Benefit/Risk Profile Remains Positive for Pioglitazone as an Important Treatment Option for Type 2 Diabetes

Osaka, Japan, December 15, 2015 – Takeda Pharmaceutical Company Limited (“Takeda”) today commented on letters to the editor published in the December 15^th Journal of the American Medical Association (JAMA), referencing Pioglitazone Use and Risk of Bladder Cancer and Other Common Cancers in Persons With Diabetes, the 10-year epidemiology study of pioglitazone use conducted by the University of Pennsylvania (U. of Penn.) and Division of Research at Kaiser Permanente Northern California (KPNC), which was published by JAMA on July 21.[i]^,[ii],[iii]

Takeda disagrees with the opinions stated in the Letters to the Editor from Benjamin J. Davies, MD, Sonal Singh, MD, MPH, and Marc. A. Suchard, MD, PhD, who purport to analyze the U. of Penn and KPNC study.^1,2 It is important to note that the study had considerable input from the United States Food and Drug Administration (FDA). It also is important to note that Dr. Davies, Dr. Singh and Dr. Suchard were commissioned to conduct their analysis by plaintiffs’ attorneys who are engaged in lawsuits against Takeda regarding use of pioglitazone.

“We are confident in the positive benefit/risk profile of pioglitazone and agree with the robust methodology that was created by the world-class epidemiologists at the U. of Pennsylvania and KPNC. This study was performed following thorough consultation with the FDA,” said Andy Plump, M.D., Ph.D., Takeda Pharmaceuticals Chief Medical & Scientific Officer. “The study authors have worked diligently over many years to deliver these findings on pioglitazone. This study is one of the most comprehensive real world data analyses ever undertaken. This is strong hypothesis driven science and I commend the investigators for their efforts.”

A Cohort Study of Pioglitazone and Bladder Cancer in Patients with Diabetes was a prospective cohort study designed to examine whether pioglitazone treatment for diabetes is associated with increased incidence of bladder cancer.³ This 10 years observational prospective study included 193,099 patients diagnosed with Type 2 diabetes between 1997 and 2012. This extensive research demonstrated no statistically significant increased risk of bladder cancer among patients ever exposed to pioglitazone compared to those never exposed. Additionally, no association was found between the risk of bladder cancer and the duration of pioglitazone use, increased cumulative dose of pioglitazone or the time since initiating pioglitazone. This is the third cohort study with long-term data to demonstrate no association of pioglitazone use and risk of bladder cancer.

“Long-term observational studies underscore the significant potential of real world data to help further understand the effects of our medicines on patients,” said Plump. “Takeda continues to ensure that all critical data is shared with regulatory bodies and with healthcare professionals so they have the best available information to make treatment decisions.”

About Pioglitazone

Pioglitazone is a thiazolidinedione for the treatment of Type 2 diabetes in adults as an adjunct to diet and exercise.

Unlike many oral antidiabetic drugs, pioglitazone is not an insulin secretagogue. Pioglitazone is an agonist for peroxisome proliferator-activated receptor-gamma (PPARγ). PPAR receptors are found in tissues important for insulin action such as adipose tissue, skeletal muscle, and liver. Activation of PPARγ nuclear receptors modulates the transcription of a number of insulin responsive genes involved in the control of glucose and lipid metabolism. Therefore, pioglitazone is a medication that depends on the presence of insulin for its mechanism of action, and it decreases insulin resistance in muscle and the liver, resulting in increased insulin-dependent glucose disposal as well as decreased hepatic glucose output.

Clinical studies demonstrate that pioglitazone improves insulin sensitivity in insulin-resistant patients. Pioglitazone enhances cellular responsiveness to insulin, increases insulin-dependent glucose disposal and improves hepatic sensitivity to insulin. In patients with Type 2 diabetes, the decreased insulin resistance produced by pioglitazone results in lower plasma glucose concentrations, lower plasma insulin concentrations, and lower HbA1c values. In controlled clinical trials, pioglitazone had an additive effect on glycemic control when used in combination with sulfonylurea, metformin, or insulin.

Important Safety Information

Contraindications

Initiation of ACTOS is contraindicated in patients with NYHA Class III or IV heart failure.

ACTOS is contraindicated in patients with known hypersensitivity to pioglitazone or any of its excipients so as to avoid inducing a potentially serious hypersensitivity reaction.

Warnings and Precautions

Fluid retention and cardiac failure: Thiazolidinediones, including ACTOS, can cause dose-dependent fluid retention, which may exacerbate or precipitate heart failure. After initiation of ACTOS, 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, discontinuation of ACTOS must be considered. ACTOS should be used with caution in patients with cardiac dysfunction whose physical activity is markedly limited. Combination use with insulin may increase risk.

Hepatic effects: Post-marketing reports of hepatitis and hepatic dysfunction have been received. Very rarely these reports have involved hepatic failure, with and without a fatal outcome, although causality has not been established. Obtain liver tests before starting ACTOS and periodically thereafter. Pioglitazone therapy should not be initiated in patients with increased liver enzyme levels (ALT> 2.5x upper limit of normal) or with any other evidence of liver disease. Existing pioglitazone therapy should be discontinued if ALT levels are persistently higher than 3x the upper limit of normal, and symptoms suggesting hepatic dysfunction should cause the liver enzymes to be checked. Pending the results of laboratory investigations, the decision as to whether pioglitazone therapy should continue must be based on clinical judgment; in the presence of jaundice, drug therapy should be discontinued.

Weight gain: Weight gain was observed in clinical trials and has been seen in post-marketing experience with pioglitazone, so patient weight should be closely monitored.

Fractures: An increased incidence of bone fracture has been noted in female patients.

Bladder cancer: Some data suggest there may be an increased risk of bladder cancer in ACTOS users and also that the risk increases with duration of use. Do not use ACTOS 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 macroscopic hematuria or other symptoms such as dysuria or urinary urgency that develop or increase during treatment as these may be due to bladder cancer.

Hypoglycemia: When ACTOS is used with insulin, a sulfonylurea or other oral hypoglycemic agents, hypoglycemia may occur.

Ovulation: Ovulation in premenopausal anovulatory women or women with polycystic ovarian syndrome may occur with ACTOS.

Macular edema: Post-marketing reports of new-onset or worsening diabetic macular edema with decreased visual acuity have been reported with thiazolidinediones, including pioglitazone. Physicians should consider the possibility of macular edema if a patient reports decreased visual activity.

Drug interactions: Use of ACTOS with CYP2C8 inducers or strong inhibitors may require dose adjustment.

Please refer to the Summary of Product Characteristics (SmPC) for ACTOS before prescribing.

ACTOS should be used according to the indication, posology and method of administration described in the SmPC.

Please consult with your local regulatory agency for approved labeling in your country.

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. Takeda launched alogliptin, a dipeptidyl peptidase-4 (DPP-4) inhibitor, in Japan in 2010. Since that time alogliptin has been launched in a variety of markets across the globe including the U.S., Italy, the United Kingdom, China, Mexico and South Korea. Diabetes prevalence continues to grow worldwide, with more than 382 million people impacted by Type 2 diabetes. As the disease becomes increasingly prevalent, Takeda remains focused on expanding access of alogliptin, especially in emerging markets like Brazil, Russia, and the Middle East. In 2015, Takeda launched Zafatek, a DPP-4 inhibitor for the treatment of Type 2 diabetes, in Japan. The company’s diverse diabetes portfolio of medications represent 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 (TYO: 4502) 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.

Contact:

Elissa J. Johnsen

+1-224-554-3185

[email protected]

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