BioWorld International Correspondent

Trion Pharma GmbH and its partner Fresenius Biotech GmbH remain on track to file for approval in Europe this year for their 'trifunctional antibody' removab (catumaxomab), which attained the primary endpoint and several secondary endpoints in a Phase II/III clinical trial in advanced cancer patients with malignant ascites.

Malignant ascites, which involve the accumulation in the peritoneal cavity of large volumes of fluid containing cancerous cells, can occur in advanced cases of cancer, particularly ovarian cancer, and are associated with a high rate of mortality. Frequent puncturing of the cavity and releasing the fluid can be necessary, although it is a painful and unpleasant procedure.

The study recruited 258 cancer patients expressing the tumor's antigen epithelial cell adhesion molecule (EpCam). Half had ovarian cancer, and half had a different form of cancer. In each of the subgroups, 85 patients received removab and 44 received placebo.

The primary end point of the study was the length of the puncture-free survival period, defined as the interval between the last infusion in the case of the treatment group (or last puncture in the case of the control group) and the next subsequent puncture required or death, whichever occurred first. Those on therapy had a four-fold increase in puncture-free survival, 46 days vs. 11 days (p<0.0001), as previously reported by Fresenius Biotech, a Munich, Germany-based subsidiary of the Fresenius Health Care Group, of Bad Homburg, Germany.

Newly analyzed secondary endpoint data confirmed the therapeutic benefit of removab, the companies said. The median time to progression of the underlying cancer for the combined treatment arms (n=170) was 111 days vs. 35 days for the combined control arms (n=88). There was little difference in the parameter when the patients with ovarian and non-ovarian cancer were considered separately. Positive survival trends also were evident.

After the primary end point of the study (puncture-free survival) was reached, the data showed that puncture intervals in patients treated with removab continued to be longer than those of the patients in the control group. The intervals between the first and second puncture were 26 and 24 days in the ovarian and non-ovarian cancer group treated with removab vs. 13 and 16 days in the control group. Numbers of EpCam positive tumor cells before and after treatment decreased strongly, while measures of leukocytes and of a pro-inflammatory cytokine and a T-cell marker increased.

The companies hope to launch the product in 2008, which would place Trion, a company that has flown well below the radar screen until now, in the front rank of German biotechnology firms. Munich-based Trion Pharma, and a sister firm, Trion Research, were formed in 1998 to commercialize a novel antibody format, called Triomab, developed by its CEO Horst Lindhofer while he worked at the National Research Center of Environment and Health (GSF), also in Munich. It is designed to augment the normal immune recruitment functions associated with traditional antibody molecules.

Most human monoclonal antibodies are based on the IgG1 isotype, which can promote antibody-dependent cell-mediated cytotoxicity, but which is limited in its ability to stimulate immune effector functions. "IgG1 is not able to select between the activatory Fc gamma receptors and the inhibitory Fc gamma receptors," Lindhofer told BioWorld International. "You cannot activate the full potential of accessory cells."

Lindhofer and his team have developed a proprietary antibody format that selectively recognizes activatory Fc gamma receptors on immune effector cells and therefore boosts recruitment of immune effector functions, which in turn upregulates co-stimulation signals necessary for T-cell activation.

"We are simultaneously and additionally recruiting and activating accessory cells," he said. The selectivity is attained by using rodent antibody isotypes known for their effects on the human immune system. "We are using rat IgG2b and mouse IgG2a," Lindhofer said. "These two isotypes are the most potent for these two species."

The antibodies are created by fusing two hybridomas. They are bispecific in terms of antigen recognition - they recognize a T-cell antigen and a tumor-associated antigen. Dosing is at microgram levels, about a thousand-fold lower than those used in the disastrous trial of TGN1412, an antibody developed by Wurzburg, Germany-based TeGenero AG.

The antibodies are highly immunogenic, which limits their use. "We have a therapeutic window of two to three weeks," Lindhofer said. However, that has been sufficient to see lasting effects, he added.

Trion has until now managed to avoid the need to take on any venture capital. It won a business plan competition in Germany, which aroused the interest of Fresenius, a diversified health care company, which reported €10.8 billion in revenues in 2006. Its biotech arm has licensed three triomab antibodies in total and has taken a minority stake in Trion. Those transactions have funded Trion's activities until now, Lindhofer said, and the company is not planning to seek any additional funding at present. "We don't really need fresh money because we are financed until market approval," he said.