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To some people, Genta's Genasense looks like an important step forward in the treatment of some dreadful diseases. To others, it's a drug with questionable efficacy and serious drawbacks. Now Genta is in the tense situation of waiting for two major regulatory agencies
-- the U.S. FDA and Europe's EMA -- to show how they feel about the
compound.
In the United States, the drug is up for approval in treatment of relapsed or refractory chronic lymphocytic leukemia (CLL). In Europe, Genta is going for approval in advanced melanoma. In both cases, the drug is given in combination with other, standard therapies. Genasense (oblimersen sodium) is an antisense oligonucleotide targeted against BCL-2, which is a major inhibitor of apoptosis (see Hot
Targets. The drug is supposed to work by making tumor cells sensitive to
chemotherapy.
The FDA has already had one look at Genasense a couple of years ago, when Genta applied to market the drug for treatment of advanced melanoma in the United States. That submission included data from the largest clinical trial ever done in this disease. But the drug had failed to meet its main end point
-- a specific gain in survival. Genta scientists argued that it had at least made a significant difference in disease progression. When an Oncologic Drugs Advisory Committee (ODAC) reviewed that data back in May 2004, they were simply not convinced any positive effects outweighed the side
effects.
Genta is now resubmitting that melanoma trial data to the EMA, with some important changes and additions. For one thing, they have followed some of the patients out much further. Looking back, says Genta CEO Raymond Warrell, it was
"a big weakness to specify an event-driven analysis in a disease that is characterized by high mortality." The first study was designed with an endpoint of 500 patient deaths: Genta researchers expected the survival curves for the responders and nonresponders to start diverging early. That didn't happen. Instead, the study mortality endpoint was reached before any effect could be seen in the long-term survival
curves.
This time, with more survivors included in the data, the drug's effect is much clearer, according to
Warrell. "We can now show the drug really extended progression-free survival," he says. Even better, the response is even clearer in a subgroup of patients
-- those with normal serum lactate dehydrogenase (LDH) levels. Looking just at that group, patients taking only the standard therapy (dacarbazine) lived an average of 9.7 months, while those also on Genasense as adjunctive therapy lived 11.4 months. Those data were statistically very
significant.
But according to Brian Rye, an analyst at Janney Montgomery Scott, the melanoma approval is still questionable because that study's primary end point was still not met even with the extended analysis. Approval, he says, will likely depend on how much unmet need there is in the disease. However, Rye believes the CLL data being submitted in the United States sounds promising:
"They did hit [that] primary end point the first time out," he says. Overall, then, Rye sees Genasense as
"an approvable drug."
Because it is the only antisense product currently near market, Genasense's future will impact the entire field. The first and last antisense-based drug approved so far is Isis'
Vitravene, an eye disease treatment that reached the market several years ago. Since that time, there have only been a string of
failures.
The stakes are highest for Genta, of course.
"Given what happened two years ago [with FDA submission], we think it is better to let the company prove itself than give it the benefit of the doubt," says
Rye.
Related
Links
www.PharmaWeek.com
Genta's Raymond P. Warrell on getting Genasense to
market
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