Washington Editor

GAITHERSBURG, Md. - On failing to demonstrate efficacy in the survival endpoint, the Oncologic Drugs Advisory Committee Monday recommended against Genta Inc.'s new drug application for Genasense, a treatment for advanced melanoma.

In a 13-3 vote, the panel said small improvements in tumor response rates and progression-free survival, as shown in the pivotal Phase III trial, do not warrant approval given the increased chance of toxicity. The FDA is not bound by the panel's recommendation.

Meanwhile, Genta, of Berkeley Heights, N.J., and partner Aventis SA, of Strasbourg, France, anticipate FDA action on or before June 8, the Prescription Drug User Fee Act III date.

Specifically, the partners are requesting approval of Genasense (olimersen sodium) Injection in combination with dacarbazine (DTIC) for the treatment of patients with advanced melanoma who have not received prior chemotherapy.

While Genta's 771-patient pivotal Phase III trial didn't show statistical significance on the survival endpoint, the firm filed its new drug application based on favorable secondary endpoints - tumor response and progression-free survival.

Patients in the treated group achieved an antitumor response rate of 11.7 percent, compared with 6.8 percent in the chemotherapy group (p=0.019). Meanwhile, treated patients showed a significant increase in median progression-free survival to 74 days vs. 49 days in the chemotherapy group (p=0.001), according to data from a last observation. (See BioWorld Today, Sept. 11, 2003.)

Indeed, Frank Haluska, an FDA reviewer, told panel members that Genasense is a novel drug with a unique mechanism of action that works when combined with DTIC.

"This is not a home run, but it does make incremental progress and I think that is important," said Haluska, a physician who treats melanoma patients.

In an 11-5 vote, the panel said differences in the response rates represented a real effect of the combination therapy, but in a 12-4 vote, the panel said differences in progression-free survival (median 13 days, p=0.006, calculated using a different statistical method) did not represent real effects of the combination therapy.

Michael Bishop, a panel member and physician with the National Cancer Institute of the National Institutes of Health, questioned whether approving Genasense on secondary endpoints would open the agency up to future approvals on such data.

In its presentation, the agency raised the case of an application similar to Genasense. The situation involved temozolomide (TMZ), also for the treatment of metastatic melanoma. Like Genta's, the TMZ application contained a Phase III trial in which the median survival on the DTIC arm was 6.4 months vs. 7.7 months for TMZ, a difference in median survival of 1.3 months.

TMZ (a single agent; Genasense is used in combination with DTIC) was not recommended for approval because the trial did not show superiority in survival to DTIC alone. The small but statistically significant difference in progression-free survival (p=0.002) and slightly higher response rate, in the absence of survival or symptomatic benefit, were not thought to represent a meaningful benefit, according to the FDA.

But Gregory Reaman, a panel member and oncologist at the George Washington University School of Medicine in Washington, said he's sorry TMZ was even brought up as a part of the Genasense discussion. He added that ODAC was between a rock and a hard place because once again it was being asked to make a decision on weak data.

But in a unanimous vote, the panel said it believed that a progression-free benefit of some magnitude did represent clinical benefit that could support regular drug approval, even in the absence of an effect on survival.

Malignant melanoma, if detected in an early stage, is usually curable surgically. However, locally advanced or metastatic disease usually is not resectable or curable and almost always is fatal. For the treatment of locally advanced or metastatic disease, physicians have used chemotherapy, immunotherapy or biochemotherapy, the FDA said.

Genasense is an antisense cancer compound that targets the Bc1-2 protein to boost the effectiveness of chemotherapy. Trial data demonstrated a 25 percent improvement rate in treated patients who finished the minimum follow-up of 12 months (n=480). Specifically, the median treatment arm survival rate was 10.1 months, compared with 8.1 months for DTIC alone (p=0.035). Analysis of all patients in the treatment arm showed a median survival of 9.1 months, compared with 7.9 months for patients on chemotherapy alone (p=0.184).

The Phase III was sized to demonstrate improvements in survival from six months with dacarbazine (DTIC) alone to eight months for the combination. A total of 771 patients were enrolled from nine countries: 56 percent from the U.S., 11 percent from Australia and the remainder from Europe and Canada. The majority of patients went off the study after six weeks (two cycles) because of progressive disease.

The data package also included a supporting trial described as a single-center, single-arm, Phase I/II open-label, dose-escalation trial involving 33 patients who received variable doses of Genasense and DTIC.

Aventis signed on as Genta's partner in the development of Genasense two years ago in a deal valued at up to $480 million. So far, Genta has collected about $250 million and would get another milestone on approval of the candidate in the first indication. (See BioWorld Today, April 30, 2002.)

The companies would co-promote Genasense in the U.S. Aventis owns the rights in other parts of the world.

In advance of the meeting, FDA reviewers released a briefing document unfavorable to the Genasense new drug application. As a result, the firm's stock (NASDAQ:GNTA) fell $5.83, or 40.4 percent, Friday to close at $8.60. After trading resumed Monday, the stock fell another $3.49, or 40.6 percent, to close at $5.11.