Erbitux Oncologic Potential Endorsed By FDA, Bristol During House Hearing

ImClone's oncologic agent Erbitux is "an active anticancer agent," Bristol-Myers Squibb and FDA Oncologic Drug Products Division Director Richard Pazdur, MD, agreed during a June 13 Energy & Commerce/Oversight Subcommittee hearing.

"I think that this drug has shown some activity," Pazdur said. "Its life-story is just beginning."

"When we see activity in terms of tumor shrinkage in heavily pretreated patients, that gives us the initial signal that there is something there to further develop," Pazdur said. "What needs to be done is obviously to show that this drug works....That is being done now."

Erbitux is a "good drug" held back by a "bad development plan," he declared.

Pazdur's comments echoed the position of Bristol during the hearing and in recent investor presentations. Bristol continues to believe that Erbitux is "an active anticancer agent," Senior VP-Global Regulatory Sciences Laurie Smaldone, MD, told the committee.

The House hearing follows an investigation into the circumstances surrounding FDA's refuse-to-file letter for the Erbitux BLA, issued in December (¹ , p. 6).

The drama of the hearing was enhanced by the arrest of former ImClone CEO Sam Waksal the day before the hearing on charges of insider trading. Waksal appeared before the subcommittee June 13 and invoked his Fifth Amendment right against self-incrimination.

The build-up to the hearing, however, also served to provide a high-profile forum for Bristol to declare its continued belief in the potential for the agent.

The importance of Bristol's endorsement of Erbitux was underlined by Rep. Richard Burr (R-N.C.). "It is extremely important that we listen very closely to BMS because they apparently saw something that was worth a tremendous amount of money...and my understanding is that their hopes have not changed," Burr said.

"If their hopes have not changed then our hopes have not changed that there may be a key that unlocks something here," Burr said.

Bristol's Smaldone highlighted the drug's action in patients with late stage colorectal cancer, who are unresponsive to other therapies. "These are patients who otherwise have few treatment options available to them," Smaldone said.

For those patients for whom the "prognosis is grim," Erbitux could provide "additional time with family," Smaldone told the committee.

"It is important for the committee to understand" that advanced refractory colorectal cancer "is particularly insidious," she said. "It is important, in the midst of all the important issues identified, that we work together and make Erbitux available to patients as quickly as possible."

"Some patients have been able to benefit from Erbitux in clinical trials and compassionate use programs," Smaldone said. However, "we know that only after approval and commercialization will all those who truly need the drug actually get it, and will physicians be able to further evaluate its role in different clinical settings."

Bristol delivered the same message in a different forum June 13, when Exec VP Donald Hayden addressed a Goldman Sachs conference in Laguna Niguel, Calif.

"I think it is unfortunate, in the external events that have swirled around the product, that the focus has occasionally been lost on what the product provides," Hayden told analysts.

Erbitux has a "good safety profile," Hayden said. The Bristol exec also highlighted data presented at the recently concluded American Society of Clinical Oncology meeting.

"In addition to the encouraging data that we saw early in refractory colorectal cancer, we have recently seen at the ASCO meeting encouraging data in a number of tumor types in head & neck cancer and non-small cell lung cancer and pancreatic cancer." Erbitux "could be an important part of combination therapy in a number of different tumor types as we move into the future," Hayden said.

Hayden highlighted the I.V. formulation of Erbitux as one advantage for the product over other drugs in the epidermal growth factor receptor class. "It is an I.V. product, which is an important point on distinction from some other epidermal growth factor receptor products, and provides convenient weekly dosing on an I.V. basis," Hayden said.

AstraZeneca's Iressa , which belongs to the same class as Erbitux, is an oral formulation. Hayden's reference to dosing as a point of distinction presumably has an eye towards Medicare reimbursement, which would be simpler for the I.V. product.

During the hearing, FDA's Pazdur presented an extensive analysis of what he felt went wrong in the Erbitux development effort.

The FDAer noted that he was not involved in the review of the BLA, which was handled by the Center for Biologics Evaluation & Research. He was joined at the witness table by four CBER reviewers who did handle the application (² (Also see "ImClone Erbitux Hearing Will Include Five FDAers Under Subpoena" - Pink Sheet, 10 Jun, 2002.), p. 14).

"The whole development of this drug...put the drug in very serious regulatory jeopardy and violated principles of medical oncology," Pazdur declared.

"First of all," Pazdur said, the clinical trial program had "a heavy reliance on preclinical activity, and preclinical design is based on animal models."

"We know that animal models can give us an inkling or suggestion of where to go, but to conduct a whole development plan, and a sole development plan, on an animal model is a very risky venture," Pazdur said.

Secondly, Pazdur said, ImClone's pivotal study involved adding Erbitux to irinotecan (Pharmacia's Camptosar ), even though patients enrolled were refractory to the Pharmacia agent.

"They are asking patients to continue a drug, irinotecan, after they have progressed or after their tumors have gotten larger on this," Pazdur said. "This violates every principle that I know in medical oncology and in order to do that you better have very good evidence that that is the thing to do here before you go ahead and just do it."

"The drug irinotecan is a fairly toxic drug, and in the original registration trials for that drug there were at least 3%-5% patient deaths, as well as about a 20% hospitalization rate for toxicity related to irinotecan," Pazdur noted.

ImClone's position was that Erbitux is not active as a single agent, the CBER representatives told the subcommittee. However, CBER concluded after reviewing the data file that ImClone had not sufficiently demonstrated that.

ImClone therefore conducted a single-agent trial of Erbitux intended to show that it is not active as a standalone; such a finding would have supported the company's pursuit of a combination claim.

"In order for that to work you had to have a 0% almost in the single-agent Erbitux study," Pazdur noted. "In essence, they were betting against their own drug to get the combination approved, which is a very faulty design."

"If they really believed that they needed the confirmation, they needed to do a randomized trial, which is being done now, looking at irinotecan plus their drug versus Erbitux alone."

"For a similar drug under development in our center, we've demanded that the sponsor do a randomized study and we worked with the sponsor to achieve that. They did, for the exact same indication, a 600-patient study and answered the question," Pazdur said.

Bristol's message that Erbitux showed activity in patients who were unresponsive to other therapies appeared to have an impact on the committee.

Committee member Rep. Ernie Fletcher, MD, (R-Ken.) noted that the single-agent study suggested a 13% response rate.

"If it is 13% effectiveness in people who have no other hope...in some very recalcitrant tumors, think what it is in some less recalcitrant tumors," Fletcher told Pazdur. "You got it," Pazdur responded.

An attempt by Bristol to personalize Erbitux' potential was not as well received. Smaldone highlighted the dramatic response of one patient in the Erbitux trials, drawing sharp questions from Rep. Diana DeGette (R-Colo.).

"I'm glad that here the cancer seems to be gone. But I think we should be clear: As far as we know she is the only patient to have had this result from this drug, wouldn't that be fair to say?" DeGette asked Smaldone. "We cannot comment on cure at this time. It is way to early," Smaldone acknowledged. "These are response rates."