After Genta Inc.'s third strike in a year with Genasense - which failed in a Phase III study last week against multiple myeloma, two weeks after a mixed outcome against leukemia that cost the company its deal with Aventis SA - investors are looking askance at Genta and, perhaps to some degree, at the whole field of antisense research.

Injected Genasense (oblimersen sodium) combined with high-dose dexamethasone missed the primary endpoint of time to progression in patients previously given extensive therapy. Genta will be evaluating the data further before figuring out where to go next with the drug in that indication.

Earlier in November, Genasense with chemo in relapsed or refractory chronic lymphocytic leukemia met its primary endpoint of complete or nodular partial remission, but that wasn't good enough for Aventis (now part of the Sanofi-Aventis Group), which dropped the potential $476.9 million deal upon learning the combination-therapy group showed no significant difference from the chemo group alone in the secondary endpoints: time to progression and overall survival.

In May, poor results against advanced melanoma caused an FDA panel to deep-six Genasense, and Genta withdrew the new drug application, reducing its work force by half to trim costs. Shareholders filed suits, claiming to have been misled.

"[Genta] said in the press release that the toxicity was similar to what you would expect for the active agent alone," said Kate Winkler, vice president of equity research for Merriman Curhan Ford & Co. "In fact, the side effects were much worse."

Genasense, which targets the Bcl-2 protein, first entered the clinic in 1995. Winkler said there's been "precious little evidence, but some" that the drug works to down-regulate Bcl-2. "Part of the problem is that there are redundant molecules that are similar that can be up-regulated," she said.

What's next for Genta? Winkler said she wouldn't be surprised to see a bankruptcy filing. The firm has a practically empty pipeline and "a ton of debt," she said, including $19 million owed to Aventis in May, when the partnership formally dissolves. Aventis forked over $35 million as an advance milestone payment tied to Genasense, and Genta has paid $16 million back with inventory of the drug, thanks to a provision in the deal that allows for it, Winkler told BioWorld Financial Watch.

Much of Genta's money came from Aventis in the form of reimbursement for trials. For the third quarter, the firm recorded gross total costs and expenses of about $25.4 million, with Aventis reimbursing $20.5 million.

For the full year of 2003, license fees and development funding revenues received from Aventis totaled about $5.2 million, or 78 percent, of consolidated revenues. Genta's sales of Ganite (gallium nitrate), the injectable drug for cancer-related hypercalcemia, brought in $1.4 million, or 21 percent.

"They quote some cash in the bank, but it's all owed," Winkler said, adding that the company has "some nucleic acid approaches in preclinical, but not anything that would resurrect it." Ganite, she said, was "a placeholder for getting their marketing up and running," but Genta has stopped actively marketing the drug.

Selling whatever technology assets are available could be an option. "You could probably scrape something together there," Winkler said.

"The best-case scenario is that someone comes in and tries to take whatever assets they have and tries to pursue a niche [indication], but frankly, if I were that person, I'd do it from a different platform," she said.

Genta last week still was showing signs of life, however, buying for undisclosed terms the worldwide rights to a Phase I potential antisense therapy from Temple University to treat chronic myelocytic leukemia.

Most worrisome now is the litigation, said Bennette Weintraub, analyst with Hibernia Southcoast Capital. "It's hard to recommend anybody buy this stock, even at a dollar, with these lawsuits," he said.

"Other companies in this situation have successfully restructured," Weintraub allowed, noting that Genta has acquired some strengths. In the summer of 2003, the firm agreed to buy privately held Salus Therapeutics Inc., which specialized in antisense and small interfering RNA drugs, as well as delivery systems for such DNA- and RNA-based compounds. In a separate but related move, Genta picked up a nonexclusive license to a broad patent covering siRNA from the Carnegie Institution of Washington.

Another possibility for the company to stay afloat is to do a reverse stock split, get some funding and explore Ganite further for non-Hodgkin's lymphoma (NHL), Weintraub said. Genta has done some work in the area but "we never saw clinical data out of that program," he added. "I think it fizzled."

In any case, "I don't think it's the way I'd go with that drug," he said, noting for one thing that "we've got Rituxan and it's a higher bar." Genentech Inc.'s Rituxan (rituximab), approved in 1997 for relapsed or refractory, low-grade or follicular, CD20+, B-cell NHL, sold $1.5 billion last year.

Neither Winkler nor Weintraub are ready to give up on antisense as a result of Genta's trouble with Genasense.

"It's not a condemnation of antisense overall," Winkler said, finding hope in such drugs as Isis Pharmaceuticals Inc.'s ISIS 301012, a second-generation antisense inhibitor of ApoB-100, for cardiovascular disease. ApoB-100 is the carrier of low-density lipid cholesterol, the "bad" lipid involved in heart disease and a target of interest but considered undruggable by traditional approaches.

In August, Isis' preliminary Phase I data reported at the Drug Discovery Technology World Congress in Boston showed the drug yielded ApoB-100 knockdown by as much as 55 percent, also reducing low-density lipoprotein, very-low-density lipoprotein and total cholesterol levels in normal volunteers with borderline elevated cholesterol.

Those findings emerged from tests with 19 patients, and the dose-escalation study was expected to enroll about 40 volunteers. Isis made news itself last week with its failure of the first-generation drug alicaforsen, but the compound was strong in three Phase II studies for ulcerative colitis. Isis is known for its patent estate in antisense, including RNA interference.

Antisense can hardly be discussed without mention of RNAi, and Weintraub pointed to a November article in Nature describing "how you might deliver small inhibitory RNAs" silencing the ApoB gene to lower cholesterol.

"Antisense is going to get disrupted by RNAi, but most investors lump those together," he said. "We're trying to focus investors on other nucleic acid therapeutics," such as Corgentech Inc.'s E2F Decoy (edifoligide), in Phase III trials for coronary artery bypass graft, and Macugen (pegaptanib sodium), the injectable candidate for age-related macular degeneration from Eyetech Pharmaceuticals Inc., partnered with Pfizer Inc. Macugen's new drug application is pending at the FDA.

Such drugs "don't work by antisense, but they validate the specificity and power of nucleic acids," Weintraub said.

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