Editor

Something of a rumble is shaping up in opioid-induced bowel dysfunction, as a pair of companies race to get a drug on the market for the condition.

Both firms made news earlier this month. Adolor Corp., with partner GlaxoSmithKline plc, disclosed positive Phase IIb data with Entereg (alvimopan), and Progenics Pharmaceuticals Inc. offered favorable top-line data from its Phase III trial methylnaltrexone (MNTX) against opioid-induced constipation.

Entereg (alvimopan) is a peripherally acting mu opioid receptor antagonist that missed its primary endpoint against post-operative ileus in a European Phase III trial. MNTX, also a peripheral opioid receptor antagonist, is similarly aimed to treat the side effects of opioids while not interfering with pain relief.

Progenics' compound is "really three drugs, with three indications, three brandings and three sets of clinical trials," said Richard Krawiec, vice president of investor relations and corporate communications.

In the most recently reported trial testing MNTX in patients with advanced medical illness, the route of administration is subcutaneous. In post-operative bowel dysfunction formulation is intravenous, and Progenics - which reported positive Phase II data in January - plans to meet with the FDA this year to discuss Phase III plans for that version of the drug. A third formulation is oral, and the company is developing that one for relief of opioid-induced constipation in patients with chronic pain, for which a Phase II study is expected to start this year.

Meanwhile, in patients with advanced medical illness getting opioids, the subcutaneous form is the subject of an ongoing second pivotal Phase III study, expected to complete enrollment in mid-2005.

Progenics chose the first indication by figuring out which might be the most direct route to approval, to be followed by supplemental new drug applications for the others - even though the first chosen is the smallest of the market opportunities.

"It's probably the one with the most desperate need," Krawiec said. "There's never been a drug that will relieve this intractable constipation." Progenics' Phase III trial is believed to be the first ever conducted in a hospice setting, he added. That proved a challenge well met, since hospices are hardly set up for clinical work.

About 1.2 million people die every year from advanced medical illness, and "the vast majority of those take opioids in the last months of their life," suffering the side effects as they suffer the symptoms of the illness itself, Krawiec said. The compound was licensed from the estate of two inventors, and was devised by a scientist with a family member dying of cancer, he added.

More than half the patients from the Progenics trial have died.

"Palliative and supportive care is a whole new area of medicine," Krawiec said, and another example of a headline-making drug in the field is Amgen Inc.'s Kepivance (palifermin), approved late last year for the painful condition mucositis in chemotherapy patients with blood cancers who get bone marrow transplants.

Getting the FDA to clear a drug in the indication will help patients in more ways than one, he said, by helping the hospice profession itself - where the turnover rate is about 40 percent annually, Krawiec noted.

"Most nurses will not stay in the profession that long," Krawiec said. "They're angels of mercy and they end up doing emergency dis-impactions at three o'clock in the morning."

Making experiments with the drug easier overall, though, is the fact that unmistakable results can be measured - no surrogate markers here - in an hour or so. The time to action also will save on nursing costs for ill people able to live at home, Krawiec said.

"The health care worker can go to the home, give the injection and see the patient laxate before leaving," he said.

Progenics licensed MNTX from UR Labs Inc. in the fall of 2001, when the drug already had undergone testing in more than a dozen trials at the University of Chicago Medical Center. Naltrexone is a well-known drug, used to reverse the side effects of narcotics. Its methylated version - MNTX - with its changed permeability, does the same but doesn't enter the spinal cord. Adolor, with Entereg already in hand, added to its strength in 2002 by licensing six patents from Eli Lilly and Co. related to peripherally selective opioid antagonists.

MNTX is hardly the only egg in Progenics' basket.

"We have a very interesting drug, a viral entry inhibitor, for HIV that is in Phase I development now," Krawiec said. A monoclonal antibody humanized by Protein Design Labs Inc., the drug is expected to "finish Phase I in the coming months, and later this year get into a Phase II program with HIV patients," he said.

In September 2003, the National Institutes of Health awarded Progenics a contract to develop an HIV vaccine, worth up to $28.6 million in funding over five years, and as of Sept. 30 - the most recently reported quarter - Progenics had cash, cash equivalents and marketable securities totaling $40.6 million. The company spent $14.7 million developing the drug in the first nine months of last year.

Also active is a joint venture called the PSMA Development Company LLC with Cytogen Corp. to research prostate-specific membrane antigen.

Getting the attention most recently, though, is MNTX for opioid-related bowel dysfunction - in some contexts called ileus by Progenics' competitor Adolor, among others.

For Progenics, that term "is too narrow a definition," Krawiec said, pointing out that ileus is sometimes defined as a physical blockage, which "causes a lot of confusion in the medical literature and among the docs. And we just see the world differently."