A few months after Entereg missed its endpoint in a Phase III European trial for post-operative ileus, the drug showed some promising benefits in a Phase II trial for opioid-induced bowel dysfunction, which Adolor Corp. reported Tuesday.
Adolor's stock (NASDAQ:ADLR) rose 16.2 percent Tuesday, or $1.43, to close at $10.25.
The Exton, Pa.-based company and its partner, London-based GlaxoSmithKline plc, announced top-line results from a Phase IIb study of Entereg (alvimopan), showing the therapy provided benefits in patients with bowel dysfunction due to chronic opioid analgesic therapy
The study evaluated Entereg as a treatment of opioid-induced bowel dysfunction (OBD), which results from the use of opioids in chronic pain patients. It enrolled 522 non-cancer patients with OBD, showing that all three oral regimens of Entereg achieved statistically significant effects on the primary and secondary endpoints compared with placebo.
"What we saw is the use of Entereg can increase both the frequency of their bowel movements," said Bruce Peacock, Adolor's president and CEO, "as well as improve the symptoms associated with the constipating side effects of opioids."
The primary endpoint, measured over the first half of the six-week treatment period, was the change from baseline in weekly frequency of spontaneous bowel movements (SBM) - defined as those occurring with no laxative use in the previous 24 hours. All groups reported an SBM frequency of about one per week during the baseline period. The average change from baseline over the first three weeks of treatment was 3.36 SBM for the Entereg 0.5-mg twice-daily group, 3.29 SBM for the Entereg 1-mg once-daily group, and 4.17 SBM for the Entereg 1-mg twice-daily group, compared to 1.65 SBM for the placebo group. All treatment groups showed a statistically significant difference from placebo (p<0.001). The changes were sustained through the six-week treatment period, and returned to baseline once treatment was discontinued.
Entereg (alvimopan) is a peripherally acting mu opioid receptor antagonist, and the first of a new class of drugs, designed to block the negative effects of opioids on the gastrointestinal system without interfering with the analgesic effects on the central nervous system.
"We're really excited about the opportunity with OBD," Peacock told BioWorld Today. "And that's the area of focus in terms of moving forward. We'll continue to work with GSK to look at the data, meet with the regulatory authorities, and map out a Phase III program."
The Phase IIb trial also showed that treatment with Entereg demonstrated significant improvements in straining, stool consistency and incomplete evacuation, compared with placebo. Entereg was generally well tolerated, with the most common adverse events being those affecting the gastrointestinal tract, including abdominal pain, nausea and diarrhea. Researchers found no evidence of antagonism of opioid analgesia based upon pain intensity scores and opioid consumption.
Analyst Gregory Wade and his colleagues at Pacific Growth Equities in San Francisco said Phase III studies likely will start in the second half of 2005 and lead to a potential new drug application filing for Entereg in OBD sometime in 2007.
"We believe that Entereg could achieve $271 million in sales in the OBD setting in the U.S. in the fourth year since launch," Wade stated in a research note.
It does not look like Adolor and GSK will pursue using Entereg for chronic constipation patients, at least not in the near term, due to lack of efficacy found in a proof-of-concept Phase IIa study. Those results, also reported Tuesday, showed Entereg did not demonstrate statistical significance over placebo in patients with chronic idiopathic constipation not associated with opioid use. The trial enrolled 217 adults who were randomized to a placebo group or three treatment groups.
In previous studies, the companies have shown that Entereg enhanced intestinal transit in normal subjects and patients with constipation not receiving opioids. The Phase IIa study was designed to test the hypothesis that abnormal responses to natural painkillers in the body could contribute to chronic constipation.
The therapy was generally well tolerated in patients receiving up to 8 mg of Entereg twice daily for eight weeks. The companies are considering further studies because some constipated patients might have achieved therapeutic benefits in the study.
But the main focus, for now, will be on getting Entereg into a Phase III trial for OBD, and getting the drug approved for post-operative ileus (POI).
Adolor and GSK submitted a new drug application for Entereg in May as a potential treatment for POI. The PDUFA target action date originally was set for April 25. (See BioWorld Today, May 10, 2004.)
However, in December Adolor announced that a Phase III study showed Entereg failed to meet the primary endpoint in a trial meant to support a marketing authorization application for post-operative ileus in the European Union. (See BioWorld Today, Dec. 27, 2004.)
The FDA since has requested complete data from that trial. If Adolor and GSK submit those within the next month, the new PDUFA date for the POI NDA will be July 25.
Despite the delay, Pacific Growth Equities expects Entereg to receive approval based on two positive Phase III studies and numerous clinical benefits, Wade said.
OBD occurs in millions of patients taking opioids to manage pain from severe back problems and osteoarthritis, as well as other conditions. Adolor expects oral Entereg to be used in conjunction with morphine, codeine or other opioids to control OBD or POI.
"In terms of numbers of patients, they're both substantial," Peacock said, "but certainly there are millions of patients who take opioids. Some can take them every day. One of the dynamics of the market for OBD is that it is a chronic market."
Patients with POI would be taking opioids only during a four- or five-day hospital stay.
Adolor and GSK formed their $270 million collaboration for Entereg in April 2002. They are sharing the worldwide development and commercialization responsibilities, and the potential profits, for the drug as a treatment for POI, OBD and irritable bowel syndrome. (See BioWorld Today, April 16, 2002.)
Results from a Phase I/II study in irritable bowel syndrome are expected in the second half of this year.