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By Jennifer Boggs
Assistant Managing Editor
Shares of Tarrytown, N.Y.-based Progenics Pharmaceuticals Inc. lost more than half their value after the company, along with partner Wyeth Pharmaceuticals, reported disappointing Phase III data of methylnaltrexone (MNTX) in postoperative ileus, casting a dark cloud of investor worry over the expansive MNTX program, which includes a pending new drug application for opioid-induced constipation.
Trading at about 25 times its normal volume, Progenics' stock (NASDAQ:PGNX) plunged 63.6 percent to close Wednesday at $4.93, down $8.62, while shares of Wyeth (NYSE:WYE) were barely nicked, losing $1 to close at $40.65.
Company executives were quick to point out, however, that the results of the trial, which failed to show a statistically significant reduction in time to recovery of gastrointestinal function compared to placebo in patients with postoperative ileus (POI) recovering from segmental colectomy surgical procedures, were drastically inconsistent with prior Phase II data, and they await further data from that and several ongoing studies of MNTX.
At this time, "we haven't any explanation for why these results occurred, especially in light of the Phase II data," said Richard Kraweic, Progenics' vice president of corporate affairs, though he added that the companies will continue to analyze those results.
The trial, conducted by Wyeth, tested intravenously administered MNTX, an opioid receptor antagonist, in doses of 12 mg or 24 mg every six hours vs. placebo. In addition to missing the primary endpoint, the study also failed to meet secondary endpoints, including time to discharge eligibility.
Even as they review those data, the partners also await results from a second similarly designed Phase III POI trial, expected in midyear. That study is being run by Progenics, and the "only real difference is that the Wyeth trial had a larger number of foreign sites," Kraweic said, though he added, "but that shouldn't be" what threw the Wyeth study off.
"From time to time, there are setbacks," he told BioWorld Today, "but we think the future for methylnaltrexone is a very positive one."
And that includes the upcoming April 30 PDUFA date regarding an application for the subcutaneous formulation of MNTX in opioid-induced constipation (OIC), an indication Kraweic described as "very, very different" from POI. He said the company does not expect the latest POI data to affect the FDA's review of the drug in OIC.
"There were no safety concerns that came out" of the POI Phase III study, he said, adding that opioid-induced constipation in a palliative care setting - a market of about 1.5 million people in the U.S. - is a "significant unmet medical need."
But some analysts were concerned that the discouraging POI results could taint the FDA's view of the drug in OIC.
Analyst Joel Sendek, of Lazard Capital Markets LLC, who downgraded Progenics' stock from "buy" to "hold," wrote in a research note that while he thinks MNTX has "better than 50 percent change of approval" in opioid-induced constipation, there's a good chance the "increasingly conservative FDA" could delay the approval to review POI safety data.
Cowen and Co.'s Leland Gershell anticipates an approvable letter at best, probably with a request for additional clinical work "given the limited database on patient exposures with" the subcutaneous formulation, he said in a note.
But Jonathan Aschoff, an analyst at Brean Murray, Carret & Co., who maintained a "buy" rating on Progenics, wrote that the pending FDA review is for a different formulation of MNTX in a different indication than POI, and "we anticipate the company will . . . receive approval for subcutaneous MNTX in terminally ill patients" by the PDUFA date.
In the POI market, estimated to comprise about 2 million patients undergoing surgical procedures in the U.S., Progenics' and Wyeth's chief competitor is Exton, Penn.-based Adolor Corp., which is developing Entereg (alvimopan) in collaboration with GlaxoSmithKline plc. Despite being nearly derailed by reported links to increased cardiovascular risks, Entereg received a thumbs-up from an FDA advisory panel in January for use in POI following partial large or small bowel resection surgery with primary anastomosis and has a May 10 PDUFA date. (See BioWorld Today, Jan. 24, 2008.)
News of MNTX's Phase III miss boosted shares of Adolor (NASDAQ:ADLR) 9.1 percent Wednesday, closing at $4.68, up 39 cents.
For Progenics and Wyeth, mid-2008 likely will mark a decisive point in MNTX's development. In addition to data from the second POI study, the companies are expecting results from two Phase II trials testing an oral formulation of the drug in OIC and from a Phase II study evaluating subcutaneous MNTX in an orthopedic rehabilitation setting.
A Phase III program is ongoing with the IV formulation in patients suffering POI following surgical repair of large abdominal hernias. Results from that study are expected in early 2009.
"We're also looking at the chronic pain setting," said Dory Lombardo, senior manager of corporate affairs. That program includes a Phase III trial of subcutaneous MNTX in patients with chronic noncancer pain.
"The key here," Kraweic said, "is that we have a lot of shots on goal with methylnaltrexone."
Under the terms of the 2005 collaboration, Wyeth gained exclusive rights to MNTX in exchange for $60 million up front and milestones up to $356.5 million. Progenics retains co-promotion rights in the U.S. and is eligible for royalties on sales ex-U.S. product sales.
Beyond MNTX, the company has PRO 140, an HIV drug that successfully completed Phase Ib testing and has fast-track status in the U.S, and a prostate cancer program that includes vaccines and antibodies targeting prostate-specific membrane antigen. | 
