A Food and Drug Administration advisory committee has withheld its recommendation of approval for a fixed-dose combination hypertension drug, saying that it offered no significant benefits over its individual components.
The Cardiovascular and Renal Drugs Advisory Committee voted 6-4 against recommending the drug, a combination of nebivolol 20 mg and valsartan 320 mg.
In a large, well-powered study, the combination lowered systolic blood pressure by a mean of 17 mm Hg, and diastolic BP by 12.5 mm Hg, for a mean benefit of 1.2 mm Hg diastolic and 2.9 mm Hg systolic over nebivolol 40 mg alone. But while the systolic endpoint was statistically significant, neither it nor the diastolic endpoint were clinically meaningful, the committee said.
About 5% more of those who took the combination than those who took nebivolol alone achieved the target systolic goals of 140 and 130 mm Hg – another nonsignificant finding.
In discussing their decisions, several committee members said that approving a minimally effective combination antihypertensive available could be counterproductive.
"Approving a drug with this small effect could lead to physicians choosing this over other combinations that work better," extending even further the time it takes patients to reach blood pressure goals, said Dr. James DeLemos, professor of medicine at the University of Texas Southwestern, Dallas. "We don’t need more combinations. We need fewer, which offer clear advantages over their individual components."
The pivotal 8-week, double-blind efficacy trial randomized 4,161 patients to five doses of the combination of nebivolol and valsartan or to the highest approved doses of the individual components, following a 4- to 6-week single-blind, placebo run-in phase. Forest Laboratories brought the 20/320 fixed dose forward to the FDA. The primary comparator was nebivolol 40 mg; the primary endpoint was change in diastolic blood pressure.
The comparison was a sticking point from the beginning, however, as committee members pointed out that nebivolol 40 mg is not an approved dose in the United States, and the likelihood of a clinician prescribing two 20-mg tablets is small. Forest considered using the 20-mg dose as the primary comparator, but went with 40 mg because FDA regulatory standards require using the highest available dose.
Dr. Stuart Rich said the comparison was unfortunate.
"We were asked to make a judgment on a combination compared to a monotherapy that isn’t even available. My sense is it works better than valsartan alone and better than the lower dose of nebivolol alone, but we’re left with this hypothetical comparison. If we had clear-cut data for the 20-mg nebivolol, the decision would be easier," said Dr. Rich, professor of medicine at the University of Chicago.
The combination was safe, with a very low rate of serious adverse events (0.2%). There were significantly fewer adverse events leading to discontinuation in the combination group than in the nebivolol-alone group (1.6% vs. 4%). These were driven by bradycardia, which occurred in three patients taking the combination (0.5%) and eight taking only nebivolol (1.3%).
However, all of the bradycardia cases were asymptomatic, a finding that led the committee chairman reviewer to question the events’ clinical significance.
"They have not provided any compelling evidence that these were clinically important events," said Dr. Michael Lincoff of the Cleveland Clinic. "It was an artificial measurement that didn’t demonstrate better tolerability of the combination."
Members of the committee had no financial disclosures.