Washington Editor

SILVER SPRING, Md. - The FDA's Oncology Drugs Advisory Committee on Wednesday rejected Genta Inc.'s new drug application for Genasense (oblimersen sodium) to treat relapsed or refractory chronic lymphocytic leukemia, driving down the company's stock value for a second consecutive day.

The shares (NASDAQ:GNTA) lost 35 cents to close at 51 cents, a 40.7 percent fall that nearly mirrored Tuesday's 38.1 percent decline from $1.39 to 86 cents. The initial stock drop was precipitated by criticism from FDA reviewers who argued that a single study underlying the NDA failed to demonstrate substantial evidence of Genasense's effectiveness, even though the trial met its primary endpoint. (See BioWorld Today, Sept. 6, 2006.)

In a 7-3 vote, the panel agreed with that assessment, essentially indicating the drug simply isn't effective enough as a so-called chemotherapy sensitizer.

Acknowledging his disappointment with the outcome, Genta CEO Raymond Warrell reiterated the Berkeley Heights, N.J.-based company's commitment to the product's development. "We strongly believe in the potential of Genasense," he said in a statement issued after the hearing, "and what it may offer patients with advanced cancer."

Though the committee's recommendation isn't binding, the FDA typically concurs with its advisers when making a final decision. The agency is scheduled to complete its Genasense review by Oct. 29, and Warrell said Genta would "be discussing next steps" with the FDA. However, a company representative told committee members that the drug would not be available for compassionate use if the agency rejects its submission.

In the randomized trial in question, Genasense was added to fludarabine and cyclophosphamide (GFC) in about half of the study's 241 patients, while the remainder received only fludarabine and cyclophosphamide. In the primary endpoint, 17 percent of those who received the GFC combination achieved complete or nodular partial responses compared to 7 percent of patients treated with fludarabine and cyclophosphamide alone (p=0.025). Nodular partial responses are complete responses by all criteria except for persistent lymphoid nodules in bone marrow, and Genta's chief medical officer, Loretta Itri, called them higher hurdles to achieve than partial responses, which she said weren't durable.

But the meaning of those primary efficacy data proved to be the crux of the issue for the advisory panel, and the company and the FDA clearly differed on interpreting the merit of that endpoint.

Supporting Genta's argument, Michael Keating, of M.D. Anderson Cancer Center, said the combination of complete and nodular partial responses were an "optimal outcome for patients" because it indicated a higher probability of long-term survival.

Itri pointed out that only 25 percent of GFC patients relapsed at two years, compared to 75 percent in the control arm, "a significant difference" in the durability of those responses.

In summation, Susan O'Brien, of M.D. Anderson Cancer Center, said the major responses are increased with Genasense treatment, and they're more durable.

On the other hand, the FDA's Richard Pazdur said the 10 percent response rate "did not predict an improvement in time to progression or other evidence of clinical benefit." More broadly, the agency's assessment noted that the GFC regimen failed to improve the overall response rate in patients who achieved a complete response, nodular partial response or partial response - it was slightly lower in the Genasense arm (41 percent) compared with the control arm (45 percent) - and there was no apparent difference in overall survival or time to disease progression between the two arms.

Further, Pazdur cautioned that the product's 10 percent improvement in the primary endpoint "must be viewed in both a risk-benefit analysis of the entire population exposed to the drug," given its toxicity, "and in the context of the totality of evidence available."

Genasense is a nucleotide polymer that binds to the messenger RNA coding for the synthesis of the Bcl-2 protein, a relevant target for chronic lymphocytic leukemia given its overexpression in patients with the disease. At one time, the FDA-designated orphan and fast-track drug was partnered with Sanofi-Aventis Group, although the Paris-based pharmaceutical firm terminated that arrangement two years ago. (See BioWorld Today, Nov. 10, 2004.)

The investigational drug has encountered past regulatory battles, most notably in 2004, when Genta withdrew an NDA for advanced melanoma after the same committee 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. In addition, the drug failed in a Phase III trial in multiple myeloma. (See BioWorld Today, May 4, 2004, and Nov. 30, 2004.)

According to the company's website, additional studies are testing Genasense in acute myeloid leukemia, hormone-refractory prostate cancer and multiple forms of lung cancer.

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, and Genta filed for accelerated approval in that indication late last year. Drugs already approved in the space include Campath (alemtuzumab, from Genzyme Corp.) and Fludara (fludarabine, from Schering AG), and physicians also employ Rituxan (rituximab, from Genentech Inc. and Biogen Idec Inc.) on an off-label basis. (See BioWorld Today, Dec. 30, 2005.)