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By Malorye A. Branca

February 18, 2004 | The first new drug in 20 years for advanced melanoma could make its way into doctors' hands this summer. Combined with chemotherapy, Genta's antisense drug Genasense (G3139) appreciably extends lives in patients with this almost untreatable cancer, and shows promise against other tumors as well.

The promise of Genasense enticed Aventis to enter a $480-million collaboration with Genta in 2002, and forecasters are bullish on its prospects. "With additional indications, it has blockbuster potential," says Tracy DeGregorio at Decision Resources.

But surprising new evidence suggests this drug's success owes nothing to its intended mechanism -- shutting down the expression of a well-known cancer gene. Lingering confusion about Genasense's precise mechanism of action raises new questions about the antisense approach in general, and G3139 in particular.

Genasense is a prime example of a "smarter" targeted drug, engineered to blunt the expression of a well-known oncogene called BCL2. This it does without question, but that may not be what matters.

Surprisingly, the man making these claims actually helped develop Genasense. Cy Stein of the Albert Einstein College of Medicine is an antisense pioneer, sits on Genta's scientific board, and is due royalties once the drug hits the market. So why is he raising questions now? "My scientific credibility is at stake," he replies. "I've spent my career saying these compounds are more complicated than we thought."  

Stein's findings will be published in an upcoming issue of Clinical Cancer Research. He uncovered this new evidence while testing RNAi in collaboration with Dharmacon -- specifically, two siRNAs that suppress BCL2 protein and mRNA levels by 85 percent to 90 percent for up to eight days.

"The best [siRNA] was really spectacular," Stein says, "and the results were reproducible." But to his surprise, both the siRNA-treated and untreated tumor cells showed the same degree of changes after a dose of chemotherapy. It was only when G3139 alone was administered that more cells stopped growing. Nor did the group see any "synergistic effect" between G3139 and chemotherapy, suggesting Genasense works by itself, not in concert with other drugs.

In another study, Stein tested the anti-cancer effects of fragments of G3139, which proved as effective at stopping cancer growth as the full-length molecule (Lai, J.C. et al. Molecular Cancer Therapeutics 2, 1031-43; 2003).

Stein suspects Genasense works not by shutting down BCL2, but by inducing an immune response that weakens cancer cells. Although he admits his work needs validation -- the RNAi studies were conducted in a prostate cancer cell line, which may not mimic the situation in patients -- he maintains, "Every study I do points to the same thing."

Stop Making Sense
Genta's CEO, Raymond Warrell, disputes Stein's theory. "It's fine to have all kinds of hypotheses, but they need to be proven," he says, edgily. "You can give interferon exogenously, and you will not see the kind of effects we see [with Genasense]."

Warrell's testy reaction is not surprising. Initial results from the Phase III trial were less than clear-cut, but there were signs the drug works better than standard therapy, which helps a meager 7 percent of patients. Genta expects to learn this month whether the drug is fast-tracked for approval, at which point the company will submit the final clinical data to the FDA.

Warrell maintains that BCL2 downregulation is the only mechanism ever "proven" for this compound, making Genasense a bona fide antisense inhbitor. But, Stein notes, "It's clearly established that if you upregulate BCL2, you get cells that are resistant to chemotherapy; nobody has proven that downregulating BCL2 makes cells less resistant."

Harvard University's Stanley Korsmeyer, who cloned the BCL2 gene, agrees with Stein: "It is an open question ... whether the antisense approach sufficiently and specifically reduces BCL2 levels, or whether reported responses might reflect another mechanism."

Regardless of mechanism, both Stein and Warrell expect the drug to succeed. Genasense "has doubled response rates, providing a 60-percent improvement in progression-free survival," Warrell says. "It improved overall survival by about 25 percent in patients who were refractory to other treatment."

Some analysts are unconvinced. "We have to wait and see," says Quyn Pham at Delafield Hambrecht. Needham & Co.'s Mark Monane, however, thinks Aventis and Genta have already "put together a compelling argument." He too is wary about the drug's mechanism of action but believes Genasense holds promise against other cancers, particularly given the dismal record of prior therapies.

Genasense would become only the second antisense molecule to win FDA approval, following Isis Pharmaceuticals' Vitravene, used to treat cytomegalovirus retinitis in AIDS patients. That would be a huge victory for the technology that has seen its share of disappointments. "The field is labeled as a sector," says Patrick Iversen, AVI BioPharma's senior vice president of research and development. "Good news, like bad news, can affect us all."

However, AVI and Isis say they do not see such off-target effects. "We don't have those effects, and so we can predict the next success," Iversen says. "We have not seen off-target effects," agrees Isis' vice president of development, Jon Holmlund.

Antisense therapy has been poised for a breakthrough for several years. "We need to get these drugs through Phase III trials," Holmlund says. Establishing the mechanism of Genasense is clearly important to the scientists. But investors may not worry. As Mohane says, "If it works, it works."


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