Adolor Corp. reported topline results from a Phase III study showing its postoperative ileus drug, alvimopan, failed to meet the primary endpoint in a trial meant to support a marketing authorization application in the European Union.
The trial of alvimopan capsules was conducted in Europe, Australia and New Zealand by partner GlaxoSmithKline plc, of London. GSK and Adolor will pore through the data to determine the next steps, including whether they still can meet a targeted second-quarter 2005 MAA filing. The companies intend to submit to the FDA safety data showing that alvimopan was generally well tolerated in the trial, but it is unclear whether the efficacy results will be added to a new drug application filed last May in the U.S.
"We will have to discuss the results further with GSK and discuss them with the FDA," said Bruce Peacock, Adolor's president and CEO. "It's not our present intention to amend the new drug application to include those results."
Still, the company's stock (NASDAQ:ADLR) fell 45.8 percent in response to the news, dropping $7.41 Thursday to close at $8.78.
"Anybody who follows the biotechnology industry knows that there can be significant volatility in the stock based on clinical trial results," Peacock told BioWorld Today. "In the end, what's going to matter is getting the drug approved, and the [Prescription Drug User Fee Act] date is still ahead of us."
In May, Exton, Pa.-based Adolor and GSK submitted an NDA in the U.S. for Entereg (alvimopan), which the FDA accepted in September, triggering a $10 million milestone payment to Adolor. The PDUFA target action date for the drug is April 25. (See BioWorld Today, May 10, 2004.)
Alvimopan is a peripherally restricted mu opioid receptor antagonist designed to block the gastrointestinal effects of opioids, such as morphine, without interfering with the analgesic effects on the central nervous system.
In the European Phase III, the primary endpoint was the time to recovery of gastrointestinal function, defined by whichever occurs later: the time from surgery until the patient first tolerates solid foods, an indicator of upper GI recovery, and the time from surgery until the patient first passes flatus or has a bowel movement, an indicator of lower GI recovery. The company needed a "p" value of less than 0.025 to reach statistical significance in the 6-mg dose group. Based on the Cox proportional hazard model, that group had a hazard ratio equal to 1.22 (p=0.042), while the 12-mg group had a hazard ratio equal to 1.13 (p=0.20), as compared to the placebo group.
However, alvimopan showed statistically significant results through the trial's secondary endpoint, a measure of time to recovery of gastrointestinal function by looking at the patient's ability to tolerate solid food and have a bowel movement. For the 6-mg group, the hazard ratio was equal to 1.39 (p<0.001). For the 12-mg group, the hazard ratio was equal to 1.30 (p=0.008).
The main difference between the primary endpoint and the secondary endpoint, Peacock said, is that the secondary endpoint did not include the flatus component.
In another secondary endpoint - time to hospital discharge order written - differences were in favor of the alvimopan-treatment groups as compared to placebo, but the differences did not reach statistical significance.
The Phase III study was designed as a randomized, double-blind, placebo-controlled, parallel-group trial that enrolled 911 subjects, including 741 bowel-resection patients and 170 radical hysterectomy patients. The primary analysis targeted only the bowel-resection patients. Patients were randomized into three arms, either 6-mg or 12-mg doses of alvimopan, or placebo, delivered orally two hours prior to surgery, and then twice a day until hospital discharge, or a maximum of seven days.
Peacock said that as GSK and Adolor continue to analyze the data, they will look at differences in how the U.S. and Europe manage bowel-resection patients.
"Some of the endpoints can be influenced by physician practice so you do see a difference in practice between the U.S. and Europe," he said. "Patients are kept in the hospital much longer in Europe than in the U.S."
It is not the first time alvimopan failed to meet the primary endpoint in a Phase III trial. A year ago, Adolor released data of a 666-patient trial that did not hit the endpoint of time to recovery in GI function, but did achieve statistical significance on the time-to-hospital-discharge secondary endpoint. (See BioWorld Today, Jan. 15, 2004.)
Another Phase III in 451 patients showed the drug hit the same primary endpoint in the 6-mg group, while demonstrating a positive trend in the 12-mg group. And alvimopan also met the same primary endpoint in a Phase III trial of 510 patients. A fourth study, which evaluated safety, demonstrated that Entereg was generally well tolerated in 93 percent of patients that completed treatment. (See BioWorld Today, April 3, 2003, and Sept. 24, 2003.)
While the company's stock dropped and soared over the last two years when Phase III data were released, Peacock believes all of the trials support alvimopan for postoperative ileus.
"In every trial there was a positive difference in favor of drug vs. placebo," he said. "But in the U.S., you had three trials and two doses in each of the three trials. In three out of six doses, you achieved statistical significance, and in the other three there was a statistically positive trend."
There are no drugs on the market to treat postoperative ileus, a gastrointestinal condition that affects patients undergoing abdominal surgery and one that can be exacerbated by opioid analgesics for pain relief. Symptoms include abdominal distension and pain, nausea and vomiting, reduced desire to eat, and an inability to pass gas or stool.
Adolor and GSK entered their $270 million worldwide collaboration for alvimopan in April 2002. The companies agreed to develop and co-promote the product and share in development expenses and commercial profits. (See BioWorld Today, April 16, 2002.)
Other potential indications for the product include bowel dysfunction and chronic constipation. NDAs for those indications are expected to be filed in 2007, Peacock said.