With positive Phase III data in hand, Genta Inc. filed for FDA approval of its lead cancer drug, Genasense, for chronic lymphocytic leukemia (CLL).

The Berkeley Heights, N.J.-based company submitted a new drug application for Genasense (oblimersen sodium) injection to be given with fludarabine and cyclophosphamide for treating patients with relapsed or refractory forms of the disease, a filing that Chairman and CEO Raymond Warrell said "is extremely important both for our company and for patients with CLL."

Genta expects to hear from the FDA in about 45 days regarding acceptance of the NDA and whether it will be considered for priority review.

"If so, that would target an action date by mid-year 2006," Warrell said.

An approval would be great news for Genasense, which has had a rocky development history. In May 2004, the FDA's Oncologic Drugs Advisory Committee voted against approval of the drug in melanoma, and six months later, the drug failed in a Phase III trial in multiple myeloma. (See BioWorld Today, May 4, 2004, and Nov. 30, 2004.)

Preliminary data from the 241-patient Phase III CLL trial released in 2004 showed that the drug achieved its primary endpoint of increasing the proportion of patients who achieved a complete or nodular partial response (CR/nPR) - from 7 percent in the chemotherapy-only arm to 17 percent in the Genasense arm - but the failure of the drug to hit secondary endpoints, including time to progression and overall survival, and the emergence of increased adverse events in the Genasense study arm ultimately cost Genta its marketing partnership with Paris-based Sanofi Aventis. (See BioWorld Today, Nov. 10, 2004.)

Since then, however, the news has gotten brighter. Further analysis of the pivotal trial in CLL showed that the addition of Genasense also extended the duration of CR/nPR significantly longer than in patients receiving only chemotherapy. The median duration of CR/nPR was 22 months for the chemotherapy group, while the Genasense group has not yet reached a median.

"Our data show that we can amplify the effectiveness of standard chemotherapy, and induce complete, long-lived remissions in patients with advanced disease," Warrell said, adding that response rate, particularly the rate of complete response, "has been the basis for the initial approval of all other drugs in both acute and chronic leukemia."

The company is in discussions with the FDA for conducting a confirmatory post-approval study.

CLL, a form of adult leukemia, affects about 60,000 people in the U.S., according to the American Cancer Society, and can affect the spleen, liver and lymph nodes and impair the production of normal blood cells. Chemotherapy aims at killing cancer cells, but defects in the Bcl-2 pathway can promote resistance to those drugs. Genasense is designed to inhibit production of Bcl-2.

Genta's Phase III data in CLL also provide some much-needed validation for antisense drugs, and an approval would be "critically important for the further development of both DNA- and RNA-based medicines," Warrell told BioWorld Today.

"Despite the broad scientific appeal of these compounds, what has been lacking to date is the economic validation of the platform," he added, and Genasense could provide "that key milestone."

Since Sanofi Aventis terminated the partnership a year-and-a-half ago, Genta has been on the lookout for potential partners. Warrell said the company plans to seek a marketing partner for outside the U.S. and might consider co-marketing arrangements inside the U.S.

In addition to its FDA submission in CLL, Genta expects to file soon for European approval of Genasense in patients with previously untreated malignant melanoma. After that, it hopes to seek approval in acute myeloid leukemia if results from an ongoing 500-patient trial prove positive. Other potential indications include hormone-refractory prostate cancer, small-cell lung cancer and non-small-cell lung cancer.

Genasense also is being studied in several trials with different chemotherapeutic agents. Earlier this month, the company reported results of a pilot study at the American Society of Hematology meeting in Atlanta showing anticancer activity of Genasense plus South San Francisco-based Genentech Inc.'s Rituxan (rituximab) and fludarabine in CLL patients.

At the American Association for Cancer Research - National Cancer Institute - European Organization for Research and Treatment of Cancer meeting in Philadelphia last month, the company presented preclinical results demonstrating the intermittent administrations of Genasense significantly increase the anticancer activity of Melville, N.Y.-based OSI Pharmaceuticals Inc.'s Tarceva (erlotinib).

Genta reported a net loss of $7.9 million, or 7 cents per share, for the third quarter of 2005, which it attributed to the termination of its Sanofi Aventis partnership. As of Sept. 30, the company's cash, cash equivalents and marketable securities totaled $28.8 million.

Shares of Genta (NASDAQ:GNTA) gained 3 cents Thursday to close at $1.39.

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