Losing half of its value, Genta Inc.'s stock slid south on Tuesday following news that Genasense did not meet key secondary endpoints and had safety issues in a Phase III trial, causing Aventis to drop out as a marketing partner.

Shares (NASDAQ:GNTA) fell 50 percent, or $1.30, to close at $1.30.

Relapsed or refractory chronic lymphocytic leukemia (CLL) patients receiving Genasense plus chemotherapy were significantly more likely than patients receiving chemotherapy alone to achieve a complete or nodular partial remission, which was the trial's primary endpoint. But the combination therapy group showed no significant difference from the chemotherapy group in time to progression and overall survival, the secondary endpoints.

Furthermore, there was a higher incidence of certain serious adverse reactions - nausea, fever and catheter-related complications - in patients treated with Genasense. Certain reactions of patients in the Genasense treatment group led to death, such as single episodes of renal failure, cytokine-release reaction and tumor lysis syndrome.

The 241 patients involved in the trial had failed standard treatment for CLL that had included fludarabine. The patients were randomized to receive standard chemotherapy with fludarabine and cyclophosphamide with or without Genasense.

Joy Schmitt, Genta's spokeswoman, referred questions regarding the terminated agreement to an Aventis release, which stated Aventis entered the agreement seeking a late-stage product that could have a near-term launch.

But things didn't work out as planned, and with the CLL trial results and a recommendation against approval of the product in May by an FDA committee, Aventis decided "it cannot continue to support the development of Genasense," the release stated.

Schmitt declined to say whether Berkeley Heights, N.J.-based Genta would seek another partner for the product or go it alone, but she did say the product has a strong future with the company.

"We believe that Genasense represents a significant advancement for the treatment of cancer patients, and we are committed to pursuing its development and approval," she told BioWorld Today.

The next step is to meet with the FDA to discuss the feasibility of submitting a new drug application for Genasense in the CLL indication. The company also plans to present study results at the annual meeting of the American Society of Hematology (ASH) in San Diego in early December.

It's not the first time Genasense has disappointed investors. In May, after the Oncologic Drugs Advisory Committee (ODAC) recommended against approval of the drug to treat advanced melanoma because it failed to demonstrate efficacy in the survival endpoint and showed signs of increased toxicity, Genta's stock fell 40 percent, closing at $8.60. The following trading day, the stock fell another 40 percent and closed at $5.11. Genta had filed its new drug application based on favorable secondary endpoints of tumor response and progression-free survival. Following the panel's decision, the company laid off nearly half of its work force and halted all active promotion of its marketed drug, Ganite, in an effort to save cash. Later in the month, it withdrew the NDA, and lawsuits against the company were filed. (See BioWorld Today, May 4, 2004; May 14, 2004; and May 17, 2004.)

Researchers first identified Genasense in 1992, and the product entered the clinic in 1995. The partnership with Strasbourg, France-based Aventis, which now is part of the Sanofi-Aventis Group, was formed in April 2002. The companies had a co-promotion arrangement in the U.S., and Aventis owned the rights in other parts of the world.

"Genta has received more than $250 million from Aventis toward the development of Genasense," Schmitt said.

As part of the termination agreement, Aventis will continue to support Genasense development for six months, until May 8. The product also is in a late-stage trial for myeloma, the results of which will be presented at ASH.

"Neither Genta nor Aventis are aware of the results of that trial," Schmitt said.

Genta intends to move forward with additional randomized trials in non-small-cell lung cancer, small-cell lung cancer, prostate cancer and acute myelogenous leukemia (AML). Genasense is the subject of more than 20 clinical trials in a variety of cancers, Schmitt said.

CLL is the most common form of leukemia in adults. About 8,000 patients will be diagnosed with the disease this year, and more than 60,000 people are living with CLL in the U.S., the American Cancer Society said.

Genasense inhibits production of Bcl-2, a protein made by cancer cells that is thought to block chemotherapy-induced apoptosis. By reducing the amount of Bcl-2 in cancer cells, Genasense may enhance the effectiveness of current CLL treatments.

Aside from Genasense, Genta has one FDA-approved product, Ganite (gallium nitrate injection), which is indicated to treat patients with cancer-related hypercalcemia that is resistant to hydration.

In addition to announcing the news on Genasense, Genta reported its third-quarter results Tuesday for the period ended Sept. 30. The company said it had revenues of $1.4 million for the quarter and a net loss of $5.6 million, or 7 cents per share. At the end of the quarter, it had cash, cash equivalents and marketable securities totaling $36.7 million.