Progenics says phase 3 trial of methylnaltrexone for constipation shows significant efficacy

By E. Janene Geiss

Philadelphia, Feb. 15 - Progenics Pharmaceuticals, Inc. announced Wednesday positive top-line results from the second pivotal phase 3 clinical trial of methylnaltrexone for the treatment of opioid-induced constipation in patients with advanced medical illness.

Methylnaltrexone is a peripheral opioid receptor antagonist that is designed to treat rapidly the side effects of opioids without interfering with pain relief. In December 2005, Progenics and Wyeth Pharmaceuticals, a division of Wyeth, announced an alliance to co-develop and co-commercialize methylnaltrexone, according to a company news release.

In this second phase 3 clinical study, subcutaneous administration of methylnaltrexone induced a bowel movement within four hours in 51.2% of severely constipated advanced-medical-illness patients at more than three times the rate of a placebo (15.5%), on average over a two-week period.

For patients who responded to methylnaltrexone (0.15 mg), median time to bowel movement was 30 minutes, officials said.

All primary and secondary efficacy endpoints of the phase 3 study were positive and highly statistically significant. The drug was generally well tolerated and there were no serious adverse events attributed to methylnaltrexone, officials said.

Most advanced-medical-illness patients are treated with opioids for pain and can experience debilitating constipation, a serious side effect that is not adequately addressed by current therapies such as laxatives or stool softeners, officials said.

"For the second time, methylnaltrexone has demonstrated a consistent, predictable and rapid response in treating opioid-induced constipation in a phase 3 study," said Charles F. von Gunten, medical director at the Center for Palliative Studies, in the release. The center is part of the San Diego Hospice and a participating site in the trials.

"The highly positive results ... fully confirm and support earlier clinical studies of methylnaltrexone in patients with debilitating constipation who were unresponsive to laxative therapy. Treatment of the complications and discomfort of opioid-induced constipation is often a greater problem than the treatment of pain in these patients. Methylnaltrexone has the potential to improve significantly the care of patients who require opioids for pain relief," von Gunten added.

The phase 3 clinical trial was a double-blind, randomized, placebo-controlled study in which 133 advanced-medical-illness patients at 27 nursing homes and hospices in the United States were randomized to receive methylnaltrexone every other day during the first week of the study.

All patients had opioid-induced constipation despite the use of laxatives and stool softeners.

If by day 8 (following a dose of study medication on days 1, 3, 5, 7), a patient had not experienced at least three bowel movements not associated with rescue, the patient was eligible to escalate to a higher dose in a blinded fashion by doubling the volume of the study medication for the second week of the study.

Subsequently, all patients were eligible to receive methylnaltrexone in an open-label study over the next three months, officials said.

Top-line statistical analyses were performed on an intent-to-treat population using the data from the two-week blinded study.

Positive and highly statistically significant results were achieved for all of the primary and secondary efficacy endpoints of the study.

Safety data from this phase 3 study showed that methylnaltrexone was generally well tolerated in patients with advanced medical illness. The most frequently reported adverse events were transient abdominal cramping and flatulence.

These events are consistent with previously reported phase 2 and phase 3 results and the drug's mechanism of action on the gastrointestinal tract, officials said.

Investigators did not report any serious adverse events as "drug-related" in this medically fragile population. There were no reports of systemic opioid withdrawal due to study medication, officials said.

"This highly successful phase 3 study in opioid-induced constipation in advanced-medical-illness patients now completes our planned pivotal trial program in the U.S. for this indication," Paul J. Maddon, Progenics' founder, chief executive officer and chief science officer, said in the release.

"We now plan to work with our alliance partner, Wyeth, to submit a New Drug Application to the U.S. Food and Drug Administration and implement a commercialization strategy," he added.

In 2006, Progenics and Wyeth plan to begin clinical studies in post-operative bowel dysfunction with intravenous methylnaltrexone in the United States and Europe, and the oral product will enter phase 2 in patients receiving opioids for chronic pain.

Under the terms of the collaboration, Wyeth will develop oral methylnaltrexone worldwide. Progenics said it will lead the U.S. development of subcutaneous and intravenous methylnaltrexone while Wyeth will lead development of these parenteral products outside the United States.

Progenics is a Tarrytown, N.Y., biopharmaceutical company focusing on the development and commercialization of innovative therapeutic products to treat unmet medical needs, especially HIV infection and cancer.

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