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Takeda Announces Results from Uloric® (febuxostat) Cardiovascular Outcomes Trial in Patients with Gout and Cardiovascular Disease

March 12, 2018

- Phase 3b trial results shared with scientific community through publication in the New England Journal of Medicine and simultaneous presentation at the American College of Cardiology’s 67th Annual Scientific Session & Expo

Deerfield, IL, March 12, 2018 – Takeda Pharmaceuticals, U.S.A., Inc. (“Takeda”), today announced the publication of findings from a Phase 3b cardiovascular (CV) outcomes trial of Uloric® (febuxostat) in the New England Journal of Medicine (NEJM) and simultaneous oral presentation as a late-breaking clinical trial at the American College of Cardiology’s (ACC) 67th Annual Scientific Session & Expo. The trial, titled “Cardiovascular Safety of Febuxostat and Allopurinol in Patients with Gout and Cardiovascular Comorbidities (CARES),” was conducted by Takeda to evaluate the CV safety of Uloric compared to allopurinol in subjects with gout and CV disease.

In 2009, Uloric was approved by the U.S. Food and Drug Administration (FDA) as a once-daily, oral prescription medication for the treatment of hyperuricemia in adults with gout, making it the first new treatment for this indication in more than 40 years. Since approval, the Prescribing Information for Uloric has included a warning and precaution that a higher rate of adverse CV events was observed in patients treated with Uloric when compared with allopurinol in clinical trials. CARES was initiated in 2010 as a post-marketing requirement by the FDA to determine if the use of Uloric had similar CV risk compared to allopurinol and was completed in 2017. Takeda has submitted the study results to the FDA and is working with the agency to conduct a comprehensive review of the data.

Uloric met the primary endpoint of CARES, demonstrating that the rate of major adverse cardiovascular events (MACE: CV death, non-fatal myocardial infarction (MI), non-fatal stroke, and urgent revascularization due to unstable angina) in patients treated with Uloric was similar to that of allopurinol. When analyzing the individual components of MACE as secondary endpoints, the individual rates for MI, stroke, and urgent revascularization for unstable angina were similar with Uloric compared to allopurinol. However, the rate of CV death was higher among patients assigned to Uloric compared to allopurinol, which also contributed to a higher rate of death from all causes. Based on analyses conducted to date, a reason for this finding has not been identified. There were no significant differences in rates of other serious CV events such as hospitalization for heart failure or arrhythmias.

Takeda submitted CARES for publication in NEJM and presentation at ACC to facilitate scientific exchange of the data with physicians treating patients with gout.

“CARES demonstrated that, overall, the rate of major adverse cardiovascular events was similar among patients treated with Uloric compared to those treated with allopurinol in gout patients with cardiovascular disease. The imbalance in cardiovascular deaths between the two treatments was unexpected and warrants further analyses,” said William B. White, M.D., Professor, Calhoun Cardiology Center, University of Connecticut School of Medicine, and lead investigator of the study.

“Patient safety is Takeda’s top priority, and CARES provides physicians with important safety information about Uloric that is useful when evaluating treatment options for patients with hyperuricemia and gout. We are actively working with regulators and medical experts to ensure physicians have comprehensive and accurate information to make educated treatment decisions,” said Darryl Sleep, M.D., Head, U.S. Medical Office, Takeda Pharmaceuticals. “CARES is the first large, multicenter, randomized cardiovascular safety trial of urate-lowering therapy, and Takeda is committed to the scientific exchange of this data to inform the medical community.”

NEJM Article: “Cardiovascular Safety of Febuxostat or Allopurinol in Patients with Gout”

The study publication in NEJM discusses findings from CARES, a Phase 3b, multicenter, randomized, double-blind, noninferiority trial comparing CV outcomes with febuxostat versus allopurinol in patients with gout and a history of major CV disease. Major CV diseases in the study population included a history of MI, hospitalization for unstable angina, stroke, hospitalized transient ischemic attack, peripheral vascular disease, or diabetes mellitus with evidence of microvascular or macrovascular disease. The primary endpoint in CARES was the time to first occurrence of MACE, a composite of non-fatal MI, non-fatal stroke, CV death and urgent revascularization due to unstable angina. The secondary endpoints included the composite of CV death, non-fatal MI, and non-fatal stroke as well as the individual components of the primary MACE endpoint. Additional safety endpoints included all-cause mortality, urgent cerebrovascular revascularization, transient ischemic attack, hospitalization for heart failure, arrhythmias not associated with ischemia, and venous thromboembolic events.

