Washington Editor

ROCKVILLE, Md. - In baseball, a tie goes to the runner, but biotech isn't baseball and nothing definitive came out of Monday's FDA advisory committee meeting on Chiron Corp.'s Pulminiq (cyclosporine).

Deadlocked panel members of the agency's Pulmonary-Allergy Drugs Advisory Committee voted 8-8 as to whether the inhaled version of the long-approved immunosuppressive drug confers a significant survival benefit among lung transplant patients. Apparently the trial's small size mattered, and despite the split vote, results from a single Phase II study contributed to a difficult decision. The FDA could ask for another study when it renders a decision on the new drug application.

"We have to talk to the division about how we get the drug approved and what the next steps are," Stephen Dilly, the company's chief medical officer, told BioWorld Today. "Really, [the FDA] has to think about what they heard, we have to think about what we heard, and we have to put our heads together and come up with the next step."

The underlying NDA is based on results from a study that included 26 patients who received the product, for which the Emeryville, Calif.-based company is seeking approval for combination use with standard immunosuppressive therapy to increase survival and prevent chronic rejection in patients receiving allogenic lung transplants, who currently have only a 50 percent chance of survival after five years.

"This is a very promising therapy," said committee member Lawrence Hunsicker of the University of Iowa, "but it is not well established."

Chiron touted findings from the study, carried out at the University of Pittsburgh over a five-year period of enrollment and follow-up, showing that the product, also called CyIS, was associated with a 79 percent decrease in the risk of death (p=0.007) and a 72 percent decrease in the risk of chronic rejection or death (p=0.001).

"This is hypothesis-generated," Hunsicker added, "and needs to be re-tested."

Both data sets represent statistically significant differences among predefined secondary endpoints from the trial, though the FDA said it was unable to conclude that the observed efficacy was attributable to Pulminiq. Its concerns dealt with the study's protocol, which did not define a means of analyzing secondary endpoints, as well as fears that the randomized trial might have become unbalanced given its small size. Also, the panel questioned if the trial was truly blind for the sole investigative team, although the chief investigator, Aldo Iacono, denied the charge.

Previously, the agency had encouraged Chiron to file on the data, and the NDA was submitted late last year. "We looked at the survival data from a number of different angles," said Sarah Noonberg, the clinical leader of Chiron's Pulminiq program, "and found the survival data to be robust."

Admittedly, the study did not meet its primary endpoint of decreasing death from acute rejection, which FDA representatives indicated to be of concern, as acute rejection is a risk factor for chronic rejection, while the company noted that such a primary measure now is understood to be a function of a vascular process. At the same time, chronic rejection is understood to relate to airway endothelium problems, caused by obliterative bronchiolitis, which supporters said can be directly impacted by an inhalation therapy.

"It makes eminent sense to employ inhaled cyclosporine to treat the endothelium," said Jeff Golden, a pulmonary physician at the University of California at San Francisco. Such therapy already is used without regulation by 10 percent of U.S. transplant centers, which mixed their own formulations, Noonberg said.

Other FDA concerns related to the safety of propylene glycol, which is used in formulating the inhaled solution and was used as placebo in the Phase II study. Also, the agency questioned Pulminiq's impact on two measures of lung function, FEV1 and BOS, as well as worries over the amount of patients who dropped out of the trial. Originally planned to enroll more than 100 patients, only 66 were included in the end, a total comprising 10 on open-label Pulminiq and 56 others randomized to the drug or placebo.

Still, not all on the advisory panel agreed with that criticism.

"I thought that this survival analysis was robust," said committee member David Schoenfeld of Harvard University. "I think the survival benefit can't be thrown away because of all these other analyses."

Should Pulminiq receive approval, Chiron said it would commit to a larger open-label study in a prospectively defined population of abut 10 times the number of patients, compared to external controls such as retrospective or contemporaneous data. Several committee members instead advocated a randomized, placebo-controlled protocol, though physicians at the hearing noted that such a trial would not be able to enroll patients given the already-publicized positive survival data.

"It was also very interesting that exactly what a confirmatory trial would look like was a topic of a lot of discussion," Dilly said. "Is it a pre-approval study, is it a post-approval study, is it a randomized study, is it a single-cohort study?"

A future study would help the company establish a carcinogenic profile of long-term immunosuppressive therapy with Pulminiq, about which worries were raised by Erik Swenson, the committee's chairman. Renata Albrecht, the director of the FDA's division of special pathogen and immunologic drug products, added that the agency has yet to receive findings from an aerosolized carcinogenicity study. In the end, the panel voted 11-5 in favor of the product's safety profile.

"Right now, my mindset, and the whole team's mindset, is what do we need to do to get across the finishing line," Dilly said. "It's all about the next months of discussion with the FDA about what the path forward looks like."

If Pulminiq is approved, most committee members suggested that its label be indicated for the broad lung transplant patient population at a 300-mg dose, with efficacy proved for up to two years.

"We were really pleased with the thoughtfulness of the dialogue," Dilly said. "As we've known from Day 1, this is a difficult, complicated situation."

On Monday, Chiron's shares (NASDAQ:CHIR) gained 8 cents to close at $37.65.