NEWS

Biotech Firm Faces Challenges from FDA, Falling Stock Prices

Tom Reynolds

At the American Society of Clinical Oncology’s May 2001 annual meeting, researchers presented findings on a promising new drug, Erbitux, that offered hope for patients with colorectal cancer resistant to standard chemotherapy.

The drug, made by ImClone Systems Inc., New York, generated unusual excitement among researchers, patients, and investors and was featured on 60 Minutes and on the cover of Business Week.

Nine months later, the company has seen its stock price plunge, it is under three federal investigations, and it has been called the Enron of the biotechnology industry. Patients may have to wait years to reap the drug’s benefits while the U.S. Food and Drug Administration determines whether it has any.

Oncologists familiar with Erbitux (also known as IMC-C225 and cetuximab) say they have seen it work, and most expect it will gain FDA approval eventually. But several other drug makers have competing agents in the pipeline, and experts say ImClone is likely to lose at least some of its potential market share.

Erbitux is a monoclonal antibody that binds to and blocks activation of the epidermal growth factor receptor (EGFR), a molecule that is expressed on the surface of many solid tumors and is associated with increased metastasis and poor prognosis. Blocking EGFR inhibits tumor growth by interfering with tumor invasion, metastasis, cell repair, and angiogenesis.

The drug was developed around 1980 by John Mendelsohn, M.D., now president of the University of Texas M. D. Anderson Cancer Center in Houston and a member of ImClone’s board. Initially, C225 failed to generate commercial interest, and Eli Lilly and Company dropped its rights to the drug. Mendelsohn eventually found a commercial partner in ImClone, a struggling biotechnology company run by brothers Samuel Waksal, Ph.D., and Harlan Waksal, M.D., which had tried and failed to develop various products since 1984.

ImClone began clinical trials of the drug, and at ASCO 2001 a group led by Leonard Saltz, M.D., of Memorial Sloan-Kettering Cancer Center in New York, reported results from a phase II trial. Of 120 patients whose colorectal tumors had progressed on standard chemotherapy—including the newest approved drug, irinotecan (also called CPT-11)—22.5% had their tumors shrink when they got both irinotecan and Erbitux. Results were perceived to be so encouraging that in September the pharmaceutical powerhouse Bristol-Myers Squibb agreed to pay up to $1 billion for 19.9% of ImClone and another $1 billion for the marketing rights to the drug—the highest price a pharmaceutical company has ever paid for a biotech company’s product, according to the New York Times.

Hoping to capitalize on these findings, ImClone pursued accelerated approval for Erbitux. In the FDA’s fast-track approval program—successfully used for several cancer drugs, including irinotecan—drug makers submit phase II results to the agency, and, if these are convincing, the drug may be approved for sale, pending confirmatory phase III results. But ImClone made an unusual decision in designing its "pivotal" trial so that, in addition to the investigational drug, all patients continued to receive a drug to which they were labeled resistant.

"One would not think, in somebody who is truly refractory to CPT-11, that continuing CPT-11 is going to cause a response later," said Mace Rothenberg, M.D., a medical oncologist at Vanderbilt University, Nashville, Tenn. "Responses to CPT-11 are usually seen early." However, the company believes a synergistic effect might exist between the two drugs, producing responses better than either drug alone.

The company filed for FDA approval and, on Dec. 28, 2001, received a "refusal-to-file" (RTF) letter in reply, meaning the agency determined it was not possible to evaluate the drug’s merit based on the data presented. ImClone officials expressed shock, but president and chief executive officer Samuel Waksal said the problem was simply one of documentation and that the company could produce data that would satisfy the FDA.

The story jumped from medical news to the business pages after the Cancer Letter, an industry newsletter, published a Jan. 4 article detailing the contents of the supposedly non-public RTF letter. According to the Cancer Letter, the problems with ImClone’s trial were more extensive than Waksal had revealed, making it appear likely that the company would have to conduct new trials to satisfy the FDA. The company’s stock, which topped $70 a share in December, fell 20% after the RTF letter and began a sharper nosedive with the revelation of its details. (The price stood at $16.20 on Feb. 11.)

Adding to ImClone’s woes, the Subcommittee on Oversight and Investigations of the U.S. House of Representatives Committee on Energy and Commerce—the same committee probing Enron’s downfall—is investigating the company. Suspicions of insider trading were based on reports that the Waksals had sold large chunks of their stock before the price tumbled. The Cancer Letter reported that the Securities and Exchange Commission and the Justice Department had also launched investigations. Several class-action lawsuits have been filed against ImClone charging that the company hid bad news from investors.

