Association for the Study of Diabetes

-- Fasiglifam Phase 3 Efficacy and Safety Data Also Presented

BARCELONA, Spain and ZURICH, Switzerland, Sept. 26, 2013 /PRNewswire/ -- Takeda Pharmaceuticals International GmbH (Takeda), a leading contributor to innovative Type 2 diabetes treatments, presented alogliptin and fasiglifam data at the 49th Annual Meeting of the European Association for the Study of Diabetes (EASD) in Barcelona, Spain. Data from the global EXAMINE (EXamination of CArdiovascular OutcoMes: AlogliptIN vs. Standard of CarE in Patients with Type 2 Diabetes Mellitus and Acute Coronary Syndrome) CV safety outcomes trial indicated that alogliptin did not increase CV ischemic events including all-cause mortality (death from any cause), nonfatal myocardial infarction, nonfatal stroke, and urgent revascularization due to unstable angina. Additionally, EXAMINE exploratory data presented showed rates of hospitalization for heart failure were comparable across alogliptin and placebo groups.

The company also presented Phase 3 data on the investigational compound fasiglifam, a potential first-in-class GPR40 agonist for the treatment of Type 2 diabetes, demonstrating the study's primary endpoint of change from baseline in HbA1c at week 24 was met. Study findings showed that fasiglifam significantly improved glycemic control with low incidence of hypoglycemia and statistically significant reductions in HbA1c, compared with placebo, at 24 weeks in patients with Type 2 diabetes inadequately controlled by diet and exercise.

EXAMINE Data
Results demonstrated that the EXAMINE exploratory adjudicated CV composite endpoint of all-cause mortality, nonfatal myocardial infarction, nonfatal stroke, urgent revascularization due to unstable angina, and hospitalization for heart failure occurred at similar rates in the alogliptin and placebo groups (16.0% vs. 16.5%; hazard ratio, 0.98; 95% confidence limits [CL] of 0.86 to 1.12). For the post hoc composite endpoint of cardiovascular death and hospitalization for heart failure, there was no difference in event rates between the alogliptin and placebo groups (7.4% vs. 7.5%; hazard ratio, 0.98; 95% CL of 0.82 to 1.20). Rates of hospitalization for heart failure were similar in the alogliptin versus placebo groups for both composite endpoints. Among other published DPP-4i CV safety outcomes trials, EXAMINE was the only trial to have evaluated Type 2 diabetes patients at high risk for major adverse cardiac events (MACE) due to recent acute coronary syndrome (ACS). Results of the global alogliptin EXAMINE trial were recently published in the New England Journal of Medicine.

"As physicians, it is critical that we understand the impact of treating high risk patient groups such as those evaluated by the EXAMINE trial," said Simon Heller, D.M., EXAMINE Steering Committee member. "Many Type 2 diabetes patients today are also living with cardiovascular disease and these additional findings on heart failure hospitalizations will provide important clinical insights for physicians helping patients manage their diabetes."

Fasiglifam Data
The presentation entitled "Efficacy and safety of fasiglifam (TAK-875), a GPR40 selective agonist, in Japanese Type 2 diabetes mellitus patients: a Phase 3, double-blind, placebo controlled, comparative study" includes findings from the CCT-003 study, which evaluated the efficacy and safety of the investigational compound fasiglifam 25 mg and 50 mg, administered once daily before breakfast for 24 weeks, in Japanese patients with Type 2 diabetes inadequately controlled by diet and exercise. Findings met the study's primary endpoint achieving a statistically significant change from baseline in HbA1c compared to placebo (p-value less than 0.0001). The difference in the least-square means in HbA1c versus placebo was -0.75% (95% CL: -0.985 to -0.521) in the fasiglifam 25 mg group and -1.01% (95% CL: -1.244 to -0.777) in the fasiglifam 50 mg group. There were no significant differences in incidence of adverse events between the fasiglifam groups and the placebo group.

"We are pleased to present the Phase 3 findings from this study on fasiglifam, which further help to demonstrate the clinical profile of this potential new option for Type 2 diabetes," said Ajay Ahuja, M.D., vice president, Global Medical Affairs, Takeda. "Takeda has built a strong foundation and maintained a robust focus in diabetes for more than 20 years, and presenting a total of seven abstracts at EASD with the scientific community underscores our dedication to addressing the needs of this growing patient population."

