Despite mediocre results from their fourth Phase III trial, Adolor Corp. and partner GlaxoSmithKline plc expect to seek regulatory approval this year for Entereg in the management of postoperative ileus.
Wall Street penalized Adolor for missing the primary endpoint in its 666-patient Phase III study (14CL308, also called study 308) reported after the markets closed Tuesday, taking 37 percent of the company's value. Wednesday Adolor's stock (NASDAQ:ADLR) dropped $8.05 to close at $13.73.
Of the financial loss, Bruce Peacock, president and CEO of Exton, Pa.-based Adolor, told BioWorld Today: "We believe the package of data supports the submission of the NDA and what we need to do is to continue to communicate our plans of that to the investment community so they can better understand it."
What the investment community might have missed, he said, is that while study 308 did not meet its statistical endpoint, it is still a study that the company believes supports an NDA filing. Regarding investors that sold off Adolor stock on the news, Peacock said: "I understand that. But what we'll do now is get the NDA filed, get it approved and we'll go from there."
Indeed, not everyone agrees that study 308 is full of gloom and doom. Thomas Dietz, an analyst with Pacific Growth Equities LLC in San Francisco released a research note characterizing Adolor's drop in value as "an overreaction [that] has created a significant buying opportunity for Adolor shares."
Data from study 308 were presented at the JPMorgan Healthcare Conference in San Francisco. Following the presentation, Peacock led a conference call telling listeners that Adolor and GSK intend to submit the NDA for Entereg late in the first half of 2004. Peacock and David Jackson, Adolor's senior vice president of research and development, said when considered together, data from the entire 2,000-patient Phase III program are very compelling.
Dietz wrote that highly statistically significant data from study 313 (part of the Phase III program) at a 12-mg dose level, as well as two positive Phase III studies conducted with a 6-mg dose, and supportive data from secondary endpoints potentially may be enough for FDA clearance.
"Given that there is no other approved therapy in the postoperative ileus setting and that the drug is apparently safe, we view this as a positive risk-benefit situation, and we would not be surprised to see both doses receive approval (with the higher dose potentially limited to more severe patients)," Dietz wrote.
Jackson said the company had not decided on a dose for the label. Decisions such as that, he said, would likely result from discussions with the FDA.
Entereg (formerly ADL 8-2698, or alvimpan) is a mu opioid antagonist being developed for postoperative ileus, or POI, and other similar conditions including opioid bowel dysfunction and constipation in patients who do not take opioids for chronic pain. POI often is associated with patients undergoing open abdominal surgery and is characterized by pain, abdominal distention or bloating, nausea and vomiting, accumulation of gas and fluids in the bowel, and delays in the passage of flatus or stool.
The agreement between Adolor and GSK, of London, to develop Entereg potentially is worth $270 million in milestones for Adolor, Peacock said. Since signing the deal in April 2002, GSK has paid Adolor $50 million. The next milestone is triggered when the FDA accepts the Entereg application for review, although Peacock wouldn't disclose the dollar amount.
Study 308 enrolled patients who were scheduled to undergo large- or small-bowel resections, or simple or radical hysterectomy, with a primary endpoint of time to recovery of gastrointestinal function. While the study missed its primary endpoint, the company said a positive trend was observed in each of the Entereg treatment groups (6 mg and 12 mg), when compared to placebo. According to the Cox proportional hazard model, the 6-mg group had a hazard ratio of 1.20 and a "p" value of 0.079. For the 12-mg group, the hazard ratio equaled 1.24 and the "p" value was 0.038.
Statistically significant differences on the secondary endpoint of time to hospital discharge were achieved in both treatment groups.
The mean times to recovery of gastrointestinal function were about eight hours and 10 hours sooner for the 6-mg and 12-mg groups, respectively, compared to placebo. Mean times to hospital discharge were about 14 and 15 hours sooner for the 6-mg and 12-mg groups, respectively.
While Adolor's stock suffered Wednesday, the company's value increased on results from earlier trials scheduled to be included in the NDA.
The company rose 31.3 percent to close at $12.95 in April when study 14CL302 (study 302), a 451-patient trial in patients undergoing large-bowel resections or simple or radical hysterectomies, hit its primary endpoint in the 6-mg group while demonstrating a positive trend in the 12-mg group. (See BioWorld Today, April 3, 2003.)
Likewise, Adolor was up 29.1 percent and closed at $19.38 in September after the release of statistically significant results in both doses in study 14CL313 (study 313). Study 313 enrolled 510 patients who were scheduled to undergo small-bowel resections, large-bowel resections or radical hysterectomies. (See BioWorld Today, Sept. 24, 2003.)
The company released in October favorable results from study 14CL306 (study 306) in 519 patients scheduled to undergo a simple hysterectomy and then receive opioids for pain. The trial was designed to assess safety as the primary objective and efficacy as the secondary objective. Patients were randomized to receive 12 mg of Entereg or placebo at least two hours before surgery and twice a day beginning on the first postoperative day for seven days on an inpatient or outpatient basis. The company said Entereg was generally well tolerated with 93 percent of patients completing treatment. Adverse events generally were nausea, vomiting and constipation.