Genta Inc. is targeting a biomarker-specific melanoma patient population for its confirmatory Phase III study of Genasense, hoping finally to clear a path to market for its beleaguered antisense drug.

The Berkeley Heights, N.J.-based firm enrolled the first patients in the AGENDA (A Randomized Controlled Trial of Genasense plus Dacarbazine Compared with Dacarbazine Alone in Patients with Advance Melanoma) study a month after European reviewers reaffirmed their negative opinion on Genasense (oblimersen) in advanced melanoma patients and indicated that an additional study would be needed.

The 300-patient confirmatory trial is expected to be similar in design to the previous 771-patient study, "with two major differences," said Raymond Warrell, Genta's chairman and CEO. The new trial will be double-blinded and will have a "biomarker-targeted population."

Subset analysis from the previous study showed that patients experiencing the greatest benefit from Genasense had normal baseline lactate dehydrogenase (LDH), a blood enzyme. Of the 274 patients in that group, 20.8 percent showed an overall response when given Genasense plus dacarbazine vs. 7.2 percent receiving dacarbazine alone. In the Genasense-treated group progression-free survival was 3.6 months, compared to 1.6 months in the dacarbazine-only group, and overall median survival was 12.3 months vs. 9.9 months. Those results indicate that LDH is "the most powerful determinant of outcome," Warrell told BioWorld Today, and, based on the "truly overwhelming data" from the previous Phase III study, "we're as optimistic as we can be," going into the confirmatory trial.

Designed to work as a chemotherapy sensitizer by blocking the production of Bcl-2, Genasense has shown some efficacy, but it seems, never enough to get through a regulatory review. The drug got an unfavorable opinion in melanoma from an FDA advisory committee in 2004, and a few months later, lost its partner Aventis SA, of Strasbourg, France. Two years later, despite meeting its endpoint in a Phase III trial in chronic lymphocytic leukemia, Genasense was deemed not approvable by the FDA, which stated that the drug's benefit wasn't substantial enough. Genta is appealing that decision, and expects a response in the fourth quarter. (See BioWorld Today, Nov. 10, 2004.)

Patient enrollment in the confirmatory melanoma study is expected to finish up within 18 months, and shortly after that, the company expects to have its first look at progression-free survival data, one of the co-primary endpoints. Overall survival is the other co-primary endpoint. Pending positive results, Genta will seek worldwide marketing approval.

"We certainly think this trial will succeed," Warrell said. In a show of confidence, perhaps, the company has restarted partnership discussions, though Warrell said he believes Genta will be able to cover the trial's expected $30 million cost. The company, which reported a net loss of $8.2 million, or 27 cents per share, for the second quarter, had $22.4 million in cash as of June 30.

And the LDH biomarker also might prove to be the key to Genasense's success in other indications. The enzyme appears to be significant in CLL and also could be linked to treatment of non-Hodgkin's lymphoma. Warrell said Genta is in Phase II testing with Genasense in NHL, and if the results are positive, the firm intends to move into registrational studies in that indication.

Shares of Genta (NASDAQ:GNTA) gained 5 cents Tuesday to close at 85 cents.