BioWorld Today Contributing Writer

Adolor Corp. and Pfizer Inc. have discontinued a 2007 collaboration to develop Adolor's delta opioid receptor agonists, ADL5859 and ADL5747. The deal, originally valued at up to $265 million, fell apart when Phase II trial results in June failed to deliver any proof of efficacy in multiple indications including post-herpetic neuralgia. With the dissolution of the Pfizer deal, the delta opioid agonist program at Adolor also will be discontinued.

"We do not expect to continue investment in the delta program. We and Pfizer have run studies in several pain conditions, and have not seen compelling evidence to support continued investment in the program," CEO Michael R Dougherty told BioWorld Today.

In the Phase IIa trial for osteoarthritis of the knee, ADL5859 and ADL5747 missed the endpoint of reduction in pain score when compared to placebo. At the time, the company attributed that to an unusually high placebo effect, and noted that oxycodone CR also failed to show statistically significant improvement over placebo. Adolor's stock dropped 18 percent immediately following the news. (See BioWorld Today, June 21, 2010.)

Opioid receptors are divided into three classes: mu, kappa and delta. Commercially available opioid receptor agonists fall into the mu category. It is thought that a delta receptor agonist could deliver the analgesic effect without side effects such as respiratory depression, constipation and chemical dependency.

Delta opioid receptor agonists have a presence in the scientific literature more for their antidepressant qualities than as analgesics. There are no FDA-approved delta or kappa opioid receptor agonist drugs. For a potential pain relief therapy, Adolor's ambiguous Phase IIa experiences seem to provide little clarity as to whether the delta opioid receptor agonist class is worth pursuing.

"The delta program was the classic high-risk/return program, a new mechanism, etc., and as such, the collaboration with Pfizer was the right way to run the early clinical studies in the program. The collaboration worked very well; we just did not see efficacy with the compounds," Dougherty said.

Under terms of its 2007 agreement, Pfizer would pay $30 million up front, with up to $232.5 million in milestones. Adolor also received $1.9 million in expenses associated with Phase IIa trials of ADL5859. The milestones broke down to $155 million for ADL5859 and $77.5 million for ADL5747. (See BioWorld Today, Dec. 6, 2007.)

The first milestones would have been due upon initiation of Phase IIb trials, a mark that Pfizer decided not to pursue, walking away from its $31.9 million investment following the disappointing IIa results.

Adolor markets the bowel drug Entereg (alvimopan), launched in 2008 with GlaxoSmithKline plc. Entereg is a mu opioid receptor antagonist that blocks the negative effect of opioids such as morphine on the gastrointestinal tract. Because it does not cross the blood-brain barrier, it can be used in concert with a mu opioid receptor agonist to fine tune pain relief without the negative bowel effects. Entereg is approved specifically for postoperative ileus following bowel resection surgery.

In addition to its delta opioid receptor agonist program, Adolor's pipeline includes two mu receptor antagonists, ADL7445 and ADL5945 for chronic opioid-induced bowel dysfunction. It acquired ADL7445 from Eli Lilly and Co. in 2009 for $2 million up front and $70 million in milestones. (See BioWorld Today, Sept. 23, 2009.)

Adolor began Phase I studies for ADL 7445 in 2009, and Phase I exploratory efficacy trials in 2010 for ADL5945. It also has some early stage opioid and nonopioid discovery programs.

Going forward, Adolor will focus its resources on its opioid-induced constipation program.