Additional Data
Additional abstracts presented include:

    "Durability of the efficacy and safety of alogliptin compared to glipizide over 2 years when used in combination with metformin"
    "Efficacy and safety of alogliptin in subjects with type 2 diabetes: a multicenter, randomized, double-blind, placebo-controlled, phase 3 study in mainland China, Taiwan and Hong Kong"
    "Pharmacokinetics (PK) and pharmacodynamics (PD) of the GPR40 agonist fasiglifam (TAK-875) and glimepiride following co-administration in type 2 diabetes subjects"
    "Distribution of costs in patients with type 2 diabetes mellitus: a retrospective claims database analysis"
    "Cost predictors in type 2 diabetes mellitus: a retrospective claims database analysis"

About EXAMINE
EXAMINE, a global, large, randomized, double-blind, placebo-controlled clinical 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 (within 15 to 90 days prior to randomization). The trial had a primary composite endpoint of CV death, nonfatal myocardial infarction and nonfatal stroke. 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. 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; hazard ratio, 0.96; one-sided repeated confidence interval [CI] bound, 1.16).

In the alogliptin group, 71.4% of patients received 25 mg, 25.7% received 12.5 mg, and 2.9% received 6.25 mg daily. Alogliptin doses were adjusted according to renal function: estimated glomerular filtration rate (eGFR) by the Modification in Diet in Renal Disease formula greater than or equal to 60 ml/min, 25 mg daily; less than 60 ml/min but greater than or equal to 30 ml/min, 12.5 mg daily; and less than 30 ml/min, 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% and 0.03% in the alogliptin and placebo groups, respectively, and the least square means difference in HbA1c between alogliptin and placebo was -0.36% (95% CL, -0.43, -0.28, p-value less than 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 Type 2 Diabetes
Type 2 diabetes is the most common form of diabetes affecting millions of people globally. Type 2 diabetes is a progressive and chronic condition and patients should work with a healthcare professional to manage and monitor their disease. In addition to diet and exercise, patients often need to take one or more medications in order to help them manage their blood glucose levels. According to the International Diabetes Federation, the global health care expenditures for diabetes (both Type 1 and 2) were estimated at more than $471 billion USD in 2012. By 2030, this number is projected to exceed $595 billion.

About Alogliptin
Alogliptin is a dipeptidyl peptidase-4 inhibitor (DPP-4i) for the treatment of Type 2 diabetes in adults as an adjunct to diet and exercise. DPP-4 is 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. A New Drug Application (NDA) for NESINA (alogliptin) was approved in April 2010 by the Japanese Ministry of Health, Labour and Welfare for the treatment of Type 2 diabetes, and the therapy is available under the same brand name in Japan. A NDA for the alogliptin fixed-dose combination (FDC) with 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 available under the brand name LIOVEL in Japan. NESINA (alogliptin) was approved by the U.S. FDA as a monotherapy and also in FDC with pioglitazone (OSENI) and metformin HCl (KAZANO) in January 2013 for the treatment of Type 2 diabetes in adults as adjuncts to diet and exercise. Alogliptin as a monotherapy is currently approved for use in 6.25 mg, 12.5 mg, and 25 mg dose tablets; the approved normal dose for alogliptin is 25 mg once daily. For patients with moderate renal impairment (creatinine clearance [CrCl] greater than or equal to 30 mL/min to less than 60 mL/min), the dose of alogliptin is 12.5 mg once daily and for patients with severe renal impairment (CrCl greater than or equal to 15 to less than 30 mL/min) and for patients with end-stage renal disease (ESRD) (CrCl less than 15 mL/min or requiring hemodialysis), the dose of alogliptin is 6.25 mg once daily.

In September 2013, the European Commission granted Marketing Authorization for alogliptin (Vipidia™) and its FDC therapies, alogliptin with metformin (Vipdomet™), and alogliptin with pioglitazone (Incresync™). The Committee for Medicinal Products for Human Use (CHMP), of the European Medicines Agency (EMA), issued a positive opinion for these products in July 2013. Alogliptin is also approved for use in China, Mexico and South Korea, though the therapy is not yet available in those markets.

The efficacy of alogliptin was studied as an adjunct to diet and exercise, and as an add-on therapy to several other classes of anti-diabetic medications, including biguanide, thiazolidinediones, insulin and sulfonylureas. In these studies, alogliptin 25 mg tablets taken once daily, demonstrated clinically and statistically significant reductions in HbA1c, with low incidence of hypoglycemia compared with active control or placebo. Study results indicated that alogliptin co-administered with either metformin or pioglitazone produced significant improvements in glycemic control compared with the respective monotherapies.

