Though reports of a potential cardiovascular risk earlier this year threatened the development of Entereg in opioid-induced constipation, its maker Adolor Corp. got a slight boost after the FDA accepted its complete response to a November approvable letter for the drug in postoperative ileus (POI).
The company's shares (NASDAQ:ADLR), which have lost half their value on Entereg's bumpy ride over the last several months, gained 44 cents, or 12 percent, Tuesday to close at $4.
Adolor and partner GlaxoSmithKline plc initially filed a new drug application in 2004 for Entereg (alvimopan) in POI, but data from a subsequent trial, Study 014 in opioid-induced bowel dysfunction (OBD), raised some safety concerns after the incidence of cardiovascular adverse events were higher in the Entereg-treated group vs. placebo. In its approvable letter, the agency asked for additional safety data and for a risk-management plan, but it looked like the drug might be in trouble when top-line Phase III data reported in April again showed an increase - though not a statistically significant increase - in cardiovascular events in the Entereg population, and the companies suspended ongoing trials in OBD and other indications. Investors certainly were shaken by that news, causing Adolor's shares to sink by more than half to close at $3.60. (See BioWorld Today, April 11, 2007.)
Despite the concerns, Adolor and GSK went ahead with their response to the FDA in POI, which included final results from the long-term, 12-month OBD trial, as well as safety data from trials of Entereg in cancer patients with OBD and in combination with hydrocodone/APAP, said Robert Jones, vice president of strategy and business analysis for Exton, Pa.-based Adolor. Final results from two-year carcinogenicity studies in rats and a risk-management plan also were included in the response.
"We undertook a fairly extensive analysis on our own," Jones said, and it will be up to the FDA to determine whether those data are sufficient to merit marketing approval. The agency set a new Prescription Drug User Fee Act (PDUFA) date of Feb. 10, 2008.
"We believe that if we get approval by that date," Jones told BioWorld Today, Entereg would "likely be the first product for POI." The drug, a peripherally-acting mu-opioid receptor antagonist, is designed to interfere with the opioid side effects on the gastrointestinal system without inhibiting its analgesic effects.
While the POI market is the initial focus, the companies still are hoping to reach the large opioid-induced constipation population. On Aug. 13, they requested that the FDA remove the clinical hold on the OBD and other trials, and a decision from the agency is expected in mid-September, Jones said.
The next steps are still to be determined and GSK is expected to provide an update on the OBD program soon, but Jones said both companies are "still very much focused on the OB dysfunction, which is an unmet need."
To date, Phase III results in OBD have been mixed. Though one trial, Study 012, hit statistical significance, a second study, 013, failed to meet the primary endpoint, though it did show supportive evidence in a secondary endpoint of change in average weekly frequency of spontaneous bowel movement. Final efficacy results from Study 014 have not yet been reported.
The overall opioid-induced constipation market is estimated at more than $500 million, and Adolor's drug is not the only one in development. Its chief competition, so far, is methylnaltrexone (MNTX) from Tarrytown, N.Y-based Progenics Pharmaceuticals Inc. which, along with partner Madison, N.J.-based Wyeth Pharmaceutical, submitted a new drug application in April for opioid-induced constipation. An FDA decision is expected early next year.