Methylnaltrexone: MNTX.

Abstract

Methylnaltrexone is a peripheral opioid receptor antagonist undergoing phase III clinical trials for the treatment of opioid-induced constipation in patients with advanced medical illness who are being treated with narcotics for pain. The compound does not cross the blood-brain barrier in humans and reverses the opioid effects without interfering with pain relief. Some opioid-induced adverse events that the drug may potentially target include constipation, nausea/vomiting, cough suppression and urinary retention. Methylnaltrexone was discovered by researchers at the University of Chicago, Chicago, Illinois, USA and is in joint development with Progenics Pharmaceuticals and Wyeth Pharmaceuticals. Progenics is conducting clinical trials with three methylnaltrexone dosage forms: subcutaneous, IV and oral. Progenics plans to complete the clinical development of methylnaltrexone alone, after which potential pharmaceutical or biotechnology partners will be looked at to provide financial support and marketing expertise, particularly outside the US market. In December 2005, Progenics and Wyeth Pharmaceutical (Wyeth) 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 bowel dysfunction. Under the terms of the licensing agreement, Wyeth has worldwide rights to the compound and Progenics retains the option to co-promote methylnaltrexone in the US. The companies will collaborate on the worldwide development of methylnaltrexone. Under the terms of the agreement, Wyeth has made an up-front payment to Progenics and will also make additional milestone payments. Wyeth will also pay Progenics royalties on worldwide sales, and co-promotion fees within the US. Wyeth is also responsible for all future development and commercialisation costs. Wyeth will develop oral methylnaltrexone worldwide. Progenics will lead the US development of subcutaneous and intravenous methylnaltrexone, while Wyeth will lead development of these parenteral products outside the US.UR Labs licensed methylnaltrexone from the University of Chicago. In October 2001, Progenics in-licensed the methynaltrexone patent portfolio in exchange for rights to future methynaltrexone royalties. In December 2005, Progenics acquired a substantial portion of the royalty and milestone payments in exchange for 686,000 shares of Progenic's common stock and 2.6 million US dollars in cash. In April 2005, Progenics Pharmaceuticals made a public offering of 2 million shares of its common stock, pursuant to an effective shelf registration statement. Progenics intends to use the net proceeds from this offering to fund clinical trials of methylnaltrexone, to fund clinical trials of other product candidates and for other research and development programs. All primary and secondary endpoints were statistically significant in Progenic's second phase III trial of subcutaneous methylnaltrexone (0.15 mg/kg or 0.30 mg/kg). The trial was initiated in January 2004 in 133 patients with opioid-induced constipation at 27 nursing homes and hospices in the US. Enrollment was completed in September 2005 and results announced in February 2006. In March 2005, Progenics announced results from the pivotal phase III trial of subcutaneous methylnaltrexone for the reversal of opioid-induced constipation. This trial involved a total of 150 patients from 16 hospices in the US who had advanced medical illnesses and who were receiving occasional opioids. Progenics has completed a phase IIb dose-ranging study with subcutaneous methylnaltrexone for treatment of narcotic-induced constipation in patients with cancer or AIDS. Positive top-line results from a phase II clinical trial of methylnaltrexone in the management of postoperative bowel dysfunction were reported in January 2005. The endpoints of the study included restoration of bowel function and discharge eligibility. Reversal of urinary retention was a secondary endpoint in this study. Progenics plans to complete a more in-depth analysis of this phase II data and present the finding to the US FDA. Methylnaltrexone (IV) is scheduled to enter phase III clinical studies in this indication in 2006. An NDA is expected to be submitted for the intravenous formulation of methylnaltrexone in late 2007/early 2008. Progenics also plans to initiate a phase II study of methylnaltrexone in women who have undergone hysterectomies. This patient population is also at high risk for ileus. In May 2004, Progenics Pharmaceuticals completed phase I clinical trials using two different oral formulations of methylnaltrexone. Analysis of preliminary data from 61 healthy volunteers who received methylnaltrexone at three dose levels indicated that the drug was well tolerated and exhibited predictable pharmacokinetics. Based on these phase I studies, Progenics selected an oral formulation and dose levels of methylnaltrexone that will be tested in phase II clinical trials for relief of opioid-induced constipation in patients with chronic-pain. The technology licensed from UR Labs, Inc., is the subject of issued US and European patents and several related US and foreign patent applications relating to certain compositions, formulations and uses of methylnaltrexone filed by the University of Chicago. Progenics have continued to expand the patent coverage relating to methylnaltrexone with the filing of new patent applications.