Washington Editor

The FDA delayed approving Adolor Corp.'s Entereg (alvimopan) for postoperative ileus yet again, pending additional safety data, causing the company's shares to tumble by 44.8 percent on Monday.

Specifically, the stock (NASDAQ:ADLR) fell $6.25 to close at $7.69 because of the approvable letter, which requested 12-month data on serious cardiovascular events from an ongoing safety study in another indication, opioid-induced bowel dysfunction. The FDA also asked for a risk-management plan as part of the resubmission.

Calls to the company were not returned. But during a conference call with investors, David Madden, Adolor's interim president and CEO, said he was "clearly disappointed" with this outcome. Looking ahead, he said he "really can't" predict how the FDA might interpret a full year's worth of further safety data, and he added that it's "very hard" to forecast the design of a risk-management plan at this point.

Nevertheless, Madden said that Exton, Pa.-based Adolor and its London-based partner, GlaxoSmithKline plc, would look to provide the FDA information "as soon as possible."

The ongoing safety study, a blinded Phase III trial called Study 014, is being conducted by GSK and is expected to be completed late next quarter. Final data would be available a quarter later.

The companies first filed Entereg's new drug application for postoperative ileus (POI) more than two years ago, and in September they submitted a six-month interim analysis of Study 014. Those data showed an increase in the reported incidence of serious cardiovascular adverse events in Entereg patients relative to placebo, though the margin was "not statistically significant," Madden said. They included patients at high risk for cardiovascular disease, did not appear to be linked to duration of dosing and were consistent with epidemiological expectations for the subject population, he added.

But there's still a lot of head scratching. "We don't know what the cause of the imbalance is," Madden said. He declined to specify the exact nature of the serious cardiovascular adverse events, and he refused to indicate whether there had been any deaths as a result.

But he did point out that preclinical studies have not shown any cardiovascular toxicity and combined results from all completed studies in chronic patients have not suggested that those on Entereg were at increased risk for serious cardiovascular events. In addition, no safety signals arose in any previous POI trials.

Study 014 is evaluating a 0.5-mg dose of the peripherally acting mu-opioid receptor antagonist twice daily for the treatment of opioid-induced bowel dysfunction in patients with chronic noncancer pain. For POI, the NDA specifies a much higher dose, 12 mg.

Study 014 was not designed to assess cardiovascular risks, but the partners have yet to discuss whether it might need to be enlarged.

Recently, Entereg's path to the market for opioid-induced bowel dysfunction has encountered some bumps. Two of three trials in that indication failed to meet their primary endpoints, including one study designed to support an NDA next year. That disclosure hurt Adolor's share value, with the stock plunging $11.32 to $13.65 just two months ago. (See BioWorld Today, Sept. 6, 2006.)

The drug is designed to interfere with opioid side effects on the gastrointestinal system without inhibiting its analgesic effects. Positive Phase III data in POI came out early this year and supported a complete response to a previous FDA approvable letter, issued last summer for additional proof of efficacy. Those findings boosted Adolor's stock by $6.53 to $22.29.

Madden indicated that the latest communiqué from the agency included no questions on Entereg's efficacy, and he added that GSK remains "committed" to its partnership on the drug. The companies entered their $270 million collaboration more than four years ago. (See BioWorld Today, April 16, 2002.)