Entereg Gets Cautious Approval Recommendation; More Safety Data Needed

FDA's Gastrointestinal Drugs Advisory Committee overwhelmingly found that GlaxoSmithKline/ Adolor's Entereg (alvimopan) demonstrates convincing efficacy, leading to a positive recommendation for approval, but the panel also expressed concerns about the limited scope of safety data and an inadequate risk management plan.

In the first of four votes, the majority of committee members (13, with two abstentions) agreed alvimopan's efficacy studies demonstrate clinical meaningfulness for short-term use in postoperative ileus patients following small or large bowel resection surgery.

Entereg is a peripherally acting mu-opioid receptor antagonist that mitigates the adverse effects of opioid analgesics on the GI tract without blocking their beneficial analgesic effects. The application has a Feb. 10 user fee date.

One of the two panelists who abstained on the efficacy vote, temporary voting member Judith Kramer, Duke University, explained that "What bothers me in terms of determining efficacy is that essentially we have a situation where this drug has been shown to be effective when the required opioid patient control is in place."

Studies for alvimopan's proposed POI indication excluded opioid-sparing techniques with the exception of one trial performed in Europe (001), which failed to achieve the clinical endpoint.

"In order to determine whether or not [alvimopan] is efficacious we have to say, 'what are we really doing? Are we minimizing the effect of opioids, and should it have that indication?'" Kramer challenged.

Other committee members echoed Kramer's concerns and suggested that the sponsors conduct additional trials to compare the effects of alvimopan with opioid-sparing techniques to existing POI study data.

Study Data Smoothes Path For Entereg Approval

The panel's endorsement of the drug's efficacy is a major step forward for the sponsors. Entereg has received two previous "approvable" letters. The first, in July 2005, cites lack of sufficient efficacy for accelerating recovery of POI. Prior to issuing that letter, the agency had asked GSK/Adolor to provide more data analysis of the failed Phase III European study 001 (¹ (Also see "FDA Requests Entereg Failed Study Data, Adolor Says" - Pink Sheet, 11 Jan, 2005.), In Brief).

The second approvable letter, from November 2006, requests additional data on myocardial infarctions observed in a long-term study in opioid bowel dysfunction, which is the other indication that GSK/Adolor have pursued for alvimopan.

In addition to the trial's measurement of composite endpoints of GI symptoms, like ability to tolerate solid food and time of first bowel movement, the committee was also convinced by GSK/Adolor's argument that efficacy was shown because POI patients given alvimopan versus placebo exhibited a decreased hospital stay by one day, on average.

"At all time points between day two and day three, which is when some patients do get out ... all the way through the 10-day observation period ... there is no point ... where we see patients receiving Entereg doing worse than placebo," Adolor Senior Medical Director Lee Techner reported.

The sponsors' data analysis shows the median acceleration of recovery on the composite endpoint GI-2 for 12 mg alvimopan patients is 10 hours, with accelerated recovery of 22.4 hours or more in the 75th percentile of study participants. The mean time to recovery is 18.8 hours. Following discussion, members agreed that reducing POI hospital stay by 12 hours is clinically significant for patients as well as hospitals, which often face bed shortages.

Among the efficacy issues discussed by the panel was the dose level for in-hospital use. Efficacy studies evaluated alvimopan at 6 mg and 12 mg. The committee noted that the higher 12 mg POI dosing choice marks a substantial increase from the .5 mg alvimopan dose intended for OBD treatment, where cardiovascular events were observed.

"There was concern [about] which dose is the best dose of this product for POI indication," Ruyi He, Division of Gastroenterology at FDA's Center for Drug Evaluation and Research, said in response to committee questions. "When you evaluate for safety signal, you do not see [alvimopan] 12 mg increase significantly [compared to 6 mg] for safety issues."

Panel Sparks "Heart-to-Heart" Safety Talk

Although committee said in a 9-6 vote that the drug's benefits outweigh risks, GSK's study 014 for alvimopan OBD out-patient use demonstrated cardiovascular events that sparked safety questions for its POI indication.

"I am persuaded the signal is real for OBD," said temporary voting member Michael Proschan, National Institute of Allergy and Infectious Diseases Office of Biostatistics Research. "The question then becomes is POI that similar, and the answer to that is I just don't know." Proshcan voiced one of the six opposing views.

"What bothers me is ... maybe you have to be on this drug long term to feel any harm or any problems, but I just don't know that and I don't have strong evidence that that's the case," he said. "For me the benefit of reducing [hospital stay] by one day versus the potential of an MI or something else is enough - enough to make me think the risks outweigh the benefits."

However, GSK/Adolor claim the long-term timeframe of events in study 014 in OBD do not overlap in the POI indication and that ischemic heart disease risk was observed largely in discharged patients - findings not observed in the POI population.

Currently, there is a clinical hold barring GSK/ Adolor from further pursuing the OBD indication because of observed cardiovascular events from study 014 (² 'The Pink Sheet' April 16, 2007, p. 16).

FDA said alvimopan studies lacked sufficient follow-up needed to fully evaluate cardiovascular risk in the POI population. The agency noted that most participants received follow-up directly after dosing, which is an insufficient timeframe to evaluate long-term effects, while more than 250 study participants received none from sponsors.

"Cardiovascular events were not collectively defined [in the studies]," said Marjorie Dannis, Division of Gastroenterology Products at CDER. "And the fact that the data wasn't there doesn't imply that there were no serious cardiovascular events that occurred."

In an added vote to assess committee views of cardiovascular events, nine members said studies suggest alvimopan may pose risk for POI patients. Temporary member Douglas Rosing, National Institutes of Health, one of six members in the minority, noted that "there is no evidence in the short-term study that there is any cardiovascular risk at all."

Next Steps For Study Design

Panelists recommended additional safety studies to more fully evaluate alvimopan's safety following the concern expressed regarding the drug's cardiovascular risk as observed in study 014 for OBD.

Temporary voting member Sean Hennessy, University of Pennsylvania, suggested sponsors implement a long-term randomized study to determine cardiovascular safety endpoints. The panel agreed GSK/Adolor should place more focus on patient follow-up in future studies. They also suggested a Phase IV trial to monitor risk of noted adverse events - cardiovascular, neoplasms and bone fractures - in patients on alvimopan.

Sponsors Should Revamp Drug's RiskMAP

In its final vote, 14 members agreed, with one abstention, that the sponsor's risk management plan is inadequate. "The RiskMAP done by the company was done haphazardly," Acting Committee Chair Alan Buchman, Northwestern University, said. "It's short on specifics."

FDA had a similar opinion of the RiskMAP. In its briefing material, FDA indicated that an effective RiskMAP could assuage concerns about Entereg's safety, particularly cardiovascular risk. But the agency noted the sponsors' proposal to limit use to in-patient hospital facilities poses challenges.

Panelists said the plan lacks clear definitions and means for patient follow-up, as well as guidelines for restricting off-label use. Patient consent, as currently outlined, also raised concern. Temporary voting member Ronald Richardson, Mayo Clinic, said patients need more information on alvimopan's adverse and long-term effects to make a valid consent decision for use. "The RiskMAP talked about getting verbal consent from patients as they are wheeled into the OR - this is not adequate," Richardson said. "Patients need to have more information."

- Carlene Olsen ([email protected])