Washington Editor

Minus the Waksal brothers, ImClone Systems Inc. and Bristol-Myers Squibb Co. forged ahead and, as planned, filed a biologics license application for the investigational IgG1 monoclonal antibody Erbitux for metastatic colorectal cancer.

Specifically, the partners are seeking approval of Erbitux (cetuximab) in combination with irinotecan for the treatment of patients with epidermal growth factor receptor (EGFR)-expressing irinotecan-refractory metastatic colorectal cancer. The BLA includes a request for priority review and accelerated approval.

Certain reviewers and senior staff at the FDA are quite familiar with Erbitux and ImClone's former management, brothers Samuel and Harlan Waksal.

The brothers filed a rolling BLA for Erbitux in the fall of 2001, just after snagging a $2 billion partnership with New York-based BMS. Days after Christmas 2001, the FDA issued a "refusal to file" letter on the application. (See BioWorld Today, Jan. 1, 2003, and Sept. 20, 2001.)

Samuel Waksal, now serving a seven-year sentence on fraud and insider trading charges, had claimed the FDA refused the application because of the "train of documentation." Later, company management agreed to conduct additional clinical trials, including two Phase III studies currently under way. In the meantime, Samuel Waksal was sent to prison and his brother, Harlan, resigned.

So, with new management and a scandal in the past, will Erbitux have a chance this time?

Cory Kasimov, a biotechnology analyst with Ryan Beck & Co. in New York, believes so.

"I would suspect that this is one of the most detailed applications that's ever been turned in," Kasimov told BioWorld Today. "They're not going to make the same mistake twice."

As far as approval goes, Kasimov said, "When you take into account that this clearly is an active drug, it is a relatively safe product that is apparently going after an unmet medical need, and that these are patients with colorectal cancer who have failed standard of care, and you combine that with the friendlier environment at the FDA where there's an apparent willingness to approve products that are safe, effective and treating an unmet medical need - yes, we are confident that the drug will be approved this time around."

Representatives from New York-based ImClone could not be reached for comment, but Kathy Baum, a BMS spokeswoman, told BioWorld Today that the BLA filing is a significant milestone. She wasn't willing to estimate a timeline for approval. Instead, she stressed simply that the companies had sought priority review and accelerated approval.

Filing the BLA does not trigger a milestone payment for ImClone, Baum said.

If all goes according to plan, Erbitux could be approved in late 2003 or early 2004, Kasimov said. Ryan Beck & Co. estimates that Erbitux could "ultimately" reach blockbuster status with additional indications.

Meanwhile, company executives likely are to be on the edges of their seats over the next 45 days as the FDA determines whether it will accept the BLA. That, of course, is the step that tripped the Waksals in late 2001.

Kasimov added that it's unclear at this point whether the FDA's Oncologic Drugs Advisory Committee will be called to hear the case.

The BLA is based on a successful Phase II trial conducted by ImClone's European partner, Merck KGaA, of Darmstadt, Germany. The trial was reported on in June at the annual meeting of the American Society of Clinical Oncology in Chicago.

Referred to as Trial 007, the study looked at 329 patients with irinotecan-refractory colorectal cancer that expressed EGFR (usually a marker of fast advance). Merck said Erbitux in combination with irinotecan slowed progression of the disease by more than four months, shrinking tumors by 50 percent or more in 22.9 percent of patients. (See BioWorld Today, June 3, 2003.)

Merck filed the European application in July. (See BioWorld Today, July 8, 2003.)

ImClone's stock (NASDAQ:IMCL) closed Thursday at $40.23, up 46 cents.