Alogliptin Important Safety Information
Alogliptin is contraindicated in patients with known hypersensitivity to alogliptin or any of its components.

Post-marketing events of acute pancreatitis have been reported for alogliptin and have been associated with other DPP-4 inhibitors. After initiation of alogliptin, patients should be observed carefully for signs and symptoms of pancreatitis. If pancreatitis is suspected, alogliptin should be promptly discontinued and appropriate management should be initiated.

Post-marketing events of serious hypersensitivity reactions in patients treated with alogliptin such as angioedema and severe cutaneous adverse reactions including Stevens-Johnson syndrome have been reported and have been associated with other DPP-4 inhibitors. If a serious hypersensitivity reaction is suspected, alogliptin should be discontinued.

Post-marketing reports of hepatic dysfunction including hepatic failure have been received. Patients should be observed closely for possible liver abnormalities. Measure liver tests promptly in patients who report symptoms that may indicate liver injury. If an abnormality is found and an alternative etiology is not established, consider discontinuation of alogliptin.

Insulin and insulin secretagogues, such as sulfonylureas, are known to cause hypoglycemia. Therefore, a lower dose of insulin or insulin secretagogue may be required to minimize the risk of hypoglycemia when used in combination with alogliptin.

Other undesirable effects of alogliptin include headache, upper respiratory tract infection, pruritus, and nasopharyngitis.

About Fasiglifam
Fasiglifam is currently in development by Takeda and is the first of a new class of drugs under investigation for the treatment of Type 2 diabetes. Fasiglifam works differently from other currently available insulin-releasing pharmacotherapies and thus is believed to be complementary to other mechanisms. Fasiglifam is an agonist of G-protein-coupled receptor 40 (GPR40) that is predominantly expressed on the surface of pancreatic beta cells, which play a key role in the secretion of insulin. GPR40 agonists enhance insulin secretion in a glucose-dependent manner, and are therefore thought to have a low risk of hypoglycemia.

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, and ongoing development of the investigational compound fasiglifam. The company's strong, diverse diabetes pipeline 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 Pharmaceuticals International GmbH
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.

The company has a commercial presence covering around 70 countries, with particular strength in Asia, North America, Europe and fast-growing emerging markets including Latin America, Russia-CIS and China. Takeda is ranked 12th by global Rx sales, 14th in the BRIC countries and 18th in Europe. Areas of focus include cardiovascular and metabolic, oncology, respiratory and immunology, central nervous system, general medicine, and vaccines.

Through the integration of Millennium Pharmaceuticals and Nycomed, Takeda has been transforming itself, broadening its therapeutic expertise and geographic outreach.

Takeda Pharmaceuticals International GmbH, headquartered in Zurich, is a wholly owned subsidiary of Takeda Pharmaceutical Company Limited.

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

This press release contains forward-looking statements. Forward-looking statements include statements regarding Takeda's plans, outlook, strategies, results for the future, and other statements that are not descriptions of historical facts. Forward-looking statements may be identified by the use of forward-looking words such as "may," "believe," "will," "expect," "project," "estimate," "should," "anticipate," "plan," "assume," "continue," "seek," "pro forma," "potential," "target," "forecast," "guidance," "outlook" or "intend" or other similar words or expressions of the negative thereof. Forward-looking statements are based on estimates and assumptions made by management that are believed to be reasonable, though they are inherently uncertain and difficult to predict. Investors are cautioned not to unduly rely on such forward-looking statements.

Forward-looking statements involve risks and uncertainties that could cause actual results or experience to differ materially from that expressed or implied by the forward-looking statements. Some of these risks and uncertainties include, but are not limited to, (1) the economic circumstances surrounding Takeda's business, including general economic conditions in Japan, the United States and worldwide; (2) competitive pressures and developments; (3) applicable laws and regulations; (4) the success or failure of product development programs; (5) actions of regulatory authorities and the timing thereof; (6) changes in exchange rates; (7) claims or concerns regarding the safety or efficacy of marketed products or product candidates in development; and (8) integration activities with acquired companies.

The forward-looking statements contained in this press release speak only as of the date of this press release, and Takeda undertakes no obligation to revise or update any forward-looking statements to reflect new information, future events or circumstances after the date of the forward-looking statement. If Takeda does update or correct one or more of these statements, investors and others should not conclude that Takeda will make additional updates or corrections.

CONTACT: Elissa J. Johnsen, Takeda Pharmaceuticals International, Inc., +1-224-554-3185, elissa.johnsen@takeda.com

Web Site: http://www.takeda.com

Posted: September 2013

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