By Lisa Seachrist
WASHINGTON — A year after analysts were declaring the drug a "shoo-in" for FDA approval, the agency informed DepoTech Corp. in a non-approvable letter that DepoCyt clinical trials failed to decisively prove the drug offers relief from neoplastic meningitis.
The news came late Friday afternoon in a fax from the FDA for the San Diego-based company and its corporate partner Chiron Corp., of Emeryville, Calif.
In the letter, the agency said evidence of patient benefit was not persuasive because the pivotal clinical trial, which was a small, open label study, didn't show statistically significant superiority for DepoCyt. The decision came as surprise to both companies, who stated they have surpassed the requirements put forth by FDA in written agreements dated October 1992.
"We are very disappointed to have clinical design issues thrown back at us as the reason [DepoCyt was rejected]," said John Longenecker, DepoTech's president and CEO. "We don't know what will be required for approval now. We are requesting a meeting with the agency in order to determine how to proceed."
Chiron's vice president of investor relations and communications, James Knighton, also expressed disappointment and some confusion over the agency's decision.
"My understanding up to now was that we were relatively comfortable that the requirements for approval had been satisfied," he said. "Something's wrong and we won't know until we meet with the agency what the source of the miscommunication is."
DepoCyt is an injectable, sustained-release formulation of the chemotherapeutic agent cytarabine. It is delivered by DepoTech's lipid-based encapsulation system, DepoFoam, and injected every two weeks directly into the cerebrospinal fluid as a treatment for neoplastic meningitis.
An almost universally fatal condition, neoplastic meningitis is caused by the metastasis of solid tumors, leukemia and lymphoma to the tissues surrounding the brain and spinal cord, resulting in progressive neurological decline.
FDA Panel Judges Clinical Evidence Insufficient
In December 1997, the company presented an FDA advisory panel with the pivotal clinical trial results. That trial involved 61 patients, 31 of whom received DepoCyt once every two weeks and 30 who received methotrexate injections twice a week.
Eight of the patients on DepoCyt had a complete response and six in the methotrexate arm experienced a complete response. This result failed to reach statistical significance.
However, patients on DepoCyt experienced a median time to progression of their disease of 166.5 days while those on methotrexate saw their symptoms become worse in a median of 66.5 days.
The panel, however, found that time to clinical progression was insufficient to recommend approval and decided the study was neither adequate nor well-controlled and refused to make a recommendation on approval. (See BioWorld Today, Dec. 19, 1997, p. 1.)
That decision sent the company's stock (NASDAQ:DEPO) plummeting $13 to $4.125 the day after the meeting. Monday's news sent the stock south 49 percent to close at $1.687, down $1.625.
In February, DepoTech laid off 29 employees and restructured the company.
Things began to look up when the agency asked the company to submit more trial data and gave DepoCyt three more months of review in March. (See BioWorld Today, March 10, 1998, p.1.)
In its amended new drug application, DepoTech submitted data from a Phase IV clinical trial of neoplastic meningitis from a number of solid tumor cancers and interim data from a Phase III study of the disease in lymphoma and leukemia. The additional submission gave the agency until July 28, 1998, to render its decision.
DepoTech Says FDA Approved Trial Design
The FDA, however, rejected the drug, citing heterogeneous source tumors, the small size of the trials, their open label design and their lack of statistical significance as reasons it would not approve the drug. In addition, FDA questioned the manner of analysis used to determine clinical progression.
Longenecker told BioWorld Today that from the outset, the trial was never designed to show statistical significance and that the agency had agreed to all aspects of the trial design.
"There is little mystery why we failed to achieve statistical significance in such a small trial," Longenecker said. "We are very disappointed that this was cited as a reason."
In its letter, the FDA noted data from the study were sufficiently promising to support an application for a treatment protocol (treatment IND) in solid tumors. Longenecker, however, is uncertain that the company would proceed with such a protocol, saying it very often fails to generate useful data for approval.
Mike King, an analyst with Vector Securities International, in Deerfield, Ill., doubts the company will conduct the treatment IND because the cost of such a program may not be justified and because the program is unlikely to lead to approval.
"It looks pretty grim," King said. "I don't know what happened, but it sounds like the FDA may have changed the rules or the company didn't understand from the outset. Whatever the case, there was clearly a miscommunication."
Chiron's stock (NASDAQ: CHIR) closed at $18.50, down $0.25. *