Wyeth Pharmaceuticals, a division of Wyeth, and Progenics Pharmaceuticals Inc. has announced the initiation of three new clinical studies for their investigational drug, methylnaltrexone, a peripherally acting mu-opioid receptor antagonist.
Two of these trials will investigate the use of subcutaneous methylnaltrexone for treating opioid-induced constipation (OIC) in patients outside of the palliative care population included in the first NDA submission. The third trial will investigate the use of intravenous methylnaltrexone for managing post-operative ileus (POI) in a surgical setting in patients at high risk for POI. Currently, the companies are studying intravenous methylnaltrexone in phase III trials to manage POI in patients undergoing segmental colectomy surgical procedures. All of the studies are intended to investigate additional patient populations for methylnaltrexone.
"Opioid-induced constipation and post-operative ileus represent important medical needs for which there currently are no approved prescription therapies," says Paul J Maddon, founder, CEO and CSO of Progenics Pharmaceuticals, Inc. "Since the beginning of our collaboration, Wyeth and Progenics have made considerable strides in the clinical, regulatory and commercial development of methylnaltrexone. These trials are designed to further our understanding of the compound in OIC and POI."
The first of the two subcutaneous methylnaltrexone trials is a phase III clinical study in OIC patients with chronic pain not related to cancer, such as chronic severe back pain that requires treatment with opioids. This trial, being conducted by Wyeth, is scheduled to enroll approximately 470 patients at approximately 100 centres worldwide. Methylnaltrexone or placebo will be administered subcutaneously during a four-week, double-blind phase, followed by eight weeks of open-label dosing. The primary efficacy endpoints are the proportion of methylnaltrexone injections resulting in bowel movements within four hours and the evaluation of the number of bowel movements per week, compared to placebo. The trial is expected to be completed by late 2008.
The second subcutaneous methylnaltrexone trial is a phase II study in OIC patients rehabilitating from an orthopaedic surgical procedure in whom opioids are used to control post-operative pain. This trial, to be conducted by Progenics, is scheduled to enroll approximately 260 patients at approximately 50 centres in the United States. Methylnaltrexone or placebo will be administered subcutaneously for up to seven days or until the patient no longer requires opioids. The clinical efficacy endpoints include relief of constipation as measured by laxation response. The trial is scheduled to begin in the fourth quarter of 2007 and is expected to be completed by the middle of 2008.
The third trial is a phase III intravenous methylnaltrexone study being conducted in patients with POI following a ventral hernia repair via laparotomy or laparoscopy. This trial, being conducted by Wyeth, is scheduled to enroll approximately 500 patients at 90 to 120 centres worldwide. Methylnaltrexone or placebo will be administered intravenously following surgery for up to 10 days. The primary efficacy endpoint is measured by time to first bowel movement after the surgical repair. The trial is expected to be completed by the middle of 2008.
Methylnaltrexone currently is under review by the US FDA, the European Medicines Agency (EMEA), and the Australian Therapeutic Goods Administration in its subcutaneous form for the treatment of OIC in patients receiving palliative care.
POI is a prolonged dysfunction of the GI tract following surgery, and is characterized by abdominal bloating and pain, nausea and vomiting, and an inability to pass gas or a stool. POI is a common response to abdominal surgical procedures, but also can occur after other types of surgery. POI can worsen when opioid analgesics, such as morphine, are given to relieve post-operative pain, potentially leading to delayed introduction of food, lengthened hospital stays and increased health care costs.
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 CNS pain relief. Methylnaltrexone is being developed in subcutaneous and oral forms to treat OIC as well as an intravenous form for the management of POI.