Washington Editor

Titan Pharmaceuticals Inc. said its monoclonal antibody, CeaVac, demonstrated a trend toward overall survival in a Phase III trial, but failed to meet the primary endpoint when studied in metastatic colorectal cancer patients.

However, company officials and at least one analyst were quick to point out that treating advanced metastatic cancer patients with an immunotherapy is risky.

"We knew from the launch of this study that it would be a challenging proposition, but we wanted to attempt to offer these patients something to help them and improve survival," Louis Bucalo, Titan's chairman, president and CEO, told BioWorld Today. "We believe that, despite the fact that we didn't achieve the primary endpoint in the study, which of course is a disappointment, there is additional information that suggests that there may be biologic activity in this drug."

Dennis Harp, biotechnology analyst with Deutsche Bank Securities Inc. in New York, told BioWorld Today: "Clearly, it failed to meet the primary endpoint, but on the other hand, we never had high expectations for it. We viewed it as a high-risk, high-reward program so we never forecasted any sales of CeaVac. While it is disappointing to see this result, it is not surprising to us."

Titan's stock (AMEX:TTP) closed Wednesday at $1.55, down 40 cents or 20.5 percent.

CeaVac, a subcutaneous injection, works by stimulating an immune response in the carcinoembryonic antigen (CEA), which is overexpressed in colorectal cancer patients.

Preliminary analysis of the Phase III trial of 631 patients showed a trend toward survival improvement of about two to three months in patients who received at least five doses of CeaVac vs. placebo (modified intent-to-treat population). However, the data did not demonstrate a statistically significant improvement in the primary endpoint of survival in the evaluable or intent-to-treat population, the company said.

The randomized, placebo-controlled study involved metastatic patients receiving chemotherapy with 5- flourouracil and leucovorin.

Patients received the drug once every two weeks for two months and then once a month thereafter. Bucalo said there was a survival trend in patients who received five doses of CeaVac vs. placebo (19.1 months vs. 17.1 months, respectively), and the trend continued for those who received eight doses (21.3 months for CeaVac vs. 18.5 months for placebo).

"We thought it would be difficult for patients who received less than five doses to benefit because our previous studies had demonstrated that, on average, about five doses of CeaVac were necessary to begin to produce an immune response," Bucalo said. "Of course, optimally one would continue to treat beyond that point to continue the immune response so that patients have the opportunity to benefit. We are not saying that we would stop at five, but we feel that five was necessary and, of course, we would like to continue to treat beyond that."

Titan will spend the next few weeks poring over the data to gain a better understanding of CeaVac. "We have a suggestion [of benefit in survival]; now we need to review it in more detail to see if that trend is strengthened," Bucalo said. "If it is, there may be more opportunities to consider evaluating CeaVac in appropriate populations with that type of regimen."

Harp said even though it is possible that CeaVac could show benefit in a different setting, he continues to view it as high risk. He added that a number of factors could have caused the failure, including the sick patient population. "They could have been so far gone that nothing could have shown a benefit," he said.

Meanwhile, CeaVac is being studied in combination with TriAb, another Titan monoclonal antibody, in resected Dukes' D colorectal cancer, a less-advanced stage of the disease. The study is supported by the National Cancer Institute in Bethesda, Md., and is being conducted by the Cancer and Leukemia Group B. The Radiation Therapy Oncology Group is conducting a Phase II study of CeaVac in combination with TriAb in non-small-cell lung cancer. (See BioWorld Today, March 4, 2002.)

Separately, Titan officials said Swiss-based Novartis AG, its partner in the development of iloperidone in schizophrenia, has not determined whether it will continue the partnership. Bucalo expects a decision in the next few months. In July, the companies said regulatory filing could be delayed due to a possible need for additional trials. (See BioWorld Today, July 23, 2002.)