Washington Editor

Introgen Therapeutics Inc. made history Monday when it submitted its biologics license application (BLA) for Advexin, the first gene therapy to use biomarker data in an FDA filing.

Introgen's Dublin, Ireland-based subsidiary, Gendux Molecular Ltd., simultaneously filed a European marketing application for Advexin, a modified adenovirus that targets the abnormal p53 tumor suppressor function, which is associated with cancer initiation, progression and treatment resistance.

The companies are seeking approval of the gene therapy to treat recurrent, refractory head and neck cancer.

"Being able to file both applications on time is no small feat for the company and is a commendable accomplishment," said analyst Joseph Pantginis, of Canaccord Adams Inc.

"There are many who believed that this event would not even come," he said in a research note.

Austin, Texas-based Introgen is seeking a six-month priority review of Advexin in the U.S., which means it potentially could be approved by the end of the year or in early 2009, Max W. Talbott, senior vice president of worldwide commercial development and regulatory affairs, told BioWorld Today. However, he noted that the product's review is being conducted by the FDA's Office of Cellular, Tissue and Gene Therapy, which has had a history of being tough with approvals, most notably, Seattle-based Dendreon Corp.'s prostate cancer immunotherapy Provenge.

The FDA in May 2007 said it needed more efficacy data on Provenge, but later agreed to accept results from an analysis from an ongoing Phase III study, which are expected soon. (See BioWorld Today, May 10, 2007, and June 1, 2007.)

Advexin has one strong advantage in its corner - its safety profile.

Phase III results released last month showed that Advexin was clearly superior in safety to that of methotrexate, the standard-of-care drug for head and neck cancer. (See BioWorld Today, May 29, 2008.)

The Phase III data also showed that biomarkers of the p53 tumor suppressor gene target of Advexin were predictive in selecting patients more likely to respond to the therapy.

Patients with p53 abnormalities can be identified through the use of immunohistochemistry and gene sequencing tests, which are available in most hospitals and clinics.

The biomarker analyses can be used to show which patients will benefit most from Advexin and which ones will respond better to other therapies, such as methotrexate, Talbott noted. "This is just absolutely huge" for personalized medicine, he declared.

While Introgen is the first firm to file an application for a gene therapy using biomarker data, South San Francisco-based Genentech Inc. was first out of the gate with Herceptin (trastuzumab) in using such markers in approval filings, Talbott noted.

UK-based Ark Therapeutics was the first to file a marketing application in Europe for a gene therapy using biomarkers, he added. However, the company withdrew its application for Cerepro, an adenoviral-mediated gene-based therapy being investigated to treat operable high-grade gliomas, after the Committee for Medicinal Products for Human Use gave it a negative opinion.

Ark, which submitted its initial European application based on Phase II data, is awaiting results from a Phase III trial before resubmitting its application to the European Medicines Agency.

Based on Ark's and Dendreon's experiences, and several discussions with drug regulators, Introgen decided to wait for its Phase III biomarker data before submitting its applications, Talbott said.

He noted that Introgen has efficacy data from about 400 patients and safety data from about 700.

While "world-class head and neck specialists" and other physicians have shown great interest about Advexin, particularly about the gene therapy's extremely low toxicity level, convincing Wall Street and the public may be a challenge for Introgen, Talbott acknowledged.

While the Street was positive Monday about Advexin's joint U.S.-European filings, sending shares up 12 percent in early trading, investors had a knee-jerk reaction to the Phase III data last month - sending the firm's stock plunging 26 percent.

Rather than focusing on the fact that the gene therapy met its primary and secondary endpoints of an increased survival and superior safety, investors reacted to the difference in survival between Advexin and methotrexate, for which there was none, noted Canaccord's Pantginis.

Explaining the complexities of Advexin, and gene therapy altogether, has been a major challenge for Introgen and all other firms in the space, Talbott said.

While drugs like penicillin can be explained simply as something that "kills the bad bugs," he said, "gene therapy is not that simple."

"People always try to view things in the framework of their own experience and traditional knowledge," Talbott explained. "I think if you look at gene therapy and you try to understand it like an antibiotic or an ACE-inhibitor or a more traditional pharmacological agent, it just doesn't work that way."

The only way Introgen can overcome the complexities of explaining Advexin and counter the biases about gene therapies, Talbott said, is to "just keep talking about our findings and keep doing additional research and publications. That will probably open up some eyes and start to broaden some of the understanding."

And maybe, he added, "the Street will follow along."

Shares of Introgen (NASDAQ:INGN) closed at $1.55, up 4 cents, or 2.7 percent.