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Background Analysis: US FDA Advisory Committee to Review Cardiovascular Safety of Takeda’s Gout Drug, Uloric (febuxostat) – Jan 11, 2019 (AAC-DSRM)


The US FDA has scheduled a joint meeting of the Arthritis Advisory Committee (AAC) and the Drug Safety and Risk Management (DSRM) Advisory Committee for Friday, January 11, 2019. The committees will discuss supplemental new drug application (sNDA) 021-856, Uloric (febuxostat) tablets, sponsored by Takeda Pharmaceuticals (Takeda), which includes the results from the postmarketing safety trial required by FDA to evaluate the cardiovascular safety of febuxostat, entitled “Cardiovascular Safety of Febuxostat and Allopurinol in Patients with Gout and Cardiovascular Morbidities (CARES).” The committees' discussion will include the results from the CARES trial, the benefit:risk assessment of febuxostat, and potential regulatory actions.

Indication Background

Description of Indication

Gout is a serious, chronic, and debilitating form of inflammatory arthritis. According to the US Centers for Disease Control and Prevention (CDC), there are more than 8.3 million diagnosed cases of gout in the US. The underlying cause of gout is hyperuricemia, or elevated serum uric acid (sUA), leading to deposits of crystals in tissues, musculoskeletal structures, and the kidneys. The deposits can lead to arthritis and the formation of visible nodules of uric acid crystals in the joints and skin, which are called tophi.

Symptoms are often treated with nonsteroidal anti-inflammatory drugs (NSAIDs), steroids, or colchicine. Those with frequent attacks, despite dietary changes, may be prescribed a xanthine oxidase (XO) inhibitor, including purine analogues (allopurinol, oxypurinol, and tisopurine) and others (febuxostat, topiroxostat, phytic acid, and myo-inositol), or a uric acid transporter 1 (URAT1) inhibitor (lesinurad).

Product Background

Description of Product

Febuxostat (US Trade name: Uloric) is an XO inhibitor indicated for the chronic management of hyperuricemia in patients with gout. It was initially FDA-approved in February 2009. On November 24, 2008, the AAC had favored approval by a vote of 12-Yes and 0-No. With the approval, the FDA required Takeda to conduct a cardiovascular safety postmarketing trial, since named CARES. Labeling for febuxostat already includes a Warning and Precaution about cardiovascular events that occurred in the preapproval trials.

On November 15, 2017, the FDA alerted the public that preliminary results of the CARES trial showed an increased risk of heart-related death with febuxostat, compared to allopurinol. On August 22, 2018, the FDA notified the public of their receipt of the full trial results and pending review. At that time, the FDA also announced that they would convene an advisory committee meeting of external experts in early 2019 to discuss the trial results and the Agency’s review. The committees' discussion will include the results from the CARES trial, the benefit:risk assessment of febuxostat, and potential regulatory actions.

Clinical Trials

Presented below is a summary of the results from the CARES trial (ClinicalTrials.Gov ID: NCT01101035), based on press releases of high-level results from Takeda. Comprehensive data, including detailed analyses by both the company and the FDA, will be presented in meeting materials posted by the FDA two days prior to the meeting. The meeting materials will be summarized on the day they are posted, in our subsequent report, the Briefing Summary.

CARES was a multicenter, randomized, double-blind, noninferiority trial comparing cardiovascular (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 myocardial infarction (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 causes (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.

On October 21, 2018, Takeda issued a press release with new analyses of CARES. At the time, the company stated that the reason for the higher rate of all-cause death had not been identified. The press release explained that the new analyses do not explain the differences, in terms of mortality rates between febuxostat and allopurinol, but were intended to provide important context for physicians who treat patients with gout, including those with moderate kidney disease and greater CV disease burden, and to provide additional insight into the secondary endpoint of CV death rates observed in the trial. The first analysis reviewed the general safety of febuxostat and allopurinol in patients with gout and CV disease. According to Takeda, overall, febuxostat and allopurinol treatments had comparable safety and tolerability for patients with gout and CV disease. The company also says there was no distinct relationship between CV mortality and reduction of sUA levels or gout flares. The second analyses included results in patients with chronic kidney disease (CKD) that, according to the company, showed rates of CV mortality were comparable for CKD patients who received febuxostat or allopurinol treatments. In this analysis, the patients with moderately impaired kidney function (53% of the CARES cohort), who required up-titration of febuxostat or allopurinol to reach the target serum urate levels, had greater gout and CV disease burden at baseline.

Regulatory Background

US Regulatory Background

August 22, 2018 - The FDA notified the public of their receipt of the full results from the CARES trial, the pending FDA review, and plans for an advisory committee discussion in early 2019.

November 15, 2017 – The FDA issued a Safety Announcement to alert the public that preliminary results of the CARES trial showed an increased risk of heart-related death with febuxostat compared to allopurinol.

February 13, 2009 – The FDA approved febuxostat to treat hyperuricemia in patients with gout (US Trade name: Uloric). The approval included a postmarket requirement to conduct a cardiovascular safety trial, since named CARES.

November 24, 2008 – The AAC supported approval of febuxostat, by a vote of 12-Yes and 0-No.

What’s Next?

Tarius will send a Briefing Summary after briefing materials are posted to FDA’s website (typically within 2 days of the meeting). This report will provide a summary of the FDA and the Sponsor’s briefing materials.

Tarius will send a Results Wire soon after the meeting. This report will include the voting outcomes, if applicable, and key outcomes of the discussion.

METADATA: Sponsor: Takeda Pharmaceuticals Drug Name: febuxostat Drug Class: xanthine oxidase (XO) inhibitor Indication: gout

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DISCLAIMER: The information in this document is for informational purposes only. The SAC Tracker Background Analysis contains information from publicly available sources, including FDA, sponsor, scientific, and clinical websites. Tarius A/S assumes no liability for any inaccurate or incomplete information, or for any actions taken in reliance thereon. © Tarius A/S. All rights reserved.