Adolor Corp. and partner GlaxoSmithKline plc submitted the first portion of a new drug application for Entereg, a candidate for the management of postoperative ileus.
The partners anticipate completing the submission by the end of June, Bruce Peacock, president and CEO of Adolor, told BioWorld Today. Entereg, Adolor's lead drug, has been granted fast-track status by the FDA. Under the best of circumstances, Entereg could reach the market in early 2005, if the FDA designates it priority review.
Adolor's stock (NASDAQ:ADLR) Friday fell $1.22 to close at $15.96.
Peacock said the filing represents an important milestone for the company.
"I think it speaks well to Adolor's capabilities that we completed a 2,000 patient clinical trial program, we pulled that data together and we have started the first part of the process of the application," he said. "This speaks to the company's continual evolution. Obviously the goal now is to get the rest of it filed and then proceed through the FDA process."
Entereg (formerly ADL 8-2698, or alvimopan) is a mu opioid antagonist being developed for postoperative ileus, or POI, and other similar conditions, including bowel dysfunction in patients using opioid analgesic products and in patients not using opioids who have chronic constipation. 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. There are no FDA-approved drugs for the management of POI.
The NDA is based on data from four Phase III trials, including a 666-patient trial (14CL308, also called Study 308) that failed to hit its primary endpoint of time to recovery in gastrointestinal function. However, the trial did achieve statistically significant differences on the secondary endpoint of time to hospital discharge in both treatment groups (6 mg and 12 mg).
Patients enrolled in Study 308 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. (See BioWorld Today, Jan. 15, 2004.)
Adolor's stock fell 37 percent, or $8.05, to close at $13.73 on the news from Study 308. By comparison, in April 2003, Adolor soared 31.3 percent to close at $12.95 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. The primary endpoint was time to recovery of gastrointestinal function. (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 resection, large-bowel resection or radical hysterectomies. The primary endpoint in that study also was time to recovery of gastrointestinal function. (See BioWorld Today, Sept. 24, 2003.)
The company released in October positive 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.
Adolor, of Exton, Pa., and GSK, of London, filed the first section of the NDA under the FDA's Continuous Marketing Application Pilot 1 Program, which is designed to facilitate the review of portions of an application and is limited to fast-track products, the companies said. They have submitted the nonclinical pharmacology and toxicology sections of the application. Peacock anticipates filing NDAs for the bowel dysfunction and chronic constipation indications in 2007.
The deal between Adolor and GSK for Entereg is potentially worth $270 million in milestone payments for Adolor. Since signing it in April 2002, GSK has paid Adolor $50 million. The next milestone is triggered when the FDA accepts the drug application for review.
In its financial report for the three months ended March 31, Adolor said it had $195 million in cash, cash equivalents and short-term investments. Those funds are expected to last until 2007. In November, Adolor raised $103.5 million in gross proceeds from a public offering of 6 million shares of common stock priced at $17.25 each. (See BioWorld Today, Nov. 7, 2003.)