The FDA's Anesthetic and Analgesic Drug Products Advisory Committee (adcom) is slated to meet Wednesday to discuss the potential cardiovascular (CV) risk associated with peripherally acting opioid receptor antagonists in development to treat opioid-induced constipation (OIC). Adcom members will examine the necessity, timing, design and size of cardiovascular outcomes trials (CVOT) to support approval of products in the class, raising the specter of longer and more costly development timetables for a number of drug candidates.

The FDA's Center for Drug Evaluation and Research explained in its briefing document that a potential cardiovascular safety signal observed in the development program for Entereg (alvimopan, Cubist Pharmaceuticals Inc.) raised questions about the amount and type of safety data that should be collected across the entire class to support approval in OIC.

Entereg is approved in the U.S. to accelerate time to upper and lower gastrointestinal recovery following surgeries that include partial large or small bowel resection surgery with primary anastomosis, but the drug carries a risk evaluation and mitigation strategy because of an increase in myocardial infarctions seen in a long-term study in patients with OIC.

Entereg originally was developed by Adolor Corp., of Exton, Pa., and partner Glaxosmithkline plc, of London. The pharma handed back its stake three years after Entereg gained FDA approval. Cubist, of Lexington, Mass., subsequently picked up Adolor in a deal potentially valued at $415 million. (See BioWorld Today, May 22, 2008, June 16, 2011, and Oct. 25, 2011.)

During the adcom, Cubist plans to share retrospective analyses about long-term use of mu-opioid receptor antagonists, but Entereg is not in development for that purpose.

Relistor (methylnaltrexone bromide, Progenics Pharmaceuticals Inc./Salix Pharmaceuticals Ltd.) also is approved to treat OIC in patients with advanced illness receiving palliative care who do not respond to laxative therapy, but the drug received a complete response letter from the FDA in 2012 on its application to extend the label to long-term use in OIC. (See BioWorld Today, July 31, 2012.)

In November 2012, officials at Salix, based in Raleigh, N.C., acknowledged the FDA had expressed concern about the CV risk associated with chronic use of Relistor in OIC and requested another large trial. Those concerns subsequently dented otherwise positive phase III findings for naloxegol (NKTR-118), another candidate in development by London-based Astrazeneca plc and San Francisco-based Nektar Therapeutics Inc.

The 12-week, multicenter, randomized, double-blind, placebo-controlled pivotal phase III KODIAC-04 and -05 trials evaluated 12.5-mg and 25-mg naloxegol administered once daily. The primary endpoint in both trials was percentage of OIC responders compared to placebo, and the data analysis indicated both naloxegol doses demonstrated statistically significant results for the primary endpoint. The analyses also showed no clinically relevant imbalances in serious adverse events, including externally adjudicated major cardiovascular events, across the KODIAK treatment arms and a safety extension arm.

Nevertheless, Nektar's shares (NASDAQ:NKTR) were dinged by the fuzzy FDA outlook for the drug class, falling 13.6 percent to close at $7.04. Volume was nearly nine times the daily average. (See BioWorld Today, Nov. 13, 2012.)

'LEAVING DOOR OPEN' TO LOOK AT CANDIDATES INDIVIDUALLY

Cubist, Salix and Astrazeneca are scheduled to make presentations at Wednesday's adcom, along with Theravance Inc., of South San Francisco, which is developing axelopran (TD-1211), and Develco Pharma Schweiz AG, of Pratteln, Switzerland, which is developing an oral prolonged-release version of naloxone.

In evaluating opioid receptor antagonists in OIC, adcom panelists are expected to weigh the size of the target population, the existence of multiple treatments and the fact that patients with OIC are not necessarily refractory to available treatments. The FDA's stance is suggested by four discussion questions and one voting question. For starters, the committee will consider whether the "totality of data" suggests a CV safety signal is associated with the use of mu opioid receptor antagonists and to assess the strength of the signal and whether that signal may be limited to one or more drugs or across the class.

The committee also will discuss the feasibility of conducting a CVOT in OIC patients with chronic non-cancer pain, with the prospect of randomizing patients to the mu opioid receptor antagonist or placebo, as add-on to background therapy. Following that discussion, the committee will vote on whether such trials should be developed in the indication and, if so, for all or only specific mu opioid antagonists.

Committee members then will review whether a CVOT, under these conditions, should be required prior to approval, as part of a post-marketing requirement or as a combination of the two. Finally, if the committee recommends that a CVOT should not be required for such drug candidates in OIC, they will discuss whether longer term controlled trials should be required prior to approval and, if so, what outcomes should be assessed.

Although the product of such discussions could portend expensive and time-consuming safety studies, J.P. Morgan analyst Cory Kasimov suggested in an email that the key takeaway from the FDA documents is that the agency "clearly seems to be leaving the door open to look at these on a product-by-product basis." That strategy is "exactly what the agency has done in other indications," such as diabetes and obesity, where the requirement for pre-approval of a CVOT has been data driven.

"With the caveat that these are handled by different divisions within the agency, we think the product-by-product approach is the most rational one and should win out in the end," Kasimov added. "Further, if the FDA applies a broad sweeping requirement for pre-approval CVOTs for these products, we think (and think the FDA is aware) it would essentially kill development of this drug class altogether."

The Nektar/Astrazeneca naloxegol program showed no imbalance in CV events between drug and placebo, he pointed out, adding, "we would be surprised if the FDA wanted to see specific CVOT data for naloxegol pre-approval."

In fact, in its briefing documents, the FDA acknowledged that "cardiovascular outcomes trials are resource intensive" and also may be "impractical" for OIC drug programs. "For assessment of cardiovascular safety, cardiovascular outcomes trials may be the best way to estimate the risk; however, the sample size and duration of study required could be an obstacle to the development of necessary new drugs."

Kasimov also was "encouraged" that the single voting question "leaves the door open for the FDA to decide on CVOTs on a product-by-product basis."

The adcom discussion does not affect the single drug approved by the FDA in OIC. The prostone-based therapy Amitiza (lubiprostone), developed by Sucampo Pharmaceuticals Inc., of Bethesda, Md., uses a different mechanism of action and did not show CV risks.