FDA panel votes against omapatrilat for hypertension

Laurent Castellucci

July 22, 2002

Mon, 22 Jul 2002 19:00:00

Bethesda, MD - In a 5-1 vote, the Cardiovascular and Renal Drugs Advisory Committee to the FDA recommended against approval of Bristol-Myers Squibb's (BMS) vasopeptidase inhibitor omapatrilat (Vanlev®) for the treatment of hypertension. The panel was unconvinced that BMS had provided sufficient evidence that the antihypertensive benefit outweighed the high risk of angioedema. It did, however, leave open the option that the company could convince it in the future.

Panel chair Dr Jeffery Borer (Weill Medical College) said that while he thought it was possible for the drug to be approved in the future, "I don't think it's an approvable drug today."

Dr Elliott Levy, vice-president of clinical development for the company, presented the data for omapatrilat, including the results of the OCTAVE trial, which had recently been presented at the ACC. OCTAVE had been designed to test the hypothesis that a low initial dose of omapatrilat would reduce the risk of angioedema to levels only slightly above that seen with an ACE inhibitor but instead showed a risk greater than 3 fold, although it clearly demonstrated a slight but significant 1.5 mm Hg reduction in blood pressure for omapatrilat over enalapril.

As a result of those findings, BMS was seeking approval for omapatrilat for hypertension with the caveat that it should be targeted to a population with high risk of cardiac events and uncontrolled blood pressure. The company also proposed an education program about angioedema risk that would accompany prescription of the drug.

Much of the panel's discussion revolved around whether it was possible to determine this theoretical target group. The panel eventually concluded it would far prefer to see that kind of data produced in a prospective manner than guess at potential benefits for a group determined after the fact. "OCTAVE was designed on the assumption that this was going to be something that would be approvable as a first-line drug," said Dr Thomas Pickering (Mount Sinai School of Medicine), a nonvoting member of the panel. It "wasn't intended specifically to focus on any high-risk population, and so any information provided is a sort of retrospective analysis."

The panel agreed that there could well be just such a target group where the benefits clearly outweighed the risks, but without a study designed to show that target group or a more convincing analysis of the data BMS already has, it was not prepared to approve the drug.


Dr Thomas Fleming (University of Washington) said that OCTAVE didn't convince the panel that the benefit seen with omapatrilat couldn't have been matched by more aggressive and thorough use of antihypertensive drugs already on the market. "I have serious concerns that we might have been able to provide alternative management that would have had much lower difference in blood pressure without the corresponding risk of life-threatening angioedema," he said.

The panel seemed unsure of how to evaluate the long-term risk and what the real meaning of the blood pressure benefit was. "It isn't just 'the blood pressure, stupid,'" Dr Steven Nissen (Cleveland Clinic) joked, sparring with FDA representative Bob Temple over whether blood pressure was such a reliable surrogate that lowering it any amount should be viewed as a benefit. Nissen pointed out that recent evidence, most spectacularly from the LIFE trial, has shown that different classes of drugs provide different benefits for the same reduction of blood pressure lowering.

"I'm certainly not sure how to estimate the magnitude of benefit of a 1.5 mm Hg blood pressure difference in a new class of drugs," Nissen said.

The small size of the blood pressure reduction compared with enalapril may well have been the sticking point for a drug that originally made its reputation by showing greater blood pressure reduction than any previous drug. "I think had the blood pressure difference been more convincing, it would have been approved," Dr Paul Armstrong (University of Alberta) told heartwire after the meeting adjourned. Armstrong suggested that if BMS had shown a blood pressure reduction closer to 10 mm Hg, "a real paradigm shift," it might have overridden concerns about risk.

The only vote in favor of recommendation came from Dr Blase A Carabello (Veteran's Affairs Medical Center, Houston), who said, "I believe that if the drug were added to the community now it would result in a substantial fall in blood pressure in our hypertensive patients." Carabello pointed to the presentation of Dr Henry Black (Rush University, Chicago) who had presented data on the high number of patients who could not be brought to target blood pressure even with the most aggressive therapy. It is a group of patients for whom "apparently we as a medical group are doing a lousy job of controlling [their] blood pressure," Carabello said while casting his yes vote. "I think it's that group of people I'm most interested in."


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