Wyeth Pharmaceuticals' constipation drug methylnaltrexone, which is co developed by Progenics Pharmaceuticals, Inc. failed in a late stage clinical trial, according to the preliminary findings from the trials. The intravenous drug candidate, methylnaltrexone, was being evaluated for the management of postoperative ileus (POI) in patients recovering from segmental colectomy surgical procedures.
Preliminary results from the phase III clinical trial conducted by Wyeth showed that treatment did not achieve the primary end point of the study: a reduction in time to recovery of gastrointestinal function (i.e., time to first bowel movement) as compared to placebo. The study also did not show that secondary measures of surgical recovery, including time to discharge eligibility, were superior to placebo. In this clinical study, methylnaltrexone was administered intravenously in doses of 12 or 24 mg every six hours and was generally well tolerated.
"Currently, we are conducting the necessary analyses to determine greater clarity regarding the outcome of this clinical study," said Paul J. Maddon, M.D., Ph.D., founder, chief executive officer, and chief science officer, Progenics. "Preliminary findings from this international study of 542 patients are inconsistent with the clinically meaningful results demonstrated in the 65-patient phase II study of intravenous methylnaltrexone for the management of postoperative ileus."
The second phase III trial of intravenous methylnaltrexone for management of POI is being led by Progenics and is similar in design to the Wyeth study. Progenics announced on January 8, 2008 that it had completed enrolment in this trial, with results expected to be reported by midyear.
"Despite the results of this phase III trial for POI, we remain confident in the methylnaltrexone development programme," said Robert Ruffolo, Ph.D., president, Research and Development, Wyeth Pharmaceuticals. "We will continue to develop the methylnaltrexone franchise to help address the unmet medical need of patients suffering with the gastrointestinal side effects of opioids."
The Wyeth and Progenics development programme for methylnaltrexone continues in multiple formulations across multiple patient populations. Following is the status of intravenous, subcutaneous, and oral formulations of methylnaltrexone currently under investigation.
In addition to the two studies in segmental colectomy patients, the companies are conducting a phase III study of intravenous methylnaltrexone for the management of POI in patients who have undergone surgical repair of large abdominal hernias. Those results are expected to be reported in early 2009, the company said.
Wyeth and Progenics are awaiting a decision from the United States Food and Drug Administration (FDA) by the end of April 2008 on marketing approval of their subcutaneous formulation of methylnaltrexone for use in the palliative care setting for opioid-induced constipation (OIC). The companies filed the New Drug Application (NDA) with the FDA for this indication in March 2007. Wyeth and Progenics are also conducting clinical studies evaluating the subcutaneous formulation of methylnaltrexone for the treatment of opioid-induced constipation in the chronic pain setting, in patients with non-malignant pain (phase III), and in the acute pain setting, in patients following orthopedic rehabilitation (phase II).
The companies are conducting two phase II trials evaluating oral formulations of methylnaltrexone for the treatment of OIC with findings expected to be reported mid-2008.
In December 2005, Wyeth and Progenics entered into an exclusive, worldwide agreement for the joint development and commercialisation of methylnaltrexone for the treatment of opioid-induced side effects, including constipation and postoperative ileus, a prolonged dysfunction of the gastrointestinal tract following surgery. Under the terms of the agreement, Wyeth received worldwide rights to methylnaltrexone, and Progenics retained an option to co-promote the product in the United States. The companies are collaborating on worldwide development. Wyeth has agreed to pay Progenics royalties on worldwide sales and co-promotion fees within the United States. Additionally, Wyeth is responsible for all ongoing and future development and commercialization costs.