BETHESDA, Md. - Patients and oncologists alike praised the ability of Corixa Corp.'s Bexxar to treat lymphoma with little to no side effects and possible long-term refractory periods in certain patients.
Following years of legal maneuverings and a contentious relationship with the FDA, the company's drug appears headed for approval, following a recommendation Tuesday from the Center for Drug Evaluation and Research's Oncologic Drugs Advisory Committee.
"We're very excited about the results of the meeting," Cindy Jacobs, senior vice president of clinical research at Corixa, said afterward. "We'll work closely with the FDA on any additional information the FDA requires."
ODAC heard first from nine people who testified to the drug's efficacy in treating cancer patients. "One pill a day is better than death," said Patricia Bashaw, a clinical trial patient from Brookfield, Wis., who asked that the committee recommend the treatment as an alternative to existing treatments. She cited the lack of side effects, and her fear of the toxic effects of chemotherapy, which is the only treatment left available to her.
Approval of Bexxar (tositumomab and iodine-131 tositumomab) is being sought by Seattle-based Corixa as a radioimmunotherapy for the treatment of low-grade or transformed low-grade non-Hodgkin's lymphoma (NHL). The company asked for accelerated approval last year for the indication based on long-term durable responses of five to eight years, as well as conventional approval for rituximab-refractory patients.
"It's important to note, especially after hearing from patients, that this drug's approval is not a bureaucratic issue as some analysts are suggesting. Unfortunately, we can't always tell the public why it's taking so long to get a drug approved," Jay Siegel, outgoing director of the Office of Therapeutic Review and Research in CBER, told the panel before hearing from FDA staff who reviewed the drug.
The FDA panel voted on four questions presented by the FDA focused on Bexxar's safety and efficacy data. The panel agreed on the first question, in a majority vote, that there was substantial evidence of clinical benefit in patients with rituximab-refractory follicular NHL. The vote also provided insight into the committee's distinction in conventional and accelerated approvals. The 10-3 vote showed that the committee favored a conventional approval in this group of patients.
For chemotherapy-refractory patients with low-grade and follicular NHL, addressed in a second question, the panel unanimously agreed that the drug proved beneficial.
The third question involved long-term response to Bexxar and Corixa's rationale for retrospectively including patients with a response of at least one year. Siegel, in an unusual move, withdrew the question following debate over being asked to interpret whether the drug was better than existing treatments.
"The available choices aren't that good," said John Carpenter, professor of medicine in the division of hematology and oncology at the University of Alabama at Birmingham, who added that Bexxar may not be the best choice but is a better choice than nothing.
There are several issues attributing to the lengthy approval process for Bexxar, and Corixa has worked closely with FDA staff in responding to those issues, he added. One issue was the manufacturing history of the drug, which has involved three different facilities. The FDA had to abstract data from several clinical trials as well as four to five amendments dating back to the early 1990s, noted Siegel.
There are 15,000 new cases of low-grade NHL each year in the U.S., according to the Atlanta-based American Cancer Society, noted Richard Fisher, assistant professor and chief of the department of hematology and oncology at the University of Rochester in Minnesota. Fisher was one of the principal investigators involved in the clinical trials. "Unfortunately with this chronic disease, there's no uniform treatment regimen, and conventional treatments, such as chemotherapy or bone marrow transplantation, usually offer short-term refractive periods," he said.
The rationale behind Bexxar's modality is that it targets radiation directly to the tumor, and iodine has a long established safety record in this country, explained Fisher. Patients receiving Bexxar are first treated with a dosimetric infusion followed by a therapeutic infusion within seven to 14 days, he explained.
Corixa presented efficacy data on a total of five studies involving 229 patients that showed "consistent results," Corixa's Jacobs said. Response rates ranged from 20 percent in chemo-refractory patients to 30 percent in rituximab-refractory patients.
Safety data were presented on more than 620 patients, with 89 percent of patients reporting some form of adverse event, with the most common being fever and nausea.
A total of 19 patients reported myelodysplasia or acute leukemia, but six were excluded based on further review that found that the condition existed before the Bexxar treatment, said Jacobs. "As of September of this year, an additional five cases have been reported as part of the expanded-access trial," she added.
Despite the accolades early in the meeting, FDA review staff cited safety concerns with Bexxar, particularly with toxicities. Toxicities included neutropenia, thrombocytopenia and anemia, Stephen Litwin, medical reviewer in CBER, told the panel. Additional toxicities within 90 days of treatment included infusion reactions, which occurred in roughly half of patients and in some instances were severe, and gastrointestinal toxicity, most likely due to binding to healthy CD20 cells.
In addition to the short-tem toxic effects, hypothyroidism was cumulatively observed in 30 percent of patients five years following treatment and 45 percent of patients seven years following treatment.
The panel's decision is the culmination of a rocky relationship between Corixa, it's partner GlaxoSmithKline plc, of London, and the FDA. Earlier this year, Corixa appealed FDA's complete review letter to not approve Bexxar. An appeal was granted in June and subsequently Corixa submitted a response to the FDA's review letter in October, countering the agency's allegations that the company failed to provide sufficient evidence of safety and clinical benefit. (See BioWorld Today, March 14, 2002; May 16, 2002; and June 28, 2002.)
Bexxar is an antibody specific to the CD20 antigen on B cells conjugated to radioactive iodine-131. It attaches to a protein found only on the surface of B cells, including non-Hodgkin's lymphoma B cells.
Corixa's stock (NASDAQ:CRXA) gained 27 cents to $7.25 Tuesday before trading stopped for the panel meeting.