Shares of Adolor Corp. lost more than half their value after the company, along with partner GlaxoSmithKline plc, reported top-line Phase III data showing an increased risk of serious cardiovascular events in patients receiving Entereg for opioid-induced constipation compared to placebo.

Those results mirror findings from the six-month analysis of Study 014, released in September, showing that patients receiving 0.5 mg of Entereg (alvimopan) twice daily for opioid-induced bowel dysfunction (OBD) showed an increase in reported incidences of heart problems, though that increase was not statistically significant. Final results from the 12-month study showed that seven patients (1.3 percent) receiving Entereg reported myocardial infarction, compared to zero patients in the placebo arm, and 14 patients (2.6 percent) showed cardiovascular serious adverse events (SAEs) vs. three (1.1 percent) in the placebo group. Cardiovascular SAEs included angina, hypertension and atrial fibrillation.

As a result, London-based GSK opted to halt an ongoing extension study of Entereg in a cancer pain population and to withdraw a special protocol assessment for an additional Phase III trial OBD trial. Adolor suspended enrollment in an exploratory trial evaluating Entereg in shoulder surgery patients pending further data analysis. But the companies plan to move forward with the submission of a response to the FDA's approvable letter for Entereg in postoperative ileus.

Adolor President and CEO Michael Dougherty told investors during a conference call that the company intended to continue work on Entereg, though he said "much additional analysis" would be needed to determine the drug's long-term development plan.

The reaction from Wall Street, however, was more immediate. Adolor's stock (NASDAQ:ADLR) fell off $5.12, or 58.7 percent, to close Tuesday at $3.60, a 52-week low for a company that was trading at more than $20 per share a year ago. Of course, back then, the company had a pending new drug application for Entereg in postoperative ileus and was looking ahead to results from ongoing trials in OBD. But in September, it reported mixed Phase III results in OBD and, two months later, received the approvable letter in postoperative ileus that requested additional safety data, anticipated to come from Study 014, as well as a risk management plan. (See BioWorld Today, Sept. 6, 2006, and Nov. 7, 2006.)

Entereg's would-be competitor, methylnaltrexone (MNTX), so far, has fared much better on the regulatory path. Tarrytown, N.Y.-based Progenics Pharmaceuticals Inc. and partner Madison, N.J.-based Wyeth Pharmaceutical submitted a new drug application on schedule last week for the subcutaneous formulation for opioid-induced constipation. The companies also are working on an oral version. News of Entereg's setback pushed Progenics' stock (NASDAQ:PGNX) up $1.27 Tuesday to close at $26.03.

In prior studies of Entereg, the cardiovascular adverse event risk has been negligible, and Adolor said the reason for the increase in risk in Study 014 is not clear, though the trial did enroll a number of patients at high risk for cardiovascular side effects, due to smoking, obesity, diabetes, hypertension or other pre-existing conditions. But, the company said, there was no obvious imbalance between the number of high-risk patients in the treatment and placebo groups.

"While we cannot exclude execution error as contributing to the CV event differences, this report causes us to turn a more cautious eye on Entereg's CV safety profile," analyst Leland Gershell, of New York-based Cowen & Co. wrote in a research note. Gershell downgraded Adolor's stock from "outperform" to "neutral."

Entereg, a peripherally acting mu-opioid receptor antagonist, is designed to interfere with opioid side effects on the gastrointestinal system without inhibiting its analgesic effects. Study 014 enrolled 805 patients, with 532 receiving Entereg and the remainder getting placebo.

Consistent with previous studies, the most common adverse events affected the gastrointestinal tract, and included abdominal pain and diarrhea. But in addition to the cardiovascular safety data, results from Study 014 also showed a greater incidence of neoplasms - benign, malignant, skin cancers and polyps - with 15 cases reported in the Entereg treatment arm, compared to two in placebo. Of those, four in the Entereg group and one in the placebo group were characterized as SAEs.

It's "difficult to define a compelling biological rationale" for those findings, said James Barrett, Adolor's senior vice president and chief scientific officer, adding that the company will undertake "further investigation and examination of the underlying cause."

Additional analysis also will be done to determine why results suggested an increased risk of fractures in the treatment group over the placebo group. No detailed data were provided on those events, but Adolor said they stand in contrast to earlier data demonstrating a similar or lower incidence of fractures with Entereg.

Despite the safety issues from Study 014, Adolor and GSK will "continue as planned" with Entereg in postoperative ileus, Dougherty said, adding that the companies will file "a complete response to the FDA approvable letter in the second quarter of 2007."

While the companies are "mindful of the ongoing analysis of the Study 014 data," Dougherty said postoperative ileus requires a short-term use of the product, as opposed to the more long-term OBD treatment. "We believe it could be a successful product in a hospital environment," he said.

But postoperative ileus represents only a small portion of the overall opioid-induced constipation market, the estimated $500 million-plus market GSK had its eye on when signing the original collaboration deal with Adolor. If Entereg only gets cleared for postoperative ileus, it could be limited to a $50 million market.

In addition, the company has not yet disclosed the proposed risk management plan it must submit along with its response letter, and Cowen's Gershell said that "such a plan could further limit Entereg's opportunity in a relatively small market."

When asked during the conference call about the future of the GSK collaboration, Dougherty responded that it was too early to tell. "Glaxo said it intended to review data and then make a decision about going forward," he said.

The Exton, Pa.-based firm entered the potential $270 million deal with GSK in April 2002. That agreement included a $50 million up-front fee to Adolor, plus milestones and a co-promotion option in the U.S. (See BioWorld Today, April 16, 2002.)