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Sep 11, 2006
 |  BioCentury  |  Product Development

No renaissance for Genasense

While the pace of discussion about adaptive trial designs has been accelerating, drug developers may be looking for concrete motivations to actually take the risk of innovating in the clinic.

Although the topic did not come up at last week’s meeting of FDA’s Oncologic Drugs Advisory Committee, it is clear that adaptive trials, especially when benefits are restricted to a small subpopulation, might nudge cancer drug development away from the conflict over the value of modest response rates that has caused several late-stage failures.

Indeed, ODAC shot down Genasense oblimersen and its sponsor, Genta Inc., with the same bullet it has used a number of times in recent years: the argument that low response rates are not compelling, especially when the sponsor fails to demonstrate a correlation between response and a clinical endpoint.

Once again, ODAC split between a minority who feel that progress against cancer will be made through modest incremental advances and a majority who are more concerned that small response rates may be spurious or that possible benefit to a fraction of patients is outweighed by adverse effects suffered by a much larger population (see BioCentury, May 9, 2005, & Dec. 6, 2004).

GNTA (Berkeley Heights, N.J.) is seeking accelerated approval of Genasense, an antisense compound that down regulates Bcl-2, a protein that is believed to block apoptosis, for treatment of chronic lymphocytic leukemia (CLL) in patients who are refractory to or have relapsed after therapy with fludarabine. Bcl-2 is thought to confer resistance to chemo- and radiation therapy.

Unconvinced

Last week’s meeting was GNTA’s and Genasense’s second encounter with ODAC. In 2004, the committee voted 13-3 that the company failed to provide substantial evidence of the effectiveness of Genasense in treating advanced metastatic melanoma. The company’s Phase III trial failed to meet its primary endpoint, although it demonstrated a significant improvement in progression-free survival, a secondary endpoint (see "Genasense Chronicles," A6)"

GNTA withdrew the NDA for the indication (see BioCentury, May 10, 2004).

This time, GNTA’s Phase III trial in CLL achieved its primary endpoint. But FDA argued the endpoint may have been wrong, and that the failure to hit any of the secondary endpoints cast doubt on the robustness of the result.

Following GNTA’s Phase I/II trial in CLL, in 2002, FDA recommended a time-to-progression (TTP) comparison of the two arms as the primary endpoint for the company’s planned randomized Phase III trial comparing fludarabine and cyclophosphamide to the two chemotherapies plus Genasense.

GNTA, however, opted for a combination of complete response (CR) and nodular partial response (nPR) as the primary endpoint, with overall response rate (CR + nPR + PR), survival, TTP, duration of response and a composite of six measures of "clinical...

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