Drug developed at the University of Chicago wins FDA approval

April 25, 2008

Methylnaltrexone, a drug developed to relieve one of the major side effects of pain therapy for cancer patients, received marketing approval from the United States Food and Drug Administration on April 24, 2008, for use in the treatment of opioid-induced bowel disorders in patients receiving palliative care for advanced illness such as cancer.

The FDA's European equivalent, the Committee for Medicinal Products for Human Use, also rendered a "positive opinion" for methylnaltrexone (to be marketed as RELISTOR™) on April 24. Health Canada, the Canadian Regulatory Agency, approved the drug on March 28.

"This new drug will be helpful to patients who experience severe constipation associated with the continuous use of morphine or other opioids, which are an important part of care for patients with late-stage, advanced illness," said Joyce Korvick, MD, deputy director of the Division of Gastroenterology Products at the FDA.

"It took almost 30 years but it finally seems that a very useful drug will at last become an option for those who desperately need it," said Jonathan Moss, MD, PhD, professor of anesthesia & critical care at the University of Chicago. "Patients who depend on opiates for pain relief at the end of life are often forced to curtail their opiates because of the side effects. This solves an important clinical problem for some of our most vulnerable patients."

In the United States, powerful opioid-based pain relievers--such as Percocet, OxyContin or morphine--are taken by more than 1.5 million people who suffer from advanced illness such as cancer. Although morphine and related compounds remain the gold standard for pain relief, these drugs often produce significant side effects. One of the most troubling for patients is severe constipation. This can be so distressing that many patients discontinue their pain medication. Methylnaltrexone blocks the side effects without disrupting pain relief.

Methylnaltrexone was invented in 1979 by the late University of Chicago pharmacologist Leon Goldberg. Struck by the suffering of dying friend with morphine-induced constipation, Goldberg tested derivatives of naltrexone, an established drug that blocks the effects of morphine, to find a drug that could no longer cross the protective barrier that surrounds the brain.

Consequently, it did not interfere with morphine's effect on pain, which is centered in the brain, but it did block morphine's effects on the bowels, which are mediated by receptors in the gastrointestinal tract.

Initial success in this compassionate-use setting drew the notice of Goldberg's university colleagues, Joseph Foss, Jonathan Moss, Michael Roizen, Chun-Su Yuan and others in the University's department of anesthesiology and critical care. They continued, after Goldberg died, to develop the compound--testing it in animals, completing the initial human safety trials, establishing its effects in early clinical studies in volunteers and patients, and extending the potential applications.

"This is a challenging, antique way to develop a drug," Moss said. This small group of investigators recognized the drug's potential and moved the studies forward, while the University continued to provide support until a partner for the final development and approval could be found.

Success in the initial studies triggered a steady stream of desperate requests for access to the drug. The husband of a cancer patient sent Moss a letter, begging for a chance to enroll his dying wife in a trial.

"The constipation," he wrote, "has become unbearable. Nothing seems to give her any relief. We have a very poor quality of life. This battle with her constipation has consumed all our daily activities. The cancer battle is bad enough, but this has made her life unbearable."

The drug will be "a revolution, a godsend for palliative-care physicians," said hospitalist Elmer Abbo, MD, assistant professor of medicine at the University of Chicago. "It opens the door to adequate and appropriate pain management by enabling us to prevent the very real side effects that often limit how aggressive we can be."

In 2001, Progenics Pharmaceuticals, Inc., of Tarrytown, NY, bought the rights to develop methylnaltrexone from the University of Chicago. In December 2005, Progenics entered into an exclusive, worldwide agreement with Wyeth Pharmaceuticals for the joint development and commercialization of methylnaltrexone for the treatment of opioid-induced side effects, , including constipation and post-operative bowel dysfunction. Moss and Yuan continue to serve as consultants for Progenics

This unusual drug inspired several unusual clinical trials. The proof of concept trial, published in JAMA (Yuan et al., Jan. 10, 2000), was performed in methadone maintenance patients, where it produced prompt laxation without producing central withdrawal symptoms. The clinical trials leading to approval were conducted in hospices and nursing homes, a rare venue for studies.

Since then, ongoing studies have uncovered several unanticipated applications for this promising drug. Moss and colleagues showed, for example, that methylnaltrexone can block the increases in HIV entry and replication that occur when immune cells are exposed to therapeutic doses of morphine. Yuan and colleagues demonstrated that nausea and vomiting induced by an anti-HIV drug, Ritonavir, can be attenuated by methylnaltrexone. More recent studies suggest it may also be useful in treating other side effects of opioids, including urinary retention, pruritus and nausea, and to facilitate feeding in critically ill patients.

"We have used this drug as a tool to determine the peripheral side effects of opiates," Moss said, "and have conducted some preliminary studies to see if it will relieve these side effects."

Methylnaltrexone is "the first approved therapy in a new class of drugs designed to relieve one of the significant side effects of opioids on the gastrointestinal tract without interfering with their ability to provide pain relief," noted Wyeth and Progenics in a press release.

"Opioid-induced constipation is a serious problem for patients undergoing palliative care," said Stephen Hanauer, MD, professor of medicine and section chief of gastroenterology at the University of Chicago Medical Center. "When you consider the necessity for pain-control in patients with terminal illness and need to counter this side effect, the importance of this drug for a patient's well-being and quality of life becomes apparent."

Relistor is an injectable medication. It can be administered as needed, but not more than one dose in a 24-hour period. The recommended starting schedule is one dose every other day as needed for patients with late-stage advanced illness.

Wyeth expects that this product will be launched and available to patients in the United States, Canada and Europe within approximately 60 days.

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