Washington Editor

SILVER SPRING, MD - Federal advisers Wednesday told the FDA that it should approve Adolor Corp.'s Entereg (alvimopan) for short-term use in hospitalized patients following partial large or small bowel resection surgery with primary anastomosis.

The FDA's Gastrointestinal Drugs Advisory Committee voted 9 to 6 that Entereg's benefits outweigh its risks in short-term use.

Adolor is seeking approval of Entereg to manage a gastrointestinal (GI) condition known as postoperative ileus (POI), the transient cessation of bowel function, or severe constipation following surgery.

Opioids used for postoperative pain management are a significant contributing factor to POI.

Entereg, an orally administered, peripherally acting mu-opioid receptor antagonist, has been shown to reverse opioid-induced changes in the GI tract without affecting opioid-induced analgesia.

Adolor is jointly developing Entereg with London-based GlaxoSmithKline plc under a 2002 agreement. However, GSK is developing a lower dose of the drug to treat chronic opioid-induced bowel dysfunction (OBD) long term in the outpatient setting.

If approved, Entereg would be the first compound on the U.S. market to treat POI. Some hospitals use drugs, such as metoclopramide and erythromycin, off-label to treat the condition, noted Ruyi He, medical team leader in the FDA's Division of Gastroenterology Products.

About 400,000 U.S. patients each year undergo small and large bowel resection surgeries, said Anthony Senagore, professor of surgery at Michigan State University. All bowel resection surgery patients experience some degree of POI, he told the committee.

The symptoms associated with the condition, such as abdominal distention and bloating, persistent pain, nausea, vomiting and the inability to pass flatus or stools, can lead to dangerous postoperative complications, such as aspiration and pneumonia.

Studies have shown that Entereg accelerated the recovery of upper and lower GI tract function by about 20 hours and reduced the length of hospital stays for U.S. patients by roughly one day.

Since Adolor first submitted its new drug application for Entereg to the FDA in 2004, regulators have raised concerns about the cardiovascular safety of the drug. An increased risk of tumors and bone fractures also has been linked to the long-term use of Entereg.

At Wednesday's advisory committee meeting, panelists discussed the results of five randomized, double-blind, placebo-controlled Phase III studies in patients at risk of developing POI.

Entereg was studied in doses of 1 mg, 3 mg, 6 mg and 12 mg in 2,610 patients at risk for POI.

Adolor is seeking approval of 12-mg capsules administered in the hospital setting twice daily over seven days for the POI indication, noted Lee Techner, the firm's senior medical director. The dosage also includes a 0.5-mg dose given two hours before surgery, he added.

While no cardiovascular risks were identified in the short-term POI studies - although patients were not followed long term to ascertain cardiovascular events - there was an imbalance of cardiovascular events in OBD studies conducted by GSK. Specifically, the FDA was concerned about an OBD study known as SB-767905/014, or study 014, a one-year, placebo-controlled, safety study of Entereg 0.5 mg administered twice daily in opioid-experienced patients with chronic noncancer pain.

Study 014 is not being considered by the FDA as part of Adolor's NDA for the POI indication.

However, in an impromptu vote, panelists voted 8 to 6, with one abstention, that based on the available data, there was reason to worry about cardiovascular events of Entereg 12 mg administered short term to hospitalized patients.

The results from study 014 also showed a numeric imbalance in reports of neoplasms and bone fractures, with a higher incidence in the Entereg treatment groups than with placebo.

However, panelists did not vote about those adverse events.

The POI studies included patients undergoing laparotomy for bowel resection with primary anastomosis or total abdominal hysterectomy (TAH) and scheduled to receive opioid-based, intravenous patient-controlled analgesia for postoperative pain management.

Since efficacy was not demonstrated in the TAH surgery subgroup in the original NDA submission, Adolor decided to narrow the proposed indication for Entereg to the bowel resection population only, He from the FDA noted.

In order to have a single measure that indicated the recovery of both upper and lower GI function, a composite endpoint was derived from the individual GI events. The composite measure was expressed as either GI-3, which uses times to first bowel movement, toleration of solid food and flatus, to calculate the endpoint or GI-2, which excludes time to flatus in the calculation.

Adolor initially had used GI-3 as its primary endpoint in its earlier POI Phase III studies, but switched the primary endpoint to GI-2 in its final trial, arguing that GI-2 is more objective since flatus is reported by patients and is therefore subjective.

The secondary efficacy endpoints in the studies included discharge orders written, or DOW, and the time from the end of surgery to the time ready for hospital discharge based solely on the recovery of GI function as determined by the surgeon.

In a 13 to 0 vote, with two abstentions, panelists said the efficacy results from the POI studies were meaningful based on the GI-2, GI-3, DOW or ready to discharge endpoints.

Because the POI indication is for 12 mg administered short term in a hospital setting, regulators were concerned that the drug might be used mistakenly in the outpatient setting, putting those patients at risk of receiving 24 times the amount being tested for the OBD indication.

Therefore, Adolor developed a risk minimization action plan, or RiskMAP, to control the distribution of Entereg.

The RiskMAP requires that wholesale distributors sell Entereg only to hospitals and that product packaging state clearly that the drug is for hospital use only.

In addition, the RiskMAP includes an alert system to alert outpatient pharmacists via the outpatient dispensing software not to dispense Entereg on an outpatient basis. Reimbursement of the drug only can be obtained through diagnosis-related group payment for bowel resection surgery under the plan.

However, regulators noted that Adolor has yet to submit to the agency full details of the RiskMAP.

Panelists voted 14 to 0, with one abstention, that Adolor's RiskMAP was inadequate to address the potential risks associated with the drug.

Panel Chairman Alan L. Buchman, associate professor of medicine at Northwestern University, scolded Adolor for failing to provide specifics about the RiskMAP to the FDA and the advisory committee. The RiskMAP as proposed, he declared, "was done haphazardly."

Trading of shares for Exton, Pa.-based Adolor (NASDAQ:ADLR) was suspended Wednesday pending the panel's review.