Washington Editor

Genta Inc. appears to be fighting an uphill battle to get Genasense (oblimersen sodium) approved, according to documents released Tuesday by the FDA that cut more than a third off the company's stock value to a one-year low.

The shares (NASDAQ:GNTA) dropped 53 cents to close at 86 cents on heavy trading in advance of today's meeting of the FDA's Oncology Drugs Advisory Committee. The panel is to consider a new drug application for the investigational drug, a nucleotide polymer that binds to the messenger RNA coding for the synthesis of the Bcl-2 protein. Genta, of Berkeley Heights, N.J., is seeking to market Genasense in combination with fludarabine and cyclophosphamide (GFC) for patients with relapsed or refractory chronic lymphocytic leukemia.

In its pivotal trial, labeled Study GL303, the GFC regimen met its primary endpoint by significantly increasing the proportion of patients who achieved a complete response or nodular partial response (17 percent) compared to those who received fludarabine and cyclophosphamide (7 percent), p=0.025. A nodular partial response is a complete response by all criteria except for persistent lymphoid nodules in bone marrow. But the FDA said it did not agree with the choice of that endpoint for the primary analysis in the 241-patient trial.

Of note, the agency's briefing documents pointed out that the GFC regimen failed to improve the overall response rate in patients who achieved a complete response, nodular partial response or partial response. In fact, it was slightly lower in the Genasense arm (41 percent) compared with the control arm (45 percent). In addition, there was no apparent difference in overall survival or time to disease progression between the two study arms.

Those secondary endpoint misses cost Genta its marketing partnership with Paris-based Sanofi-Aventis Group. Prior to Study GL303, the FDA had suggested that a time-to-progression comparison of the two study arms would be more informative than the measure of complete and nodular partial responses. (See BioWorld Today, Nov. 10, 2004.)

For today's meeting, the agency is asking its committee members to consider whether the open-label, randomized study demonstrates substantial evidence of effectiveness in the context of Genasense-related toxicity. The FDA said the product's addition to fludarabine and cyclophosphamide appears to add to the treatment's toxicity.

In the trial, the investigational drug was administered via a central venous catheter by continuous infusion for one week of each monthly cycle, and up to six cycles were planned for patients tolerating therapy and not progressing. Appropriate dose modifications for fludarabine and cyclophosphamide were provided, and all patients were required to receive supportive therapy.

Genta filed the NDA late last year for accelerated approval. (See BioWorld Today, Dec. 30, 2005.)

Genasense has encountered past regulatory battles, most notably in 2004 when Genta withdrew an NDA after ODAC voted against approval. That's because a previous Phase III failed to achieve its primary endpoint of improved overall survival with the addition of Genasense. Progression-free survival was not substantially improved, according to the FDA, and response rates were low on both the combination arm (11.7 percent) and the DTIC-alone arm (6.8 percent). In addition, the drug failed in a Phase III trial in multiple myeloma. (See BioWorld Today, May 4, 2004, and Nov. 30, 2004.)

Chronic lymphocytic leukemia, a form of adult leukemia, affects about 60,000 people in the U.S., according to data from the American Cancer Society.