In total, 6,190 patients were followed for a median of 32 months. In the complete analysis, the primary MACE endpoint occurred at similar rates in the febuxostat and allopurinol treatment groups (10.8% vs. 10.4% of patients, respectively; hazard ratio [HR] 1.03; one-sided repeated confidence interval [CI] 0.87-1.23). In the analysis of the individual components of MACE, the rates of events were similar in the febuxostat and allopurinol groups for non-fatal MI (3.6% vs. 3.8% of patients; HR 0.93; 95% CI 0.72-1.21), non-fatal stroke (2.3% vs. 2.3% of patients; HR 1.01; 95% CI 0.73-1.41) and urgent revascularization due to unstable angina (1.6% vs. 1.8% of patients; HR 0.86; 95% CI 0.59-1.26). The rates were higher with febuxostat than allopurinol for CV death (4.3% vs. 3.2% of patients; HR 1.34; 95% CI 1.03-1.73) and death from all cause (7.8% vs. 6.4% of patients; HR 1.22; 95% CI 1.01-1.47). Rates of adjudicated hospitalization for heart failure, hospital admissions for arrhythmias not associated with ischemia, venous thromboembolic events and hospitalization for transient ischemic attacks were comparable for febuxostat and allopurinol.

Use of ULORIC (febuxostat) 

ULORIC is a prescription medicine used to lower blood uric acid levels in adults with gout. ULORIC is not for the treatment of high uric acid without a history of gout.

Individual results may vary.

Important Safety Information 

Do not take ULORIC if you are taking azathioprine or mercaptopurine.

ULORIC may cause serious side effects, including:

Gout Flares. Gout flares can happen when you first start taking ULORIC. Your healthcare provider may give you other medicines to help prevent your gout flares.

Heart Problems. People who take ULORIC can have serious heart problems including heart attacks, strokes and heart-related deaths. It is not known that ULORIC caused these problems. Call your healthcare provider right away or get emergency medical help if you have any of the following symptoms: chest pain, shortness of breath, dizziness, numbness or weakness on one side of your body, trouble talking or headache.

Liver Problems. Liver problems can happen in people who take ULORIC. Your healthcare provider may do blood tests to check how well your liver is working before and during your treatment with ULORIC.

Severe Skin and Allergic Reactions. Serious skin and allergic reactions that may affect different parts of the body such as your liver, kidneys, heart or lungs, can happen in people who take ULORIC. Call your healthcare provider right away or get emergency medical help if you have any of the following symptoms: rash, red and painful skin, severe skin blisters, peeling skin, sores around the lips, eyes or mouth, swollen face, lips, mouth, tongue or throat, or flu-like symptoms.

The most common side effects of ULORIC include liver problems, nausea, gout flares, joint pain, and rash. Tell your healthcare provider if you have any side effect that bothers you, or that does not go away.

Please see the accompanying complete Prescribing Information and talk to your healthcare professional.

You are encouraged to report negative side effects of prescription drugs to the FDA. Visit www.fda.gov/medwatch, or call 1-800-FDA-1088.

About Gouty Arthritis

Gout is caused by a buildup of uric acid in the body. Uric acid forms crystals in the joints, which can lead to the inflammation and pain of a gout attack. As the uric acid level rises, so does the chance for gout and gout attacks. Over time, these attacks, or flares, can involve more joints, last longer, and happen more often.

An estimated 8.3 million Americans have gout, which may be increasing. Half of gout patients have three or more attacks per year; a typical gout attack can last at least 4 days.

About Takeda Pharmaceutical Company Limited

Takeda Pharmaceutical Company Limited (TSE: 4502) is a global, research and development-driven pharmaceutical company committed to bringing better health and a brighter future to patients by translating science into life-changing medicines. Takeda focuses its R&D efforts on oncology, gastroenterology and neuroscience therapeutic areas plus vaccines. Takeda conducts R&D both internally and with partners to stay at the leading edge of innovation. Innovative products, especially in oncology and gastroenterology, as well as Takeda’s presence in emerging markets, are currently fueling the growth of Takeda. Around 30,000 Takeda employees are committed to improving quality of life for patients, working with Takeda’s partners in health care in more than 70 countries. For more information, visit https://www.takeda.com/newsroom/.
Takeda Pharmaceuticals U.S.A., Inc. is located in Deerfield, Ill., and is the U.S. marketing and sales organization of Takeda Pharmaceutical Company Limited.
Additional information about Takeda is available through its corporate website, www.takeda.com, and additional information about Takeda Pharmaceuticals U.S.A., Inc. is available through its website, www.takeda.us.


Kara Hoeger    

Takeda Pharmaceuticals U.S.A., Inc.   
TEL: 224-554-1277    
[email protected]