Washington Editor

Partners Adolor Corp. and GlaxoSmithKline plc began a broad Phase III program to investigate the use of Entereg (alvimopan) for opioid-induced constipation and associated symptoms.

"The results from Phase IIb studies were very positive and very encouraging," said James Barrett, a senior vice president at Adolor and its chief scientific officer. "I think the shear, overwhelming positive nature of those studies provided a lot of impetus to really get [Phase III] going very quickly."

The international program is made of three studies expected to enroll about 1,700 patients in North America, Europe and other parts of the world. The partners plan to have everything completed in time for U.S. and European regulatory filings in late 2007. Entereg is designed to inhibit the negative effects of opioids, like morphine or codeine, on the gastrointestinal system without interfering with the analgesic effects on the central nervous system.

"By blocking the actions of the opioid [with Entereg]," Barrett told BioWorld Today, "it stops the normal inhibitory control of the gastrointestinal function, namely peristalsis, secretion and other things that result in constipation."

The Phase III will compare multiple doses of the oral product to placebo. Barrett declined to specify the coming studies' primary endpoints, though Phase IIb measured spontaneous bowel movements in more than 500 patients. Previous secondary endpoints examined the drug's ability to impact constipation symptoms.

Gastrointestinal side effects are experienced by many of the millions of people who take opioids for pain, with constipation affecting about half of them. Such sufferers also may experience abdominal pain and discomfort, bloating and loss of appetite.

There are no drugs approved specifically for treating opioid-induced constipation and its associated symptoms, though the companies said patients take stool softeners and bowel stimulants while increasing daily fluid and fiber intake and exercise to manage the condition. Laxatives also can provide relief, but are not recommended for long-term use.

"There is no option at this point, other than laxatives, which are by and large not very effective," Barrett said. "And since they don't target the principle cause of the constipation, they leave a lot of opportunities unfulfilled."

The opioid-induced constipation indication continues the partners' wide-ranging development plans for the peripherally acting mu-opioid receptor antagonist, which already has received an approvable letter from the FDA for postoperative ileus. That action, though, could require another study to demonstrate efficacy in that indication.

But Exton, Pa.-based Adolor, which has the lead role in the postoperative ileus program, is awaiting word on whether an ongoing trial could provide that information. Referred to as Study 314, its primary focus has been to examine previously unquantified quality-of-life measures. Secondarily, it is looking at efficacy. (See BioWorld Today, July 25, 2005.)

"That study began some time ago," explained David Jackson, Adolor's chief medical officer, "so it would be very good from our point of view if that study met the deficiency outlined in the approvable letter rather than a requirement for starting anything from scratch now."

Adolor and GlaxoSmithKline are collaborating on Entereg's worldwide development and commercialization for both indications. Barrett declined to reveal whether the new Phase III program triggered any milestone payment. Their agreement was formed three years ago 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, while London-based GlaxoSmithKline is footing all overseas development bills and Adolor would receive royalties. GlaxoSmithKline also is conducting a study of Entereg's efficacy in patients suffering pain associated with cancer. (See BioWorld Today, April 16, 2002.)

For Adolor, beyond Entereg, its focus remains in the pain space. The company also is developing a sterile lidocaine patch, which has entered Phase II for post-incisional pain, and a number of discovery research programs are focused on identifying compounds for pain. On Monday, its shares (NASDAQ:ADLR) gained 6 cents to close at $9.85.