Uses expand for drug developed at UChicago


In the United States, powerful opioid-based pain relievers are taken by more than 1.5 million people who suffer from advanced illness such as cancer. Although morphine and related compounds are the gold standard for pain relief, these drugs produce significant side effects. One of the most troubling is severe constipation. This can be so distressing that many patients discontinue their pain medication.

MNTX1Methylnaltrexone, a drug developed at the University of Chicago in 1979, blocks the side effects without disrupting pain relief.

It took 29 years for methylnaltrexone to win approval from the United States Food and Drug Administration for opioid-induced constipation (OIC) in patients taking morphine or its derivatives for non-cancer pain. On April 24, 2008, the FDA granted marketing approval for its use in the treatment of opioid-induced bowel disorders in patients receiving palliative care for advanced illness such as cancer.

It took six more years for the drug to get approved again. The FDA declined, in 2012, but approved subcutaneous injections of methylnaltrexone bromide in patients taking opioids for non-cancer pain—a significantly larger market—on September 29, 2014.

The expanded indication has the potential to take royalties for the University from methylnaltrexone into “the mid-seven-figure range,” said Alan Thomas, Director of the Center for Technology Development & Ventures (UChicagoTech). “We’re delighted to see growing success for this drug after heroic persistence by its developers over such a long period.”

A Godsend for Thousands

The announcement gave a huge boost to the companies that make and market the drug—Progenics Pharmaceuticals and Salix Pharmaceuticals. Reuters reported that expanded use for methylnaltrexone, marketed as Relistor®, could increase potential peak sales from about $137 million to more than $300 million, quoting a Salix executive.

“My colleagues and I are pleased that the FDA has approved Relistor for use in non-cancer patients with chronic pain,” said Jonathan Moss, MD, PhD, professor of anesthesiology at the University and one of the developers of methylnaltrexone. “This drug has been a godsend for hundreds of thousands of patients with advanced cancer who have had to choose between pain control and bowel function.”

MNTX2Approval was based on a randomized, double-blind, placebo-controlled trial including 312 patients. All had confirmed constipation. Within four hours of the first dose of the drug, marketed as Relistor, 33 percent of treated patients had a spontaneous bowel movement.

In a statement from Progenics and Salix, Eugene Viscusi, MD, director of acute pain management at Thomas Jefferson University in Philadelphia, pointed out that “constipation is one of the side effects for which patients do not develop tolerance with chronic exposure. It can be a significant burden affecting a patient’s ability to function adequately.”

Patients generally experience a rapid bowel movement following administration of methylnaltrexone, often within 30 minutes, he added. “Most patients describe the sensation like a normal bowel activity.”

The most common side effects were abdominal pain (21%), nausea (9%), diarrhea (6%) and hyperhidrosis (6%).

Methylnaltrexone is approved for use in more than 50 countries worldwide, including the European Union, Canada, and Australia, and applications in additional countries are pending.

There is growing competition. Last year, the FDA approved lubiprostone (Amitiza, Sucampo Pharmaceuticals/Takeda Pharmaceuticals USA), the first oral treatment for OIC in adults with chronic non-cancer pain. In September, it approved naloxegol (Movantik, AstraZeneca) for the treatment of OIC in adults with chronic non-cancer pain.

Made in Hyde Park

Methylnaltrexone was developed by the late Leon Goldberg, a University of Chicago pharmacologist. 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, until he found a drug that could not cross the protective barrier that surrounds the brain.

constipation-remedyConsequently, 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, Moss and Chun-Su Yuan in the University’s department of anesthesiology and critical care as well as former faculty members Michael Roizen and Joseph Foss. They continued 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.

In 2001, Progenics Pharmaceuticals, Inc., of Tarrytown, NY, bought the rights to develop methylnaltrexone.

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.

  • Yuan and colleagues demonstrated that nausea and vomiting induced by an anti-HIV drug, Ritonavir, can be attenuated by methylnaltrexone.
  • 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.
  • Other molecular, cellular and animal studies by Moss and colleague Patrick Singleton have described effects of the mu opiate receptor on angiogenesis and tumor progression, which can be blocked by methylnaltrexone.

Based on these observations at the University of Chicago, there is an investigator-initiated clinical trial underway at MD Anderson to see if Relistor, in combination with other chemotherapeutics can attenuate tumor progression in patients with advanced cancers. “This could confirm an important new target for treatment and potentially help some of our sickest patients,” Moss said.

UPDATE: In June 2015, the European Commission approved the usage of Resistor to treat patients with OIC, making it available to a much larger population.

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