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Methylnaltrexone Well Tolerated in Phase II Trial in Opioid-Induced Constipation
TARRYTOWN, N.Y.--(BUSINESS WIRE)--April 30, 2003-- Progenics Pharmaceuticals, Inc. (Nasdaq: PGNX - News) today announced top-line results from a phase 2 clinical trial of its investigational drug, methylnaltrexone (MNTX), for the treatment of opioid-induced constipation.
Bowel dysfunction is a debilitating problem for patients with advanced medical illness who are being treated with narcotics for pain. In December 2002, the Company reported preliminary results from the open-label portion of this clinical study. Now, analysis of the randomized double-blind results show that the study met its objectives, and that the drug continued to show evidence that it was well tolerated. The results confirm and extend the findings from the previously reported open-label portion of the study and support the dosing regimen selected for the ongoing phase 3 clinical trial that began late last year. A presentation of the data is scheduled for the 40th Annual Meeting of the American Society of Clinical Oncology (ASCO), in Chicago, in early June.
"Terminally ill patients suffer from opioid-induced constipation that is exacerbated by inadequate fluid and fiber intake, as well as immobility caused by disease progression," said Robert J. Israel, M.D., Progenics' Senior Vice President of Medical Affairs. "Therefore, we were particularly pleased to see that patients in this study laxated promptly after MNTX administration, typically within one hour. We believe that with further study MNTX has the potential to be an important new therapy for the supportive care of more than one-million patients in the U.S. who die from advanced medical disease each year."
The study enrolled 33 patients with advanced medical illness who were experiencing opioid-induced constipation. Subjects were randomly allocated to receive one of four fixed doses of subcutaneous MNTX (1.0 mg, 5 mg, 12.5 mg, or 20 mg). Patients were treated every-other-day (days 1, 3 and 5) in a blinded fashion for one week, and laxation times were recorded. On day seven, they were eligible to enter into the open-label study for an additional three weeks.
On average, 60% of patients who received doses greater than or equal to 5 mg laxated within four hours as compared to less than 8% at lower doses (p = less than 0.0001, Fisher's exact test, two tailed). The median frequency of pre-dose laxations increased from two per week to four-to-six bowel movements per week at the higher doses of MNTX. Median time to laxation was approximately one hour after receiving greater than or equal to 5 mg of MNTX.
The results from the blinded portion of the study support the weight-based dosing of the ongoing phase 3 clinical trial. At doses equivalent to less than 0.05 mg/kg, the laxation rate was 7%, at 0.05 to 0.25 mg/kg it was 61%, and at greater than 0.25 mg/ kg it increased to 69%, (p = less than 0.0001, Chi-square test, two tailed). The doses chosen for phase 3 are 0.15 mg/kg, 0.30 mg/kg and placebo.-- MNTX was well tolerated at clinically relevant doses, there were no serious adverse events related to study medication, and there was no evidence of breakthrough pain or opioid withdrawal. The most common side effects were flatulence and transient abdominal cramping. These symptoms were interpreted as activation of the gastrointestinal tract, a necessary physiological prerequisite to bowel movement in patients with significant constipation.
Progenics is developing MNTX in three parallel clinical programs to address unmet medical needs in broad markets. Subcutaneous dosing of MNTX for opioid-induced bowel dysfunction in advanced medical illness is being evaluated in a phase 3 clinical trial, intravenous dosing for post-operative ileus is scheduled to begin phase 2 shortly, and a phase 1 clinical trial of an oral formulation of MNTX for use in individuals taking opioids chronically is planned for this year.