Washington Editor

Adventrx Pharmaceuticals Inc. finds itself once again requesting a meeting with the FDA so it can make its case for lung cancer drug Exelbine.

Last year, the meeting followed a refuse-to-file letter from the FDA because of manufacturing concerns. This time, it's a complete response letter, which also raised manufacturing issues and requested a repeat of a pivotal bioequivalence study conducted in Argentina.

Although Adventrx won't make a final decision about the future of Exelbine (vinorelbine injectable emulsion) until after meeting with the FDA, it hopes to find some gold in the silver lining.

"We could realize significant cost savings from delaying or discontinuing the Exelbine program, in particular as it relates to commercial activities, which would provide us with additional cash runway as we continue to advance our ANX-188 and -514 programs," CEO Brian Culley said in an investors call Wednesday.

With a Sept. 1 PDUFA date, the San Diego-based company had been gearing up for a fourth-quarter launch of Exelbine as a treatment for non-small-cell lung cancer. All of that was put on hold when the biotech received the complete response letter this week.

If the FDA won't back down on its request for another bioequivalence study, Adventrx will look to out-license Exelbine, Culley said. That would save the company the cost of another trial, as well as launch expenses.

While the cost of running the trial is relatively low, about $1 million to $2 million, and the company has the capital; time is an issue. Culley estimated such a trial could stretch out 18 to 24 months.

"Our resources and focus are on ANX-188 and ANX-514, which we believe are the long-term value drivers for our company," Culley said. "Our cash and equivalents of $40.7 million at July 31, plus cost savings from delaying or potentially discontinuing the Exelbine program, will provide us the capital to continue to advance both of these programs."

The biotech is finalizing the protocol for a Phase III pediatric sickle cell trial for ANX-188 that's expected to begin next year. ANX-514, also in late stage, is a detergent-free reformulation of Sanofi SA's blockbuster cancer drug Taxotere, which recently went off patent.

In light of these other products, "our goal is to make a decision regarding the future of the Exelbine program as rapidly and with as little capital outlay as possible," Culley said.

The majority of the issues the FDA raised in the complete response letter dealt with product quality. Adventrx had already responded to all of the issues, which have been raised in the past. Culley noted that the agency's complete response letter did not take into consideration the responses the company made this past spring and summer.

In the refuse-to-file letter issued last year, the FDA said Adventrx's commercial manufacturing site was insufficient to support a commercially viable expiration dating period for Exelbine. The agency requested 12 months of site-specific, real-time stability data from the intended commercial manufacturer. That letter set the Exelbine program back several months. (See BioWorld Today, March 2, 2010.)

Sites Discarded Study Samples

This week's complete response letter also raised concerns about the pivotal bioequivalence study conducted in Argentina under the 505(b)(2) pathway that compared Exelbine with GlaxoSmithKline plc's Navelbine. Based on inspections at two of the seven clinical sites this year, the FDA said it could not verify the authenticity of the drug products used in the trial, placing the results of the trial into question.

FDA regulations require clinical sites to maintain reserve samples of the drugs used in a trial so its inspectors can ensure that no alterations or substitutions were made. But the two sites inspected were not able to produce the reserve vials.

Culley explained that the study used commercially approved vials of Navelbine, which expired in March 2008. Following the expiration date, the sites removed the samples from refrigerated storage and then destroyed them. Given that the samples would have been expired for more than three years, they would have been difficult to authenticate at the FDA's June inspection.

Culley acknowledged mistakes were made. But since the study was not blinded and the study and reference drugs had different packaging, preparation procedures and physical characteristics, sites would not have confused the two products, he said.

It would be like confusing skim milk with water, Culley added, noting that Navelbine is transparent and colorless, while Exelbine is semitransparent and white to off-white.

"For these reasons, we stand by the authenticity of the study drugs used in the Exelbine pivotal study and the integrity of our data," he said.

Should Adventrx decide to out-license Exelbine, it would conjure more deja vu. The company out-licensed its folate-based cancer drug CoFactor to Theragence Inc., of San Diego, last year. Adventrx had shelved the drug for a few years following disappointing Phase IIb data so the company could focus on Exelbine. (See BioWorld Today, June 11, 2010.)