| June 9
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
"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