NEWS

For Bexxar, FDA Meeting Offers Long-Awaited Chance at Approval

Ken Garber

Twelve years after it was first used to treat cancer patients, Bexxar (iodine 131 tositumomab) has finally arrived on the doorstep of the U.S. Food and Drug Administration. On Dec. 17, the FDA’s Oncologic Drugs Advisory Committee will consider Bexxar for the treatment of patients with relapsed or refractory low-grade or transformed low-grade B-cell non-Hodgkin’s lymphoma (NHL).

It has been a long and frustrating journey for the drug, which is an I-131-radiolabeled monoclonal antibody. The original biologic license application for Bexxar was submitted in June 1999, but the FDA has repeatedly sent it back, and in March 2002, the agency demanded new clinical trials.

The drug’s sponsor, Corixa Corp., based in Seattle, Wash., filed a successful appeal and the path is now clear for approval—or rejection. But should the FDA clear Bexxar for marketing, the drug faces stiff competition from IDEC Pharmaceuticals’ Zevalin (yttrium-90 ibritumomab tiuxetan), a yttrium-radiolabeled antibody that was approved in February and is now on the market.

The FDA’s interactions with Bexxar have become one of oncology’s great political mysteries and one that has no obvious explanation. Zevalin, on the other hand, was quickly approved. Why one and not the other? "I don’t know," said Sally DeNardo, M.D., professor of internal medicine and radiology at the University of California at Davis. "And neither do most of [my] colleagues around the country and the world." Bexxar, DeNardo pointed out, is also clearly effective against a cancer that badly needs new treatments.

For the incurable relapsed "low-grade" forms of lymphoma, there has been no major improvement for three decades. Patients given chemotherapy typically go into remission but invariably relapse, with each subsequent chemotherapy-induced remission lasting a shorter and shorter time. The 1998 introduction of Rituxan (rituximab), an anti-CD20 monoclonal antibody, provided a welcome alternative to last-ditch chemotherapy but only slightly altered the grim NHL survival curve.

Bexxar seemed to promise better. In a pivotal phase III trial involving 60 patients who had failed multiple chemotherapy regimens, the response rate was 65%, including 20% complete responses. These results were much better than patients’ most recent chemotherapy (28% response rate with 3% complete responses). Almost three times as many patients had a longer duration of response after Bexxar than after the last chemotherapy. "As a result of these data, clinicians and patients are eagerly awaiting the commercial availability of tositumomab," wrote Bruce Cheson, M.D., head of hematology at the Lombardi Cancer Institute in Washington, D.C., in an editorial last year in the Journal of Clinical Oncology. It has been a long wait.

Radioimmunotherapy for cancer has an even longer history. In the 1970s, doctors first treated cancer patients using polyclonal antibodies linked to iodine-131. Sally DeNardo and her husband Gerald DeNardo, M.D., used iodine-labeled monoclonal antibodies targeting the Lym-1 antigen to treat lymphoma patients beginning in 1985, obtaining some complete, long-term remissions.

In 1980, Lee Nadler, M.D., of the Dana Farber Cancer Institute in Boston, discovered an antigen, CD20, only found on B cells, and derived an antibody to the antigen. In the late 1980s, University of Michigan hematologist Mark Kaminski, M.D., and radiologist Richard Wahl, M.D., used Nadler’s antibody to kill tumors in animals. Seeking even greater potency, the Michigan group then conjugated anti-CD20 to I-131 to create what is now known as Bexxar.

It seemed a perfect marriage of drug and disease. Lymphomas are exquisitely sensitive to radiation, and a targeted radionucleotide seemed a perfect way to deliver radiation to tumors without excess toxicity. Lymphomas are also highly vascular, allowing easy antibody penetration. The CD20 antigen was a promising target, since it is anchored solidly in the cell membrane and does not get shed or internalized into the cell, where cellular enzymes could clip off and eject the iodine. Thus, radiation exposure lasts longer. The antibody also induces cell signaling that triggers apoptosis, while a "crossfire effect" exposes surrounding cancer cells lacking the antigen to lethal radiation.

California biotech company Coulter Pharmaceuticals provided the drug and sponsored clinical trials. Of nine patients treated, six responded, including four complete remissions. These phase I results, reported in 1993, seemed to put Bexxar on the fast track.

Subsequent trials highlighted Bexxar’s therapeutic potency. Phase I/II results showed Bexxar to be effective against the especially deadly low-grade and transformed non-Hodgkin’s lymphomas, with 83% of relapsed patients responding. Many were complete remissions lasting years. Tried as first-line therapy for low-grade follicular lymphoma, Bexxar had a 97% response rate and a 76% complete response rate. Bexxar also worked in patients who did not respond to rituximab therapy. Although Bexxar has not been tried head-to-head against Zevalin, Bexxar activity appears to be similar. And "there’s a longer track record with Bexxar [with] longer documented responses," noted Oliver Press, M.D., professor of medicine at the University of Washington, Seattle.

Yet Zevalin, whose biologic license application was filed 15 months after Bexxar’s, sailed through its FDA approval process while Bexxar has suffered continuous setbacks.

"They’ve had a devil of a time getting through the FDA, but no one seems to be able to figure out what the FDA doesn’t like about [Bexxar]," said stock analyst Paul Latta, of McAdams Wright Ragen in Seattle. The FDA returned Coulter’s 1999 application, requesting more data. Coulter’s second try the following year received a similar response. Corixa acquired Coulter in December 2000, and approval seemed imminent after Corixa’s new application was formally accepted in September 2001. Then, last March, the FDA sent Corixa a request for new clinical trials. The data "do not provide sufficient evidence that Bexxar addresses an unmet medical need," the FDA told Corixa, according to a Corixa press release. Corixa’s application "did not provide sufficient evidence of the safety and net clinical benefit of Bexxar."

"We were shocked," said Latta, who owns Corixa stock. "My personal feeling is it was not a safety, dosing, or efficacy issue, it was a bureaucracy issue or a process issue."

The FDA does not publicly comment on drug reviews, but its concerns about Bexxar will be thoroughly aired on Dec. 17. That may solve the mystery. "ODAC might well spell out what the real issue is," said Latta. "If there is anything funny about the drug that the company has not been forthright about, ODAC will find it."

Differences between Bexxar and Zevalin may or may not account for some of Bexxar’s problems. Iodine emits gamma radiation while yttrium does not, so there is some radiation exposure risk to caregivers and family members from Bexxar, although simple precautions have worked well during clinical trials. Bexxar is more likely to generate human anti-mouse antibodies, which can rule out repeat treatments with Bexxar and may also preclude Zevalin treatment. The incidence of myelodysplatic syndromes (MDS) is higher for Bexxar than for Zevalin, although it is impossible to know if MDS is treatment-related. But Bexxar seems slightly less toxic to bone marrow. And thanks to Bexxar’s gamma emissions, dosing can be precisely individualized based on patients’ clearance of the drug, whereas Zevalin dosing relies on body weight.

Given Bexxar’s mystifying past problems, no one is placing bets on the outcome of the meeting this month. "It’s a tossup at this point," said stock analyst Andrew Heyward of Ragen MacKenzie in Seattle.

Washington’s Press said he thinks Bexxar should be approved. "It’s a safe product that has shown efficacy, and it’s easier to use than a lot of the chemotherapy that we’re already using," he said. Sally DeNardo said she considers Bexxar fully as deserving as Zevalin to be made available to oncologists. "Both have shown efficacy in the appropriate clinical trials," she pointed out. "Why should they not both be approved?"



             
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