Wyeth Pharmaceuticals, a division of Wyeth and Progenics Pharmaceuticals, Inc., announced preliminary results from a phase 1 clinical trial of a new oral formulation of methylnaltrexone. Oral methylnaltrexone is an investigational drug being developed for the treatment of opioid-induced constipation (OIC). The latest data showed positive activity (as assessed by the occurrence of a bowel movement) in patients receiving the higher of the two doses tested of the new oral formulation.
The phase 1 clinical trial was conducted by Wyeth as a double-blind, randomized, single-dose, crossover pharmacokinetic/pharmacodynamic study in subjects receiving methadone, an opioid used to treat addiction. A substantial majority of patients experienced a bowel movement after receiving the higher of two doses of oral methylnaltrexone. The new oral formulation was generally well tolerated in this phase 1 study. Based on these findings, the companies plan to conduct further clinical testing of new oral formulations.
"I am pleased by the rapid development and testing of a new formulation of oral methylnaltrexone," said Paul J. Maddon, M.D., Ph.D., Progenics Founder, chief executive officer and Chief Science Officer. "We believe an oral form of methylnaltrexone may provide important benefits to those suffering from opioid-induced constipation."
Previously, in March 2007, the companies announced that an initial formulation of oral methylnaltrexone was generally well tolerated but did not exhibit sufficient activity in patients for further development. Now, the companies will initiate an additional phase 1 trial in the coming weeks to optimize further the new oral formulation. Additional details regarding this clinical trial will be provided on the Web site www.clinicaltrials.gov.
Opioids provide pain relief by interacting with specific opioid receptors located in the central nervous system (CNS) - the brain and spinal cord. However, opioids also interact with the receptors outside the CNS, such as those affecting the gastrointestinal (GI) tract, altering intestinal motility and resulting in constipation that can be debilitating. Patients suffering from OIC may experience dry, hard stools, straining during evacuation, and incomplete and infrequent evacuation. Other symptoms of OIC can include nausea, vomiting and abdominal discomfort or pain. If left untreated or unresolved, OIC can lead to fecal impaction that may require manual removal.
Methylnaltrexone is a peripherally acting mu-opioid receptor antagonist that is being studied as a treatment for the peripheral side effects of opioid analgesics. It is designed to mitigate the effect of opioids on peripheral receptors without interfering with central nervous system pain relief. Methylnaltrexone is being developed in subcutaneous and oral forms to treat OIC as well as an intravenous form for the management of post-operative ileus, a prolonged dysfunction of the GI tract following surgery.
Currently, there is no approved medication that specifically targets the underlying cause of OIC to relieve constipation in this patient population. In March 2007, Progenics submitted an NDA for subcutaneous methylnaltrexone to the FDA, followed in May 2007 by the submission by Wyeth of a Marketing Authorization Application (MAA) in Europe to the European Medicines Agency (EMEA). The NDA and MAA have been accepted and validated for review by the FDA and EMEA, respectively. The FDA has set a Prescription Drug User Fee Act (PDUFA) date of January 30, 2008 to complete its review of the NDA, and completion of the MAA review by the EMEA is expected to occur in 2008.