June 9 U.S. Food and Drug Administration advisers are set to vote this week on whether more clinical trials are needed to assess cardiovascular risk in a class of drugs used to treat opioid-induced chronic constipation.
The drugs, known as peripherally acting mu opioid receptor antagonists, include Salix Pharmaceuticals Ltd's Relistor, also known as methylnaltrexone, and Cubist Pharmaceuticals Inc's Entereg, also known as alvimopan.
AstraZeneca Plc and Nektar Therapeutics have a product, naloxegol, in development.
Constipation is a common side effect of opioid painkillers such as morphine.
One of several late-stage studies of Entereg found a greater number of heart attacks in patients taking that drug. The FDA nonetheless approved it for short-term use because other trials did not show a similar so-called cardiovascular (CV) safety signal.
"Controlled, long-term safety data, similar to that which generated the potential CV signal for Entereg, seem critical for preliminary assessment of CV risk for the development of other drugs in this class," FDA reviewers said in a report posted on the agency's website on Monday ahead of the advisory committee meeting on Wednesday and Thursday.
"However," the reviewers said, "it's important to note that a key underlying assumption of this paradigm is whether or not the cardiovascular event rate imbalance observed in the Entereg opioid-induced-constipation program actually represents a true signal of increased cardiovascular risk."
Last year, the FDA said, it met with AstraZeneca to discuss its concerns over potential cardiovascular risks associated with opioid receptor antagonists and about a possible association between withdrawal from naloxegol and cardiovascular problems. The agency recommended additional analyses and data.
AstraZeneca argued that a controlled clinical cardiovascular trial was not necessary or practical. While the FDA initially disagreed, it later said results of a such a trial would not be needed for the company to file for approval.
The agency also met with Theravance Inc which is developing a product, axelopran, for opiod-induced constipation and Develco Pharma, which is developing a prolonged release tablet version of naloxone for the same indication. Naloxone is contained in a variety of fixed-dose products with other medications to treat pain and to treat opioid addiction.
The FDA conveyed its concerns to both companies and invited them to make presentations at the advisory committee meeting.
The committee will discuss whether the evidence available suggests that there is a cardiovascular risk associated with opioid receptor antagonists and whether any risk is limited to certain drugs. They will also discuss the feasibility of conducting a cardiovascular safety trial and whether the trial should include all drugs in the class or only select products. (Reporting by Toni Clarke in Washington; Editing by Jonathan Oatis)