By Mary Welch

The FDA requested that Coulter Pharmaceutical Inc. and SmithKline Beecham plc modify their biologics license application (BLA) for Bexxar, submitted last month for the treatment of relapsed or refractory low-grade or transformed low-grade B-cell non-Hodgkin's lymphoma.

"Obviously, we're disappointed in their decision and will work quickly to get the BLA back on track," said Michael Bigham, Coulter's president and chief executive officer. "We expect that we'll be able to get everything together by mid-October, and hopefully get approval around April of next year. It really is a modest request."

Investors quickly penalized the company for the delay as Coulter shares (NASDA:CLTR) fell 32 percent Monday, or $10.937 per share, to close at $23.50.

The companies submitted the BLA in early July and expressed confidence that Bexxar (iodine-131 tositumomab) could be approved and on the market by year's end. At the time of the filing, one analyst estimated Bexxar could be a $400 million drug within the next three to five years. (See BioWorld Today, July 1, 1999, p. 1.)

"We're trying to understand what they want and we see the principal portion of their fax to us being a request for formatting changes of data," Bigham said. "They are requesting an easier database access and we'll be happy to provide it now."

Another item was a small clarification as a result of a computer glitch. "One descriptor fell off," Bigham said. "That's an easy correction."

The FDA also wanted a reorganization of the analysis, although there was no request for additional data from ongoing trials or any demand for new trials.

"In one section, they wanted a different way of looking at the data. We gave them several ways but they wanted a few more. It's not a problem," Bigham said. In another section, the FDA wanted more radiographs and images on non-critical organs. "Again, we have all that."

Bigham estimated it will take South San Francisco-based Coulter about two to three weeks to gather the data and then another couple of weeks to reorganize the filing.

"The filing was 55 boxes," he said. "I don't know how many pages that is but reformatting and making sure that everything is in sync, is a logistics challenge."

"We're disappointed and it sets back the timetable by at least four months," said Thomas Dietz, managing director of research at Pacific Growth Equities Inc. in San Francisco. "It's a bit unusual because they seem to be more procedural issues. The FDA isn't requesting any new trials, no new data from the existing trials. There are no safety and efficacy issues being addressed and nothing on manufacturing, which we thought could be the one point where the FDA could hound them."

Dietz said he is "baffled" by the actions. "I came to the quick conclusion that the FDA was trying to buy a little time," he said. "I think they have so many priority review applications that they just needed a little extra time. The basis of the FDA's comments seem so trivial that one would have expected them to be addressed during the review sessions rather than up front before accepting the BLA. It seems more like a delaying tactic than the FDA having actual issues with the filing."

The FDA's action is having a short-term effect on Coulter's bottom line. As part of its $132 million deal with London-based SmithKline Beecham, Coulter is to receive several million dollars when the BLA is accepted and additional money upon approval. (See BioWorld Today, Dec. 12, 1998, p. 1.)

"This action delays two milestones," Bigham said. "The money we were expecting for the BLA acceptance won't occur this quarter, and the approval milestone, which was expected for the end of the year, has been moved to second quarter 2000."

Bigham said SmithKline "clearly remains enthusiastic about the filing and Bexxar. We're working together to get the refiling finished."

The BLA is based on data on 432 non-Hodgkin's lymphoma patients who had received a variety of other treatments before receiving Bexxar. Of those patients, 58 percent remained free of disease progression. (See BioWorld Today, June 8, 1999, p. 1.)

Bexxar is a radioimmunotherapy involving an antibody specific to the CD20 antigen on B cells, which is conjugated to iodine-131 and attaches to a protein found only on the surface of B cells, including non-Hodgkin's lymphoma B cells.

In the intravenous antibody approach, a treatment to determine proper dosage is given, and about a week later a therapeutic dose is administered. Conventional chemotherapy treatments are given over the course of several months.

It is believed Bexxar works though multiple mechanisms of action resulting in immune system activity of the monoclonal antibody and the therapeutic effects of the iodine radioisotope. With Bexxar's approach, the tumor cells receive a greater concentration of the therapeutic radiation relative to normal tissues.