Oncology News Updates

FDA Refuses to File BLA for Cancer Gene Therapy

The Pink Sheet Daily
Sep 02, 2008

Introgen Therapeutics' hopes have ended for a December approval of its first-in-class gene therapy Advexin to treat recurrent, refractory head and neck cancer after FDA said the BLA is incomplete and cannot be filed. The biopharma reported the "refuse to file" setback Sept. 2.

Austin, Texas-based Introgen filed marketing applications with both U.S. and European regulators in June, requesting a priority six-month FDA review ("The Pink Sheet" DAILY, June 30, 2008). The firm announced Aug. 18 that the European Medicines Agency had accepted the Advexin marketing authorization application.

Details on the FDA action are sparse. Introgen said only that it would meet with the agency to get more clarity and to determine next steps. In a release, the company said it would appeal the action.

Introgen is one of a growing list of development-stage companies operating with less than one year's operating capital. On Aug. 7, the firm reported second quarter 2007 financials, claiming cash, cash equivalents and short-term investments of $11 million. Operating expenses for the quarter, meanwhile, were $6.6 million, down from $8.3 million for the same quarter in 2007.

Income from Introgen's contract research organization, Introgen Technical Services, and other sources was $121,000 for the second quarter, trending up from $82,000 in the year-ago quarter, but not enough to compensate for the burgeoning shortfall.

In July, noting it was still looking to partner the novel cancer therapy, Introgen announced it would restructure to divert resources from Advexin research and development and regulatory preparations to support the regulatory process and an eventual launch ("The Pink Sheet" DAILY, July 8, 2008). The company cut its work force from 70 to 20 but said some employees would move to the CRO.

Novel therapy faces regulatory challenges

Advexin is the first tumor suppressor cancer therapy to get this far in development. If approved, its orphan drug status will allow it extended market exclusivity in the head and neck indication. But gene therapies and their vectors, in this case the adinovirus that carries Advexin's payload into position to "fix" normal but malfunctioning p53 genes, raise huge safety signals.

Introgen claims its adenoviral delivery system is "non-replicating" and "non-integrating," meaning the modified virus won't get into the body and reproduce or insert itself into the patient's genome. But those innate virus goals are the basis of some safety fears.

The regulatory filings are supported by Phase III data showing increased tumor response and improved survival with Advexin monotherapy compared to methotrexate in patients identified through biomarker testing.

Patients with tumors expressing a wild-type (not mutated) p53 gene - the majority of head and neck cancer patients - are candidates for the therapy, which works by delivering normal p53 genes to tumor cells expressing abnormal p53 function, triggering natural tumor-suppression mechanisms without harming normal cells, a big side effect selling point for Introgen.

In July, Introgen released additional Phase III data included in the applications. The analysis showed that p53 appropriate patients demonstrated statistically significant increased survival both at six months (p=<0.0051) and overall (p=0.0265) following treatment. Methotrexate was shown to increase survival for patients with tumor p53 profiles not conducive to Advexin therapy, also with statistical significance.


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