West Coast Editor
Positive top-line Phase III data in primary and secondary endpoints for Progenics Pharmaceuticals Inc.'s methylnaltrexone against opioid-induced constipation gave the company's stock a boost.
Shares (NASDAQ:PGNX) closed Thursday at $19.72, up 49 cents.
"This is the smallest of the three indications [for which the drug is being studied], but probably the one that has the most desperate need," said Richard Krawiec, vice president of investor relations and corporate communications at Tarrytown, N.Y.-based Progenics.
Progenics' shares jumped higher in January on satisfying Phase II news with the compound in another indication - post-operative bowel dysfunction - rising 13 percent, to $17.16. (See BioWorld Today, Jan. 21, 2005.)
The opioid-induced constipation indication "we believe is the most direct route to the FDA," and likely will be the first use for which the drug is approved, Krawiec told BioWorld Today.
"It's very encouraging for us to have a clinically relevant endpoint that we can measure in about an hour," he added, noting that the data have "been anticipated for a long time" and look very similar to the Phase II results in constipation.
Some analysts may have seen the additional good news coming. Wachovia Securities earlier this month initiated coverage of Progenics with an "outperform" rating. Legg Mason, which upgraded the stock to "buy" in January, raised its price target from $23 to $31 at the start of this month. CIBC World Markets in February hiked its rating to "sector outperform."
The Progenics Phase III news comes one day after competitor Adolor Corp., of Exton, Pa., disclosed top-line results from a Phase IIb study of Entereg (alvimopan), showing the therapy provided benefits in patients with bowel dysfunction due to chronic opioid analgesic therapy. Adolor and partner GlaxoSmithKline plc, of London, submitted a new drug application for Entereg in May as a potential treatment for a separate indication, post-operative ileus, which is decreased or stopped bowel motility. (See BioWorld Today, March 9, 2005.)
"We got away from the word [ileus]," Krawiec said, noting that Progenics also is investigating the post-operative indication. "It causes too much confusion in the medical community." Because ileus is sometimes defined as a blockage, Progenics went with "bowel dysfunction." Also, he said, ileus narrows the field of benefit, and Progenics found that its compound "enhanced every segment of the recovery process."
In the Phase III with constipated patients who have advanced medical illness, a laxative effect took place within an hour in patients treated with methylnaltrexone (MNTX) and worked within four hours at more than four times the rate of placebo. Results added up to high statistical significance, and the drug was well tolerated.
Conducted at 16 hospice centers in the U.S., the trial randomized 154 accrued patients to get one of three blinded doses of medication: placebo, MNTX 0.15 mg/kg or MNTX 0.30 mg/kg.
All of the terminally ill patients had a life expectancy of less than six months, no laxative events for 48 hours despite the use of laxatives and stool softeners, and stable opioid therapy. The primary endpoint was whether a single subcutaneous dose of study medication induced a laxative effect within four hours.
Top-line analysis was performed on data from the blinded portion of the study, on an intent-to-treat basis using two-sided tests. Reaching the primary endpoint were 62 percent of patients at the 0.15-mg/kg dose (p<0.0001), 58 percent at the 0.30-mg/kg dose (p<0.0001) and only 13 percent given placebo.
Achieving a laxative effect within 24 hours without rescue medication - a secondary endpoint - were 68 percent of patients given 0.15 mg/kg (p=0.0004), 64 percent given 0.30 mg/kg (p=0.001) and 33 percent on placebo.
In another secondary endpoint, median time to a laxative effect, the results were 70 minutes for patients given 0.15 mg/kg (p<0.0001), 45 minutes for those given 0.30 mg/kg (p<0.0001) and more than 24 hours for placebo patients.
Most patients with advanced medical illness treated with opioids such as morphine or codeine can get debilitating constipation.
"They're on two laxatives a day and stool softeners, and they don't do any good," Krawiec said. "We can control the pain, but the constipation that results is really problematic."
MNTX, a peripheral opioid receptor antagonist, treats the side effects of opioids while not interfering with pain relief.
Progenics is developing the drug for three different indications that correspond to three dosage forms. In advanced medical illness, a subcutaneous form is the subject of a second pivotal Phase III study, expected to complete enrollment in mid-2005.
"The design's a little bit different," Krawiec said, and will involve dosing every other day for two weeks, testing efficacy in accordance with what's been dubbed the Rome criterion, which specifies that normal bowel movements are those taking place anywhere between three times per day and three times per week. If the data prove positive again, a new drug application could be submitted as early as the end of this year.
MNTX's post-operative bowel dysfunction formulation is intravenous, and Progenics plans to meet with FDA this year to discuss Phase III plans for that version of the drug. A third formulation is oral, and Progenics is developing it for relief of opioid-induced constipation in patients with chronic pain, for which a Phase II study is expected to start this year.
But the focus this week is on constipation. About 1.2 million patients die from acute medical illness in the U.S. every year, Krawiec said, and "the vast majority take opioids in the last months of their life," enduring the side effects as best they can until the end.
"We're grateful to the patients in this trial," he said, calling it the first Phase III ever conducted in the difficult hospice setting. During the study, "68 patients died - that's more than one death a day," he said.
Though MNTX is the compound getting attention now, Progenics is hardly a one-drug company, Krawiec added.
Among the projects in the works is "a very interesting drug, a viral entry inhibitor for HIV that is in Phase I development now," he said. The monoclonal antibody, humanized by Fremont, Calif.-based Protein Design Labs Inc., will finish Phase I testing in the coming months, "and later this year get into a Phase II program with HIV patients," Krawiec said.