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By Malorye A. Branca

June 17, 2004 | Despite completing the largest melanoma clinical trial ever attempted and landing one of the biggest deals in biotech history, Genta watched its hopes for Genasense get neatly torpedoed by a pair of soft-spoken FDA statisticians on May 3. The pair deconstructed the case for Genasense, pointing out critical weaknesses in how the Phase III trial data were analyzed. Its star compound won’t be approved by this summer as hoped, but Genta has not given up and is mustering all of its resources to try and get the drug back on track for approval.

Just days before the May 3 Oncologic Drugs Advisory Committee (ODAC) meeting on Genasense, the FDA posted a brief that raised doubts the drug would be approved.  Pivotal data from the Phase III trial “could be falsely positive,” the reviewers wrote.

Genta and partner Aventis, which paid about $480 million for rights to co-develop Genasense, weren’t even claiming the drug extended lives -- the trial’s main goal. Instead, the companies sought approval based on other effects. Genasense, they said, at least shrank tumors or stemmed their growth in some patients. 

“Statistical Integrity”
The trial data suggested only about 10 percent of patients reaped such benefits from Genasense. Given the typically inexorable progress of this deadly disease, that could still be worth FDA approval, if true. Some physicians and patients involved in the study showed up to vouch for the drug. “Patients value responses,” one of the physicians said. Genasense, he argued, might give some patients “an extra visit to the oncologist without being told their disease is progressing.”

The company also played heavily on new information: A handful of patients who took the drug improved dramatically after the trial’s end, suggesting that in some patients it works extremely well. But it took longer than expected to see those “complete” responses, so those data were not part of the original application and have not yet been confirmed by the FDA, according to Genta spokesperson Joy Schmitt.

By missing the trial’s primary goal of extending life, the companies raised the burden of proof. “You can win on secondary endpoints,” said the FDA’s Richard Pazdur, director of the Division of Oncology Drug Products, “but there are important issues of statistical integrity.” In Genasense’s case, the statistics ultimately outweighed even the living. “The patients who are here must be surprised that based on modeling, they shouldn’t be,” commented one reviewer, speaking of the handful of patients who appear to be “late responders” to the drug. FDA statisticians showed that the small improvements Genasense seemed to confer could simply be an artifact of how the data were collected and analyzed.

It was even more difficult to judge the drug’s performance because it was given in combination with another standard melanoma treatment -- dacarbazine (DTIC).  “One has to look at the total denominator and ask whether those ‘responses’ would not have happened just with DTIC,” Pazdur said. The drug must also be given through an intravenous line over several days. “As one ODAC member pointed out, this is not a nontoxic pill,” Pazdur added.

The panel voted overwhelmingly against recommending approval.

Just days after the ODAC meeting, Genta appeared to be pressing its case.  “We will work with the FDA,” Schmitt said at the time. 

But by mid-May, that changed. Genta announced it would withdraw its application and restructure to focus all its resources on rescuing Genasense. The company cut more than 80 jobs, and will stop marketing its only commercial product: injectable gallium nitrate (Ganite). 

Major questions remain about Genasense. One of the most important involves that group of apparent “late responders.” A small subset of patients with great responses was enough to get AstraZeneca’s Iressa approved, and scientists recently uncovered a rare genetic effect explaining that phenomenon. Genasense theoretically acts by downregulating the gene BCL2 (see Minority Report, page 6), but it’s not clear that explains the drug’s activity, and BCL2 levels were not measured in the Phase III trial.

Genta’s best hopes may rest on data from some of the many other trials being conducted on the drug. “Genasense is the focus of more than 20 clinical trials in a variety of tumor types,” Schmitt said. The company plans to analyze data from other recently completed trials by the second half of 2004.

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