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New Class of Drugs Nearing Approval to Relieve Opioid Bowel Dysfunction

Within the next year, the first of a new class of drugs, peripheral mu opiate receptor (MOR) antagonists, could receive approval from the FDA for treatment of postoperative ileus (POI).

Alvimopan is the first of this new class of compounds to be submitted to the FDA. The agent is being developed by Adolor and GlaxoSmithKline as Entereg/Entrareg, and it could receive approval from the FDA as early as November to treat postoperative ileus. Late-stage trials also have been performed with alvimopan, although at much lower doses, in patients with chronic pain and cancer pain.

Alvimopan is an oral, peripherally acting MOR antagonist designed to inhibit the negative effects of opioids on the gastrointestinal system without interfering with the analgesic effects on the central nervous system.

Another drug of the same class is scheduled for submission of a new drug application (NDA) in early 2007 for treatment of opioid bowel dysfunction in advanced illness. Methylnaltrexone (MNTX) is being developed by Progenics Pharmaceuticals and Wyeth, after its discovery by physicians at the University of Chicago. Two phase III trails of subcutaneous MNTX to relieve opioid-induced constipation in advanced illness have been reported.

MNTX is able to antagonize the peripherally located opioid receptors selectively because it is a charged molecule that does not cross the blood-brain barrier. In clinical trials, it has been given subcutaneously for cancer pain, intravenously for POI, and orally for chronic pain. In addition to reversing opioid-induced constipation, trials so far show parenteral MNTX also has the potential to reduce other side effects of opioids, including urinary retention and itching.

"This new class of drugs is developing rapidly," says Jonathan Moss, MD, PhD, professor of anesthesiology and critical care at the University of Chicago, and one of the developers of MNTX. He is also a consultant to Progenics.

University of Chicago pharmacologist Leon I. Goldberg began developing MNTX about 25 years ago. Goldberg, known for his pioneering work with dopamine, had a friend who suffered from opioid -induced constipation.
"This is going to be a very active area," Moss says. "I think if these drugs are approved, they are really going to present clinicians with options they have not had before, and it could be a big help to our patients. I think we'll be able to solve very troubling clinical problems."