FDA is examining a possible dose and duration-of-use link between Takeda's thiazolidinedione Actos (pioglitazone) and bladder cancer.

Although interim five-year data from a 10-year epidemiological study did not show a statistically significant overall increase between Actos exposure and bladder cancer (hazard ratio 1.2, 95% CI: 0.9-1.5), an increased risk was seen among patients with the highest cumulative dose and the longest duration of exposure. This increased risk reached statistical significance at 24 months, FDA said.

The median duration of therapy among Actos-treated patients in the study was two years, with exposure ranging from 0.2 years to 8.5 years.

The agency said it has not concluded that Actos increases the risk of bladder cancer and its review of the data is ongoing.

A possible association between pioglitazone and bladder cancer is not new. Since the drug's approval in July 1999, Actos' labeling has reflected preclinical data on development of bladder tumors in rats following exposure to pioglitazone.

Labeling was revised in 2006 to add clinical trial data from two three-year studies - the PROACTIVE trial and a liver safety study - reflecting a higher incidence of bladder cancer cases in pioglitazone-treated patients compared with those receiving control.

A Balance Of Risks

Actos' potential bladder cancer risk was also referenced during advisory committee meetings on the cardiovascular safety of GlaxoSmithKline's competing thiazolidinedione Avandia (rosiglitazone) in July 2007 and July 2010, particularly in the context of discussions over whether Avandia should come off the market because it appears to have a less attractive CV profile than Actos (Also see "Avandia Can Be Saved With New Warnings and REMS, Advisory Cmte. Says" - Pink Sheet, 14 July, 2010.).

In her briefing memo for the 2010 meeting, FDA Metabolism and Endocrinology Products Division Director Mary Parks said any consideration of regulatory action for rosiglitazone based on the comparative safety profile of the two thiazolidinediones "must consider the entire safety profile of both. While both agents share increased risk of fractures in women, anemia, weight gain, macular edema, peripheral edema and fluid retention, and exacerbation of heart failure, pioglitazone has an additional risk signal of bladder cancer."

Both Avandia and Actos are potent agonists for peroxisome proliferator-activated receptor-gamma. Bladder tumors have also been seen in preclinical studies for PPAR agents that demonstrate dual alpha and gamma activity, she noted.

Some committee members who voted against withdrawing Avandia from the market in 2007 and 2010 worried that Actos would be shown to have other deleterious effects down the road.

Labeling Change Not Expected

As an FDA post-marketing commitment, Takeda is sponsoring a 10-year observational cohort study, with a nested case-control study, in diabetic patients who are members of the Kaiser Permanente Northern California health plan. The cohort includes more than 193,000 patients who were age 40 years or older at the time of study entry.

New diagnosis of bladder cancer with exposure to Actos is the primary outcome measure. Data on drug dose, duration of exposure and potential confounding factors are also being examined. The planned five-year interim analysis was performed with data collected through April 2008.

Robert Spanheimer, Takeda's medical director for Actos, said in an interview that Kaiser Permanente holds the database and Takeda is not involved in the analysis. However, he stressed that the findings of increased cancer risk related to dose and duration of use are based on a post-hoc analysis of interim data, and he does not anticipate FDA will seek a labeling change at this juncture.

Pre-specified interim analyses are being conducted every two years, and the full study is expected to complete in 2013, he said.

- Sue Sutter (s.suttter@elsevier.com)

Actos' Bladder Cancer Signal May Hinge On Dose, Duration Of Use

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