Washington Editor

Two firms scheduled to go before the Oncologic Drugs Advisory panel today took painful financial hits on Friday when FDA reviewers released unfavorable comments about their respective cancer treatments.

First up this morning is Genta Inc. and partner Aventis SA. The firms want FDA approval to sell Genasense (olimersen sodium) Injection in combination with dacarbazine to treat patients with advanced melanoma who have not received prior chemotherapy.

Genta's stock (NASDAQ:GNTA) fell $5.83 Friday, or 40.4 percent, to close at $8.60.

Meanwhile, Allos Therapeutics Inc. (NASDAQ:ALTH) fell $2.09 Friday, or 45 percent, to close at $2.55, in response to an FDA briefing document discussing RSR13 (efaproxiral), a synthetic small molecule proposed for use as an adjunctive therapy to whole-brain radiation therapy (WBRT) for brain metastases originating from breast cancer.

Genasense Misses Primary Endpoint, Shows Benefit

Genasense is an antisense cancer compound that targets the Bc1-2 protein to boost the effectiveness of chemotherapy. FDA reviewers criticized the single, randomized, open-label study submitted as the basis of the Genasense new drug application.

The NDA centers around a 771-patient Phase III trial that missed its survival (primary) endpoint, but revealed a positive trend among advanced melanoma patients, Genta said. Participants, all of whom were chemotherapy-na ve, were randomized to receive Genasense plus dacarbazine, or dacarbazine alone. (See BioWorld Today, Sept. 11, 2003.)

Specifically, the agency said: "Any claims of improved efficacy based on secondary endpoint, progression-free survival and antitumor response rate are questionable because of the open-label nature of the study, missing data and differences in assessment interval between the two treatment groups. The findings could be falsely positive, especially in view of the lack of confirmation by a second well-controlled and well-conducted trial."

Joy Schmitt, spokeswoman for Berkeley Heights, N.J.-based Genta, told BioWorld Today the firm would not comment in advance of the meeting.

Phase III trial data demonstrated a 25 percent improvement 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 to 8.1 months for dacarbazine alone (p=0.035). Analysis of all patients in the treatment arm showed a median survival of 9.1 months, compared to 7.9 months for patients on chemotherapy alone (p=0.184).

Genta and Aventis hope the FDA will grant approval based on favorable secondary endpoints, including tumor response and progression-free survival. Specifically, patients in the treated group achieved an antitumor response rate of 11.7 percent, compared to 6.8 percent in the chemotherapy group (p=0.019).

Meanwhile, treated patients showed an increase in median progression-free survival to 74 days vs. 49 days in the chemotherapy group (p=0.001). Aventis, of Strasbourg, France, signed on as Genta's partner two years ago in a deal valued at $480 million. So far, Genta has collected about $250 million and is poised for another milestone on approval 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. Under guidelines established in the Prescription Drug User Fee Act III (PDUFA III), the FDA is compelled to take action on the application on or before June 8.

Allos Seeks Approval On Non-Prespecified Subset

RSR13 increases the release of oxygen from hemoglobin, which is important in treating hypoxia in connection with radiation treatments for cancerous tumors. It is designed to make radiation therapy more effective.

Allos' Phase III trial evaluating RSR13 in 538 patients suffering from brain metastases that had originated from different types of cancer revealed improved life expectancy in the breast cancer population, the company said. (Specifically, 56 percent of participants had non-small-cell lung cancer [NSCLC], 21 percent had breast cancer and 23 percent had other cancers.)

Median survival time in breast cancer patients with brain metastases showed a near doubling, from about 4.6 months in the control group to 8.7 months in the treatment arm, the company said. That subset included 115 patients. (See BioWorld Today, April 23, 2003, and Nov. 18, 2003.)

The briefing document notes that the Phase III trial demonstrated no statistically significant difference in survival between the two study arms, and that the breast cancer population represents a non-prespecified subgroup "which should be considered exploratory."

But Michael Hart, president and CEO of Westminster, Colo.-based Allos, contended that there is clear benefit in the breast cancer population.

"If there is a drug out there that can nearly double survival, then that drug ought to be approved," he said. "In the breast cancer subgroup, we had a 90 percent improvement in median survival." RSR13 has fast-track and priority-review status in the breast cancer indication.

"[The FDA is] saying that breast cancer was a non-prespecified subgroup and I think the FDA is going to spend a lot of time kind of laying out why they don't believe subset analysis should be considered as a basis for approval," Hart told BioWorld Today. "That's really where this is heading, in terms of potentially setting a precedent for the industry."

While he agreed that subset groups can be ambiguous, Hart said the case with Allos' RSR13 Phase III is different.

"Breast cancer, for the purposes of a subset analysis, is treated as an intent-to-treat group, so it is very different from prior trials where sponsors have tried to get approval based upon subset analyses," he said.

Allos' PDUFA date is June 4. In the Phase III trial, patients receiving RSR13 plus WBRT experienced a 17.6 percent improvement in median survival, compared with patients receiving WBRT alone (about 5.3 months vs. 4.5 months; p=0.17; n=538). In the intent-to-treat group of patients with brain metastases from only breast cancer and NSCLC, patients receiving RSR13 had a 32.4 percent increase in median survival vs. control (about 5.9 vs. 4.5 months; p=0.12; n=414).

Also, the company said there was a 48 percent increase in median survival among patients in the breast cancer and NSCLC intent-to-treat subgroup who were diagnosed with their original cancer before they were diagnosed with brain metastases and were treated with RSR13 plus WBRT (about 6.6 months vs. 4.5 months; p=0.003; n=273).