By Kim Coghill

Washington Editor

BETHESDA, Md. ¿ In a unanimous decision Wednesday, an FDA advisory committee recommended against a new drug application submitted by Maxim Pharmaceuticals Inc. for Maxamine, or histamine hydrochloride injection, for use in patients with advanced metastatic melanoma that has metastasized to the liver.

Following the 14-0 vote, Maxim officials declined to speak with BioWorld Today.

The FDA has final approval of the application, but one administration official said generally the FDA follows the recommendation of the advisory committee, in this case the Oncologic Drugs Advisory Committee.

At this point Maxim has choices, according to Stacy Nerenstone, committee chair and associate clinical professor of Oncology Associates at the Helen & Harry Gary Cancer Center at Hartford Hospital in Hartford, Conn. Maxim can either "go back to the drawing board or redo Phase III trials," she said. "It was not a well done trial."

Richard Simon, committee member and chief of biometric research at the National Cancer Institute in Bethesda, said, "I think from this particular trial there are too many imbalances and ineligible patients. I don't find this convincing evidence."

In his presentation of the drug application, Kurt Gehlson, Maxim's senior vice president and chief technical officer, said the Phase III study met its primary efficacy endpoint, which was survival, and "we didn't observe any adverse events that were not expected."

Maxim enrolled 305 patients in the study and sought the use of Maxamine based on efficacy results in a subgroup of 129 patients with liver metastases.

According to the FDA, there were many imbalances in known prognostic factors and in other patient characteristics between the two treatment arms in the subgroup of patients with liver metastases. The imbalances consistently favored the histamine/interleukin-2 arm and when the data were adjusted for imbalances, the result became less favorable, losing statistical significance. The combination was tested against IL-2 alone.

Rob Toth, an analyst at New York-based Prudential Vector Healthcare, said the FDA rejection hurts Maxim in a variety of ways, from its reputation with current investors to the perception of its other programs on Wall Street.

"I think it sounds pretty clear that the FDA wanted to set a precedent with this ODAC meeting showing companies that they need to come forward with very compelling evidence of efficacy if they want to get their drug approved," Toth told BioWorld Today after the recommendation. "It's clear that the communication between the company and the FDA is critical to avoid getting blindsided."

That breakdown in communication could have long-term effects on Maxim, he said.

"I think there was a communication breakdown between the FDA and the company and the company and Wall Street. I think a lot of investors will feel misled," Toth said. "It's very important to stay on the same page as the FDA when you're doing clinical development. I think a lot of investors are going to feel misled by the way the story unfolded."

Maxamine is a histamine type-2 receptor agonist. Its mechanism of action aims at shutting off free radical production, thus protecting T cells. It is designed to offer therapeutic effect by eliminating the body's restraint of tumor detection and killing mechanisms through combination therapy with immunostimulatory cytokines.

Maxim submitted a new drug application for Maxamine as an adjuvant to IL-2 for treatment of Stage IV melanoma to the FDA in July. The FDA informed the company at that time that the drug was eligible for priority review, and in September the FDA granted priority review status to the drug.

That NDA was supported by results from the pivotal Phase III trial of Maxamine in combination with IL-2 compared to IL-2 treatment alone in patients with end-stage melanoma. That study was completed in March.

The 305-patient study found a median survival rate for patients receiving the combination therapy of 363 days, compared to 251 days for control patients who received IL-2 alone. (See BioWorld Today, July 20, 2000.)

Prior to that, Maxamine logged positive results in a Phase II dose-ranging study of the compound in combination with interferon-alpha for treatment of chronic hepatitis C.

Maxim's stock (NASDAQ:MAXM) dropped 21.6 percent Wednesday, falling $3.625 to close at $13.125 before trading was halted pending ODAC's recommendation. The shares had taken a worse hit Tuesday as Maxamine data came under fire from the FDA on the agency's web site, closing at $16.75, down $13.31, or 44 percent. Questions from the FDA about the company's Phase III trial and the compound's efficacy were published on the Internet at www.fda.gov/ohrms/dockets/ac/cder00.htm.

Crystal Rice, FDA public affairs specialist in the Center for Drug Evaluation and Research, said the practice of publishing information available to advisory committee members on the web is more than a year old and mandated by a court settlement.

"In July of 1999," Rice told BioWorld Today, "access to advisory committee briefing information was to be made available on or before the day of the meeting. This was the result of a legal settlement between the Public Citizens Health Research Group and the FDA."

She added that briefing information on every advisory committee meeting is posted on the website.

"Basically, at that point, after July 16, the FDA was to make the material provided to advisory committee members available to the public before or on the day of the advisory committee meeting, and that's when we started making a practice of posting the information on the web the day before."

And what Maxim will do now is anyone's guess. Toth said there are other Phase III trials in progress, including one in myelogenous leukemia that should be completed in about 16 months. Another trial in hepatitis C remains under way.

"The company is clearly not going out of business," Toth said. "They've got cash and though they're burning substantially now, things remain to be seen. I think the stock's probably dead money for a while until their strategy becomes clear, and I think it's important for Maxim to build confidence on The Street. That's an achievable hurdle, but it's going to take some work. I think investors could be inclined to heavily discount Maxim's other programs in light of the FDA bringing up some quality issues as to the way this trial was run." n

Matthew Willett contributed to this article.