Actos News

New Allegation in Ongoing Actos Trial: Takeda Blocked FDA Efforts
to Add Bladder Cancer Warning to Actos Label   
March 15, 2013

At the center of the ongoing trial involving drug maker Takeda Pharmaceuticals and a California man who has terminal bladder cancer, is Takeda’s diabetes drug Actos. Plaintiff Jack Cooper began taking Actos in 2006 and claims that Takeda did not do enough to warn him and his physician of a link between Actos and bladder cancer. 

Actos received FDA approval as a medication to improve glycemic control in patients with Type 2 diabetes in 1999. It is now the subject of thousands of lawsuits. Cooper’s lawsuit is the first Actos bladder cancer case to go to trial. It is currently underway in the Central Civil West Courthouse, Superior Court of California in Los Angeles.

Actos is in a class of drugs known as thiazolidinediones, or TZDs, which includes two other diabetes drugs with troubled histories, Avandia and Rezulin. Avandia has been withdrawn from the market in Europe and its use in the U.S. is severely restricted by the FDA due to cardiovascular problems. Rezulin was withdrawn from the market in both the U.S. and Europe after being linked to liver failure in patients taking the drug.

All three of these drugs are classified as dual PPAR agonists. The “R” in PPAR stands for receptor. These drugs work by binding to particular receptors (protein molecules) on the surface of a cell and thereby causing a change in cell activity. Dual PPAR agonists bind to two different receptors that affect glucose and cholesterol. 

The problem for Takeda was that by 2002, dual PPAR agonists had also been linked to bladder cancer. In a report prepared for the plaintiff, defense expert Dr. Howard Greenburg stated that “all of the dual-PPAR agonists were discontinued from development due to adverse events and safety concerns, and were the subject of several published articles and FDA reviews of this class of compounds.”

According to a plaintiff’s memorandum filed with the court, in 2002 the FDA contacted Takeda about Rataglitazar, a dual PPAR drug similar to Actos, whose clinical development had been suspended by manufacturer Novo Nordisk after finding bladder tumors in a number of rats and one mouse.

Quoting Takeda documents, the plaintiff alleges that Takeda responded with an initiative designed to distance their drug from any association with PPARs, to “protect Actos” and “develop a rationale to argue against the FDA’s ‘PPAR hypothesis.’”

Following meetings with Takeda, the FDA sought to add language to the Actos label stating that “a receptor-mediated mechanism for tumor induction cannot be ruled out” with PPAR agonists. Takeda resisted, claiming that “current evidence was insufficient to justify the proposed label change.”  

Ultimately, Takeda succeeded in stopping any substantive changes to the Actos label. Attorneys for Cooper will argue at trial that this was just one of several opportunities that Takeda could have taken to warn consumers of an Actos bladder cancer risk. Instead, say Cooper’s attorneys, Takeda pursued policies that would keep consumers and physicians in the dark about Actos for years, until, in 2011, the FDA finally added language regarding the bladder cancer risk to the Actos label’s “Warnings” and “Precautions” sections.