The long and short of Entereg
FDA's decision on the NDA for Entereg alvimopan due early next month could provide yet another indicator of the agency's risk tolerance. The decision also will provide insights into the risk evaluation and mitigation strategy (REMs) process that will come into effect later this year.
In making a decision, FDA's task will be to weigh the efficacy of Entereg in hastening the resumption of gastrointestinal function following bowel resection surgery, a benefit that does not save or extend lives, against an ambiguous signal of increased risk of serious and fatal cardiovascular events.
The agency's Gastrointestinal Drugs Advisory Committee voted 9-6 last week that Entereg's benefits outweigh the risks in the treatment of postoperative ileus (POI) following partial large or small bowel resection surgery. The committee voted 13-0, with two abstentions, that the efficacy results from studies of Entereg in POI were clinically meaningful. Entereg was developed by Adolor Corp. and is partnered with GlaxoSmithKline plc.
But faced with data from more prolonged use of the drug, the committee also voted 8-6, with one abstention, that it is concerned about the potential cardiovascular risks posed by Entereg based on signals from a long-term study in opioid-induced bowel dysfunction (OBD). The panel was unimpressed by Adolor's risk management plan, voting 15-0, that the plan is not adequate.
FDA already has a clinical hold in place for Entereg, and has said it is unlikely to approve the drug without a strong risk management plan. If the agency decides to approve Entereg, the Feb. 10 PDUFA date will test its ability, as well as the sponsors', to agree on a plan quickly.
If it is approved next month, the selective peripherally acting mu opioid receptor antagonist would be the first drug approved for POI.
A complex past
Entereg has been in development for seven years and is on its third review cycle for POI (see "Entereg Regulatory Timeline").
Efficacy has been demonstrated in short-term POI trials, while the safety signal comes from a long-term trial to treat OBD.
The first Entereg NDA, submitted in 2004, sought a broad indication for a 12 mg dose prior to surgery and twice daily following surgery through discharge "to accelerate time to recovery of gastrointestinal function following major abdominal or complex pelvic surgery." FDA's approvable letter cited "insufficient proof