FDA panel advises against approval of Advanced Magnetics’ contrast agent

Sixteen years after Advanced Magnetics first conceived of the MR contrast agent Combidex, the drug's future looks bleak. The agent, designed to differentiate between cancerous and noncancerous lymph nodes, failed March 3 to sufficiently impress an FDA advisory panel, which voted overwhelmingly against its approval.

"Is it dead?" asked Jerome Goldstein, founder, chairman, president and CEO of the company. "I hope not. I don't believe there's any right-thinking person who doesn't believe this drug has significant benefit."

Unfortunately for Advanced Magnetics, most of the FDA's Oncologic Drugs Advisory Committee believed the case for this drug was not sufficiently proved, voting 15-4 against recommending FDA approval, citing safety and efficacy issues.

The vote occurred more than four years after the FDA sent the Cambridge, MA, company a letter saying it found the drug approvable for its principal indication as a lymph node imaging agent. In those four years, Advanced Magnetics was not able to satisfy the preconditions for approval, and the drug went to an advisory committee for review.

The FDA plans to send by March 30 an action letter regarding the approvability of the contrast agent, according to George Mills, director of medical imaging for the FDA. The future of Combidex rests largely on the contents of that letter, Goldstein said.

"What they put in the action letter will determine what we do," he said.

The Combidex odyssey began in 1989, when the concept of the drug was first developed. Over the ensuing decade, Advanced Magnetics developed and then clinically tested the contrast agent, submitting a new drug application to the FDA in January 2000. Just five months later, the FDA issued a letter indicating that Combidex was approvable for its principal indication, the imaging of lymph nodes.

The letter went on to state, however, that Combidex could not be approved for its secondary indication, imaging of the liver and spleen. The letter contained a number of recommendations, which Goldstein at the time planned to address. But Advanced Magnetics did not submit a complete response to the approvable letter until September 2004, more than four years later.

In an interview with DI SCAN following the decision of the advisory panel, Goldstein refused to say exactly what the FDA had required some five years earlier as preconditions for approval of the agent. He stated his belief, however, that the company had achieved "a lot of them."

"Clearly, since the FDA accepted what we gave them as a complete response, they had to feel that we responded to issues that they raised in the approvable letter," he said.

In the meantime, the case was forwarded to the agency's advisory panel, which found that "generalizibility and validity of study findings are still issues" and that "dilution and slow infusion are not entirely risk-free."

Advanced Magnetics had claimed that Combidex offers high sensitivity and specificity, noting that no deaths or life-threatening episodes were associated with dilution and slow infusion. Now, in the wake of the advisory committee's review, Goldstein fears that Combidex may never be approved for the indication for which it was designed, lymph node imaging.

"The best possibility is approval for a truncated indication - say, in the pelvis, abdomen, head and neck, or any or all of the above," he said.

This bleak outlook, however, may not be warranted. Dr. Joanne Mortimer, a member of the advisory panel, noted that the members were "actually very enthusiastic about this drug. It just needs to be tested further."

The problem may have been in the number of patients involved in the clinical research.

"There really weren't that many patients in the trial," she said. "There were a handful of prostate patients; a handful of head and neck patients. But it sure looked like there was something valuable there."

The questions troubling the committee might be answered by more research. Specifically, the panel questioned whether the available data adequately documented the benefits of the agent. They wondered also about false positives and false negatives and even about how the lymph nodes were assessed. A less tangible, but nonetheless disturbing aspect, was the length of time between the company's receipt of the approvable letter in 2000 and its response to the FDA.

"It makes you wonder what happened," Mortimer said.

When asked about the four-year gap, Goldstein said a significant delay was caused by the reassignment of the FDA's division director.

We tried to address the issues as quickly as we could," he said.

George Mills, director of medical imaging for the FDA, would not discuss the Combidex case. Also tight-lipped was Dr. Zili Li, medical team leader for the FDA's Division of Medical Imaging and Radiopharmaceutical Drug Products, although he suggested that long delays following approvable letters are not necessarily uncommon with drugs. Efforts to interview advisory panel members other than Mortimer were not successful.

With the negative decision by the advisory panel, Advanced Magnetics' stock plunged $11.76, or nearly 62%, to $7.29 on the American Stock Exchange. It recovered to $10 a few weeks later but has since drifted back into single digits.

"This will be an important year for the company as we await final FDA action on Combidex and continue to advance our development program for ferumoxytol," Goldstein said.

Ferumoxytol is being developed as an iron replacement therapeutic for anemic chronic kidney disease patients. The drug is in an advanced stage of its phase III clinical trials, according to Goldstein. The anemia drug gives the company an important fallback, considering the uncertainty surrounding Combidex.

"We're not at a crossroads," he said. "We're well along in our development processes of this other drug."

Just as Advanced Magnetics' stock price had benefited from the hope of FDA approval for Combidex, so had the stock price of Cytogen. That company had contracted with Advanced Magnetics to distribute Combidex in the U.S. Its shareholders had bid up the price of Cytogen to $13 prior to the panel's decision. The price fell to $7.45 immediately after the decision was announced and has dropped since then to under $6.

Michael Becker, CEO for Cytogen, remains hopeful. While not predicting whether the company's stock price would move back up in a reasonable amount of time, he said Cytogen's financial guidance for 2005 is based largely on the two products the company is currently marketing: Quadramet, a treatment for pain due to bone metastases, and Prostascint, a radionuclide for prostate cancer. The failure of Combidex to take the next step toward market, however, has affected the company.

"I'd love to say it had no impact, but clearly the market reaction has demonstrated the opposite," Becker said.