In the RTF letter, the FDA wrote that ImClone’s trial "was not adequate and well-controlled," according to the Cancer Letter. The FDA said ImClone failed to show that patients in the trial had tumor progression on irinotecan before starting Erbitux—something that could be best shown on CT scans—and that the trial did not permit the effects of the two drugs to be disentangled. FDA also had concerns that ImClone presented no clear rationale for the dose of Erbitux that was used, and reported only three of 21 patient deaths.

ImClone’s trial design "was a somewhat risky strategy, because it was without real precedent in the United States," said Louis Weiner, M.D., chairman of the Department of Medical Oncology, Fox Chase Cancer Center, in Philadelphia.



View larger version (133K):
[in this window]
[in a new window]
 
Dr. Louis Weiner

 
"When we develop a new drug, particularly in patients who have received many prior treatments for cancer, we typically test it as a single agent in people who have clearly progressed on prior therapy and have had a 30-day or longer washout period," he explained. "Rather than stopping the chemotherapy, and after a suitable washout period treating the patients with [Erbitux], they added the antibody to irinotecan. ... It becomes very difficult to ascertain whether the antibody is truly adding anything to patient benefit." Conversely, as the FDA reportedly noted, it was also impossible to tell if Erbitux alone might work just as well without irinotecan.

The FDA reportedly warned ImClone in August 2000 that the company would have to present data that clearly separated the effects of the two drugs. In response, ImClone performed a smaller confirmatory trial of Erbitux alone, which Weiner took part in. But results were less impressive: Six of 57 patients (11%) showed a response.

Rothenberg, who has reviewed the RTF letter, said a nonrandomized, "open-label" trial such as ImClone’s demands a higher level of evidence for patient eligibility than a randomized trial would.

"With a randomized trial, you can rely on the assessment of the physician to say ‘this person has progressed’ and document that clearly in the records," he said. "And whatever influence [physicians’] personal preference or judgment might have would be equally distributed among the two or three or more treatment arms.

"But in the Erbitux trial, physicians and patients who enrolled knew that the trial allowed them to access an exciting new compound" so that "the onus shifts onto the investigators and the company to more clearly and convincingly demonstrate that this patient sample had refractory cancer. You really have to nail that down."

Rothenberg said the FDA likely wanted to see two CT scans on each patient before they got Erbitux—one showing the best response, if any, the patient had to irinotecan, and a subsequent scan showing tumor progression—and further scans showing a response to Erbitux. ImClone could have added an Erbitux-only arm to the trial, Rothenberg said, and "they tried to fill that gap by doing another trial, but because it wasn’t done concurrently and wasn’t randomized, that data is always going to be subject to some question."

According to Weiner, "Based on what was published in the Cancer Letter, it seems that FDA was very clear in telling ImClone what was needed, and for whatever reason it didn’t get done. Drug development is not easy, and not all companies are as well equipped to deal with it as they think they might be. There’s no doubt in my mind that [Erbitux has] potentially meaningful clinical activity," he added. "It’s a pity that it was not approvable."

Waksal has reportedly admitted that "mistakes were made" and said the company is discussing remedies with the FDA. An FDA spokesman said he could not comment on the ImClone case.

On Feb. 5, Bristol-Myers Squibb proposed a drastic restructuring of its agreement with ImClone, including sharp cuts in payments Bristol was to have made to ImClone and a provision that ImClone’s top executives step aside temporarily to let Bristol take the lead in getting FDA approval for Erbitux. Bristol’s influence is based not only on its 20% share but on the threat that ImClone stock could dive further if its big pharmaceutical partner bails out. ImClone rejected Bristol’s proposal in mid-February. Neither company would comment beyond its published statement.

An ImClone spokesperson referred questions to a representative from a New York public relations firm, who failed to return repeated phone calls from this reporter.

ImClone has several ongoing trials of Erbitux. They include phase III trials of the drug in combination with either cisplatin or radiation as first-line therapy for head and neck cancer, and phase II trials in combination with gemcitabine for pancreatic cancer and with carboplatin and paclitaxel for non-small-cell lung cancer.



             
Copyright © 2002 Oxford University Press (unless otherwise stated)
Oxford University Press Privacy Policy and Legal Statement