An approvable letter caused quite a swing in Adolor Corp.'s stock Friday.
Before the bell rang, the company's shares (NASDAQ:ADLR) were down more than 10 percent in premarket trading, but by the end of the day, the stock had swung back into the black and gained 22 cents to close at $10.48.
The market volatility followed the FDA's communication on a marketing application for Entereg (alvimopan), under review for the management of postoperative ileus by acceleration of the time to recovery of gastrointestinal (GI) function following bowel-resection surgery.
"We intend to request a meeting with the FDA as soon as possible," Adolor President and CEO Bruce Peacock said during a conference call, noting that before Entereg can receive approval, the company must provide additional proof of efficacy. He told BioWorld Today that the company would request "a so-called 60-day meeting" in order to sit down with the agency by the end of September, but added that such a timeline "is more up to them than us."
In issuing its approvable letter, the FDA indicated that this could be achieved by demonstrating statistically significant results in at least one additional clinical study, and an ongoing trial labeled Study 14CL314 could potentially fit that requirement, though its primary endpoint is slightly different from that measured in previous pivotal trials. The agency also said that Adolor must provide justification that the median reduction in time to gastrointestinal recovery seen in bowel-resection patients treated with Entereg is clinically meaningful.
"We certainly think that the data we have, and the data that we're gathering from 314," Peacock said, mentioning prior findings related to fewer hospitalizations, less long-term hospital stays, and decreases in nausea and vomiting, "show that Entereg has a clinical benefit. But that's something we're going to have to sit down and talk with them about."
Study 314 is designed to enroll 660 bowel-resection patients, and the Exton, Pa.-based company said it expects top-line data in the first half of next year. Participants are being randomized into placebo or 12-mg Entereg arms, with initial doses administered 30 to 90 minutes prior to surgery. Previous Phase III studies required the first dose to be administered at least 120 minutes prior to surgery. Study 314's primary endpoint is time to recovery of GI function (GI2), a composite measure of the time to recovery of both upper and lower GI function as defined by time to tolerability of solid foods and time to first bowel movement, whichever occurred last. In six previous clinical trials, the GI2 endpoint has been met five times.
"We will need to discuss this design with them," Peacock said, later adding that "we want to affirm that this primary endpoint - GI2 - will meet their requirements."
Entereg's new drug application was submitted a little more than a year ago, with efficacy data based largely on findings from three Phase III studies called 302, 308 and 313. In the first, results showed 6 mg of Entereg produced a statistically significant reduction in GI3, a measurement of recovery of GI function that includes the upper section (through the ability to tolerate solid food) and the lower section (through phlatus and bowel movement). In Study 313, both 6 mg and 12 mg Entereg doses generated statistically significant reductions in GI3, but neither was statistically significant in Study 308. (See BioWorld Today, May 10, 2004.)
Entereg, a peripherally acting mu-opioid receptor antagonist, is designed to inhibit the negative effects of opioids on the gastrointestinal system without interfering with the analgesic effects in the central nervous system.
Late last year, Adolor said a Phase III study showed that the product failed to meet the primary endpoint in a trial meant to support a marketing authorization application for post-operative ileus in Europe. Peacock said GlaxoSmithKline, which is directing the drug's overseas development, is reviewing its original plans to file for approval this year "in light of the FDA actions." (See BioWorld Today, Dec. 27, 2004.)
More recently, top-line Phase IIb results showed that Entereg provided benefits in patients with bowel dysfunction due to chronic opioid analgesic therapy. That led the companies to announce Phase III plans in that indication. "Our goal is to initiate those studies as soon as possible," Peacock said, indicating plans for filing a new drug application in 2007. (See BioWorld Today, March 9, 2005.)
Adolor partnered the product three years ago with London-based GlaxoSmithKline in a $270 million worldwide collaboration. The companies agreed to jointly develop and co-promote the product in the U.S., where they would share development expenses and commercial profits. Abroad, GlaxoSmithKline is footing all bills and Adolor would receive royalties. (See BioWorld Today, April 16, 2002.)
Apart from Entereg, Adolor is developing a sterile lidocaine patch that is scheduled to enter Phase II testing later this year for post-incisional pain, a timeline also planned for filing an investigational new drug application for a delta receptor opioid pain product produced through the company's internal discovery efforts.