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Patients Exhibit Faster Gastrointestinal Recovery in Phase 2 Methylnaltrexone Study
A total of 65 patients at eight surgical centers participated in the double-blind, randomized, placebo-controlled phase 2 trial. Subjects underwent segmental colectomies - removal of a portion of the colon - primarily due to cancer or diverticular disease. Shortly after surgery, study medication (0.3 mg/kg MNTX or placebo) was administered intravenously at six-hour intervals for a maximum of seven days. This proof-of-concept phase 2 study was designed to investigate the activity and tolerability of MNTX in the post-operative setting.
Accelerating gastrointestinal recovery with MNTX
The top-line analysis of data yielded the following statistical measures of improvement in gastrointestinal recovery by MNTX treatment relative to placebo:
-- Time to tolerance of first full-liquid meal (p=0.05), accelerated by 30 hours
-- Time to tolerance of first solid meal (p=0.12), accelerated by 25 hours
-- Time to first bowel movement (p=0.01), accelerated by 23 hours
-- Time to tolerance of first solid meal and first bowel movement (p=0.06), accelerated by 27 hours
-- Time to discharge eligibility (p=0.03), accelerated by 30 hours
-- Time to actual discharge (p=0.09), accelerated by 25 hours.
Analysis of gastrointestinal recovery times were performed using Kaplan-Meier time-to-event methods, and mean values are reported above. Statistical evaluations were based on a predefined intent-to-treat analysis, using a log-rank 1-sided test, with significance testing at the 0.05 level, when MNTX treatment was compared to placebo.
"Effective management of post-operative bowel dysfunction is a major unmet medical need, and these data suggest that MNTX offers the potential to shorten hospital stays for millions of patients who undergo major abdominal surgery each year," said Eugene R. Viscusi, M.D., Director, Acute Pain Management Service, Thomas Jefferson University and a principal investigator in the clinical trial. "Ideally, post-operative patients should not be discharged until they have return of bowel function. In my experience, there is no benefit to allowing the gastrointestinal tract to remain inactive after surgery - the earlier the bowel becomes active, recovery is accelerated and the patient can be discharged from the hospital sooner."
MNTX generally well tolerated
MNTX was generally well tolerated in this study. The most common adverse events reported were fever and nausea, which occurred at similar rates in the MNTX and placebo-treated groups. There were no serious adverse events related to study drug, and no patient withdrew from the study for adverse events. Overall withdrawal for all reasons was four patients in the MNTX treatment group and nine placebo subjects. Administration of the peripheral opioid receptor antagonist, MNTX, did not result in any differences in pain scores compared to placebo.
"We are delighted that this first-ever clinical evaluation of MNTX for the management of post-operative bowel dysfunction yielded consistent improvements in medically meaningful endpoints," said Robert J. Israel, M.D., Progenics' Senior Vice President, Medical Affairs. "We are also pleased that in this modestly sized proof-of-concept phase 2 study, measures of gastrointestinal recovery clearly favored MNTX over placebo, and the drug was generally well tolerated. This clinical trial has provided the key signals of clinical activity that we were seeking before advancing into phase 3 development of MNTX in post-operative bowel dysfunction. In the coming months, we plan to complete a more in-depth analysis of the data and to meet with FDA to discuss the results."
"A cascade of events indicating gastrointestinal recovery must occur before a patient is eligible for discharge from the hospital after surgery," explained Alton B. Kremer, M.D., Ph.D., Progenics' Vice President, Clinical Research. "Typically, post-operative patients must first tolerate a liquid diet, progress to solid food and have a bowel movement, and then they become eligible for discharge. Compared to placebo, MNTX accelerated the average gastrointestinal recovery by at least one day in this phase 2 study. Accelerating the time to a patient's first bowel movement after surgery may be the most clearly evaluable measure of gastrointestinal function and a critical gating factor that physicians use to assess discharge eligibility. Based on these results, we believe that MNTX represents an important new therapy to improve patient care and comfort as well as to reduce hospitalization costs."
During surgery, the body releases endogenous opioids, called endorphins, that bind to opioid receptors in the gastrointestinal tract and contribute to post-operative bowel dysfunction. This condition is exacerbated by opioid pain medications that most patients receive during and after surgery. Post-operative bowel dysfunction can lead to the inability to tolerate oral liquids or solid food, nausea and vomiting, abdominal discomfort, and constipation. Because patients cannot be discharged from the hospital until gastrointestinal function returns, this debilitating condition is a leading cause of prolonged patient hospital stays and increased healthcare costs. By blocking opioid receptors within the gastrointestinal tract, MNTX is designed to treat post-operative bowel dysfunction. Pain palliation occurs when opioid pain medications such as morphine activate opioid receptors in the brain and spinal cord and block the perception of pain. Since MNTX has not been observed to cross the blood-brain barrier nor to interfere with pain relief provided by opioid medications, it has potential applications in the post operative setting.
Progenics is developing MNTX for three different indications that correspond to three distinct dosage forms. Each form is potentially useful in clinical applications where onset of action, routes of administration, and ease of use can be tailored to fit the needs of the patient and healthcare professional. In addition to intravenous MNTX for post-operative bowel dysfunction, the Company is evaluating MNTX in the following settings:
-- In advanced medical illness (AMI), subcutaneous MNTX is being studied in two pivotal, phase 3 clinical trials in opioid-induced constipation. Top-line results from the first phase 3 study in AMI are expected in the first quarter of 2005. The second phase 3 study is expected to complete enrollment in mid-2005. Given positive results, a New Drug Application for MNTX in AMI could be submitted to the U.S. Food and Drug Administration as early as the end of 2005.
-- Progenics is developing oral MNTX for relief of opioid-induced constipation in patients with chronic pain. Phase 1 clinical studies have been completed in healthy volunteers and the Company is preparing to begin a phase 2 clinical studies.
Source: Progenics Pharmaceuticals