Wyeth Pharmaceuticals, a division of Wyeth, and Progenics Pharmaceuticals, Inc has announced the initiation of a phase 2 clinical trial, to evaluate once-daily dosing of oral methylnaltrexone. This trial is designed to identify the dose of methylnaltrexone to be taken forward into the phase 3 clinical studies that will evaluate the efficacy, safety and tolerability of oral methylnaltrexone for opioid-induced constipation (OIC) in patients treated with opioids for chronic pain.

Opioid analgesics, such as morphine, are widely used to treat patients with moderate to severe pain. In addition to their ability to palliate pain via their interaction with the central nervous system, these medications also interact with opioid-specific receptors outside the brain and spinal cord, often resulting in constipation. Methylnaltrexone is a peripheral mu opioid receptor antagonist designed to reverse the effect of these medications on opioid receptors outside the central nervous system. Because methylnaltrexone acts outside of the central nervous system, it does not interfere with brain centred pain relief.

More than 100 clinical sites in 21 countries are expected to participate in this randomized, double blind, placebo-controlled, parallel-group phase 2 trial, and recruiting approximately 200 to 400 patients. After discussions with the US Food and Drug Administration (FDA), the companies elected to employ an adaptive trial design to expedite the selection of the dose of methylnaltrexone to be studied in phase 3.

The primary efficacy endpoint of the phase 2 study is the number of spontaneous bowel movements per week for six weeks in the methylnaltrexone and placebo groups compared to baseline. Completion of the study is expected to take less than a year and to be followed by phase 3 trials initiating in 2007. The companies anticipate no change in their previously announced submission date for a New Drug Application (NDA) to the FDA for oral methylnaltrexone, which is expected to occur in late 2008 or early 2009.

"Our phase 2 trial is designed to enable Wyeth and Progenics to efficiently determine which of the five tested doses of oral methylnaltrexone will be most appropriate for further evaluation," says Gary L. Stiles, MD, Executive Vice President, Chief Medical Officer, Wyeth Pharmaceuticals. "By using an adaptive trial design, we may have the potential to enrol fewer patients than with a traditional approach, thus potentially accelerating the transition into phase 3 studies."