Washington Editor

BETHESDA, Md. - Protein Science Inc.'s goal of being the first company in the U.S. to gain approval of a cell-based flu vaccine may have been dashed Thursday after an FDA panel said FluBlok's safety data were insufficient and the efficacy data would only support approval in adults 18 to 49 years, but not older patients.

The panel voted 9 to 2 in favor of the efficacy data for adults 18 to 49 years, but voted 6 to 5 and 9 to 2 that the data were too weak to support approval in patients 50 to 64 years and 65 and older, respectively.

The panel voted 6 to 5 that the safety data were insufficient in all age groups.

Manon Cox, chief operating officer at Meriden, Conn.-based Protein Sciences, said she was "dumbfounded" by the panel's votes on the efficacy data, "because in principle, efficacy studies are only allowed in individuals 18 to 49 years of age" for influenza vaccines.

Beyond that age group, she said, "you are forced to do immunogenicity comparison studies."

The committee's decision not to back FluBlok's efficacy data for older adults "has basically said that all of the other vaccines also don't meet the criteria and are not effective," Cox argued. "I'm really lost," she added.

But panelist Jose Romero, chief of pediatric infectious diseases at the Arkansas Children's Hospital, said the data presented for analysis at Thursday's meeting were "not the type of data that I need to make a really informed and conscientious decision" about FluBlok, a trivalent recombinant hemagglutinin influenza vaccine candidate, which is produced using baculovirus technology in cells from the Spodoptera frugiperda, or fall armyworm.

"We need more data," Romero insisted.

FluBlok's safety database consisted of 3,233 adults. While there was no imbalance of serious adverse events, there were at least two hypersensitivity reactions likely linked to the vaccine, including one case of pleuropericarditis in a 47-year-old man 11 days after vaccination. The other case involved a 22-year-old woman who experienced an abrupt onset of swollen lips and tongue about 10 hours after FluBlok vaccination.

In addition to the two serious hypersensitivity events, a 57-year-old man experienced vasovagal syncope, which also was deemed a serious.

And while study investigators determined that a mild episode of Bell's palsy in one trial participant was unrelated to FluBlok, panelist Vicky Debold, director of patient safety for the National Vaccine Information Center, said it "matters" if there is the potential that the vaccine could exacerbate existing illnesses in patients given the shot.

Protein Sciences originally submitted its biologics license application for FluBlok in April 2008 with a request for accelerated approval, but the FDA issued a complete response letter the next August "stopping the clock," said Rakesh Pandey, a medical reviewer in the FDA's Office of Vaccines Research and Review. The company provided additional clinical endpoint data last April and requested traditional approval of FluBlok for adults 18 years or older, he said.

FluBlok's application was based on one Phase II study and three Phase III trials, two of which were noninferiority trials comparing FluBlok to Sanofi Pasteur's licensed seasonal flu vaccine Fluzone.

While the administration of FluBlok at the 135-mcg total recombinant hemagglutinin elicited an immune response that exceeded the FDA's guidance criteria for the H1 and H3 strains in all four studies, which represented different age groups and populations and reflected manufacturing over three influenza seasons, the B strain failed to meet immune response endpoints in three of the four studies and failed a noninferiority comparison to Sanofi's Fluzone in one of two studies, said Cynthia Nolletti, a medical reviewer in the FDA's Office of Vaccines Research and Review.

But Fluzone also failed to meet immune response endpoints in older adults, not only for the B strain, but also for H3 and H1 strains, she said. Nolletti noted, however, that the B strain met the immunogenicity endpoints in the FluBlok treatment group in study PSC04, Protein Sciences' pivotal randomized, placebo-controlled clinical endpoint trial of 4,648 healthy adults 18 to 49 years.

While clinical endpoint data were collected from all four of Protein Sciences' studies, which comprised a total population of 3,231 adults, only study PSC04 was powered to test a formal null hypothesis for the clinical endpoint, Nolletti said. PSC04 demonstrated that, in an influenza season characterized by a predominance of antigenically mismatched strains, the protective efficacy of FluBlok against culture confirmed influenza illness due to any virus strain, regardless of antigenic match, was 44.8 percent, with a lower bound of the two-sided 95 percent confidence interval of 24.4 percent.

Some of the panelists raised concerns about the fact that the flu strains tested against during studies PSC06 and PSC03 were mismatched. But panelist Theodore Eickhoff, professor emeritus at the University of Colorado School of Medicine, argued that all licensed influenza vaccines during the 2006-07 and 2007-08 U.S. flu seasons faced the same dilemma of not matching all of the strains that were circulating those years.

"What we are dealing with is a pretty mediocre vaccine, and I include not just the manufacturers of this vaccine, but trivalent influenza vaccines in general," Eickhoff contended. The "huge advantage" of FluBlok, he said, is that it can be produced much quicker than the currently marketed trivalent-inactivated vaccines.

According to Protein Sciences, the cloning and manufacturing processes for FluBlok takes only two months, and the production process can be scaled to produce large quantities of antigen.

"Make no mistake, I think that is a major advantage, and is a breakthrough in many ways for the United States to have a vaccine available made in this way with recombinant hemagglutinin," Eickhoff declared. "It would certainly have been helpful to have this available this fall."

Published  November 20, 2009