UPDATE 2-FDA panel advises against large opioid constipation drug safety trials

Thu Jun 12, 2014 2:30pm EDT

(Adds details, background, paragraphs 7-12)

By Toni Clarke

WASHINGTON, June 12 (Reuters) - An advisory committee to the U.S. Food and Drug Administration recommended on Thursday that the agency not require large cardiovascular safety trials for a class of drugs used to treat opioid-induced chronic constipation.

Seven panelists voted in favor of such trials, five voted in favor for select products and 12 voted against. But in a post-vote discussion, several panelists said they misunderstood the question and would have voted against the requirement.

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 also have a product, naloxegol, in development. Constipation is a common side effect of opioid painkillers such as morphine.

The panel met to discuss the matter because 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 safety problem.

While the panel did not recommend that companies be required to conduct large, randomized, controlled trials prior to approval, which would be expensive, time-consuming and complex, they did recommend studies be conducted to monitor for safety after the drugs reach the market.

They also suggested that modified trials be conducted prior to approval. Companies had argued that conducting large-scale randomized trials, the gold standard in assessing safety and efficacy, would be impractical.

FDA reviewers said in a report posted on the agency's website on Monday that controlled, long-term safety data similar to that which generated the potential cardiovascular safety signal for Entereg "seem critical for preliminary assessment of CV risk for the development of other drugs in this class."

The agency asked the panel to discuss whether the imbalance in the cardiovascular event rate respresented a "true signal of increased cardiovascular risk."

The preponderance of opinion on the panel was that the signal was real, albeit modest and that there was no evidence that the risk extended to drugs in the class. However, they said data presented to them was not sufficient for them to rule out a potential cardiovascular risk either.

Other companies with drugs in development include Theravance Inc which is developing a product, axelopran, for opioid-induced constipation and Develco Pharma, which is developing a prolonged release tablet version of naloxone for the same indication.

Entereg is approved to treat constipation following surgeries that include partial bowel resection. It is only available through a restricted program for short-term use.

(Reporting by Toni Clarke in Washington; Editing by Eric Beech, Will Dunham and Tom Brown)

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