Washington Editor

SuperGen Inc. filed the final section of its rolling new drug application for Orathecin, a proposed treatment for pancreatic cancer patients who are refractory or resistant to current therapies.

Because the NDA was filed under accelerated approval guidelines, SuperGen expects FDA action in six to eight months. Orathecin also has been granted fast-track status by the FDA.

SuperGen's application contains data from two Phase III trials and one Phase II trial. In total, the data include information on about 1,000 pancreatic cancer patients, 600 of whom received Orathecin (rubitecan) capsules.

Although now filed, the road to the completed NDA has not been without a few potholes for SuperGen, of Dublin, Calif. The company commissioned three large Phase III trials for Orathecin, including a front-line 1,000-patient trial, which has yet to be unblinded, Tim Enns, SuperGen's vice president, investor relations and business development, told BioWorld Today.

The likelihood of the front-line trial ending with a positive overall survival rate is limited because of the rate of crossover, or percentage of patients who failed in the control group and went on to receive the active agent. Enns said between 40 percent and 50 percent of patients in each of the trials fell into the crossover category, which means resulting data would be a comparison between early product use and late product use.

"This is a very well known and documented problem in oncology trials," Enns said. "What do you do when you have these patients who are end stage and you have a product that appears to be efficacious? It's tough not to have crossover."

The front-line trial compares Orathecin to gemcitabine HC1 in na ve patients.

The NDA includes data from a 409-patient Phase III of Orathecin compared to the most appropriate chemotherapy - or physician's choice - in patients who had failed other prior treatments. While the survival endpoint was not hit, the secondary endpoints of time to disease progression and response were achieved. Data from another 400-patient Phase III designed to compare Orathecin to 5-FU in patients who had progressive disease following gemcitabine HC1 treatment also are being submitted.

Meanwhile, the Phase II 58-patient study demonstrated the drug's activity in refractory pancreatic cancer patients who had failed prior treatments. Among 45 patients with measurable disease, 10 had objective partial tumor responses; three responded with a greater than 50 percent reduction in tumor size; and seven saw their disease stabilize. Median survival for the 10 responders was more than 10 months, compared to three months in the overall target population. Five of the 10 lived for more than a year, two for more than two years and one for more than three years and is still alive.

By filing the NDA under Subpart H of the accelerated approval guidelines, SuperGen can win marketing clearance either on evidence from adequate and well-controlled studies of the drug's effects on a surrogate endpoint that reasonably suggests clinical benefits or on evidence of the drug's effect on a clinical endpoint other than survival, provided the company agrees to a confirmatory study.

Enns does not believe the blinded, front-line study would serve as the confirmatory trial, if the FDA were to request one.

"What one would need to do is have a trial where one didn't have crossover and had survival as an endpoint, or one would need a differential design where crossover wasn't an issue, or one could do the study in a country where the drug is not yet approved," Enns said.

Orathecin is a topoisomerase I inhibitor extracted from the bark and leaves of the Camptotheca acuminata tree in China.

In 1999, SuperGen and Abbott Laboratories, of Abbott Park, Ill., signed a deal valued at $150 million for the development of Orathecin. Abbott terminated the deal a year ago, citing the need to conserve cash. (See BioWorld Today, Dec. 23, 1999, and March 6, 2002.)

Enns said SuperGen expects to take the candidate to market on its own in the U.S. and in some parts of Europe. However, the company will probably seek a partner in Asia and areas of southern Europe. European filing is expected toward the year's end.

Orathecin is being studied in other tumor types, including breast, lung, gastric, hepatocellular, colorectal, ovarian and prostate.

SuperGen's stock (NASDAQ:SUPG) moved up 41 cents Tuesday to close at $12.14.

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