Trials halted after bowel drug linked to heart risk

Entereg (alvimopan) was being evaluated in a Phase III clinical trial of over 800 patients.

A full analysis of the trial data has now revealed that a significant number of patients on Entereg suffered serious side effects, such as heart attacks and neoplasms - unusual cellular growth, which can be benign, malignant, skin cancers and unspecified.

Entereg is a potential first-in-class drug that was designed to prevent the debilitating side effects caused by opioid pain medication, such as morphine.

In doing so, the companies hoped these drugs could be administered more freely to those in severe pain.

Now, GSK have halted all development of the drug pending further data analysis.

"Patient well-being is always our primary concern.

These unexpected findings are not yet fully understood and require further analyses to ascertain the significance of the data.

We are working to gain a better understanding of these findings, which will help guide our future development," said Yvonne Greenstreet, head of research and development at GlaxoSmithKline.

In the clinical trial 14 patients (2.6 per cent) receiving Entereg suffered serious adverse cardiovascular effects, compared to 3 on placebo (1.1 per cent).

Of those 14, half suffered heart attacks.

An increase in the number of fractures was also observed in those patients receiving the experimental drug.

15 patients in the Entereg arm of the study suffered from neoplasms compared with two on placebo treatment.

Opioids work by binding to nerve receptors and preventing the nerve from transmitting pain signals.

However, the receptors are also present in the gastrointestinal (GI) tract and the drug also disrupts its function, causing side effects such as constipation, bloating, nausea and vomiting.

Not only are these effects painful in themselves, but they can limit the dose of opioid given and thus lead to inadequate pain relief.

Entereg is a peripherally-acting mu opioid receptor (PAM-OR) inhibitor.

Although GSK are responsible for the development of the drug as a treatment for Opioid Bowel Dysfunction (OBD), Adolor control development for Postoperative Ileus (POI).

Two weeks ago, Progenics Pharmaceuticals and Wyeth submitted a New Drug Application to the US Food and Drug Administration (FDA) for a subcutaneous formulation of methylnaltrexone.

Also developed to treat opioid-induced constipation and post-operative ileus (in its intravenous formulation), the drug is based on naltrexone.

It differs in that it does not cross the blood-brain barrier and acts as a selective peripheral opioid receptor inhibitor.

Naltrexone itself is primarily in the management of alcohol dependence and opioid dependence.

Despite the disappointment over the failure of Entereg, Adolor said it is yet to decide the ultimate fate of the drug, with respect to the collaboration with GSK.

"We continue to believe in the clinical benefit of Entereg," said Michael Dougherty, CEO of Adolor.

"We are committed to working with GSK to provide an update on further clinical development plans in the opioid-induced bowel dysfunction program as soon as is possible.

With regard to the POI program, we continue to target the second quarter of 2007 to submit to the FDA a Complete Response to the November 2006 approvable letter."

However, on the news, Adolor stock crashed around $5 (€3.74) to $3.75 in after-hours trading.