Fresenius Biotech has received approval from the Austrian Federal Office for Safety in Health Care for the use of a polyclonal antibody in stem cell transplantations (SCT). The preparation - ATG-Fresenius S - can be used in the indication "conditioning prior to SCT for prevention of graft-versus-host disease (GVHD) after SCT". The approval is based on proof of significantly fewer GVHD complications following administration of ATG-Fresenius S. Austria is now the fifth country to approve the preparation in this indication, after Germany, Argentina, Portugal and Thailand.

According to the approval, ATG-Fresenius S may be used to treat adult patients with malignant hematologic diseases who undergo SCT involving HLA-compatible, unrelated donors. In such cases, ATG-Fresenius S is administered in combination with standard GVHD prophylaxis. The approval is based on results of a prospective, randomized, multi-center study of HLA-compatible unrelated SCT with 201 patients. The study compared the efficacy and tolerability of ATG-Fresenius S in combination with standard GVHD prophylaxis versus standard GVHD prophylaxis alone. One-year data were published in October 2009 in "The Lancet Oncology" medical journal (Finke et al.)*.

New long-term data were published in April 2011 in the "Blood" medical journal (Socie et al.)**. With regard to acute GVHD grade III-IV, study results showed a significantly reduced incidence of 11.7% vs. 25.5% (p=0.0392) in ATG-Fresenius S and non-ATG-Fresenius S groups, respectively. The extensive chronic GVHD rate was significantly lower in ATG-Fresenius S patients, compared with the control group (12.2% vs. 45%; p<0.0001). The probability of survival without systemic immunosuppression therapy was three times higher in the ATG-Fresenius S group. Relapse of underlying malignant disease, mortality and overall survival were comparable between both groups.

*Finke et al., Standard graft-versus-host disease prophylaxis with or without anti-T-cell globulin in haematopoietic cell transplantation from matched unrelated donors: a randomised, open-label, multicentre phase 3 trial, Lancet Oncology, 2009;10:855-864
**Socie et al., Chronic graft-versus-host disease: long-term results from a randomized trial on GvHD prophylaxis with or without anti-T-cell globulin ATG-fresenius, Blood, published April 5, 2011, 10.1182/Blood-2011-01-329821

About ATG-Fresenius S
ATG-Fresenius S is a polyclonal antibody that is used for GVHD prophylaxis shortly before stem cell transplantation is performed. The preparation's mode of action, which mainly targets activated T-cells, includes complement-mediated cytolysis and apoptotic induction of T-cells and antigen-presenting cells.
ATG-Fresenius S prevents the adhesion of T-cells to the endothelium, minimizes T-cell infiltration and blocks numerous signal transmission paths within the immune system. Furthermore, ATG-Fresenius S has a propagating effect on regulatory cells. A direct anti-tumor effect is described in various hematologic tumors.
The polyclonal antibody ATG-Fresenius S was developed in Germany over 30 years ago for the treatment and prophylaxis of acute rejection reactions in the transplantation of solid organs. ATG-Fresenius S has been approved for use in these indications worldwide in more than 45 countries.

About GVHD (graft-versus-host disease)
GVHD is a frequent complication of stem cell transplantation, which is associated with a high degree of morbidity and mortality. GVHD is an immunological reaction of the donor lymphocytes to the patient's foreign antigens. The following GVHD risk factors are known: the patient's age, the degree of kinship between the donor and the recipient, the type of preparation used for stem cell transplantation as well as the source of the graft. Several components contribute to GVHD's development, among others, tissue damage during preparations for stem cell transplantation, cytokine production and lymphocyte activation. Various immune cells (T-cells, antigen-presenting cells and natural killer cells) are involved in the GVHD mechanism. GVHD frequently causes severe organ and tissue damage, which can become chronic to some extent. GVHD can affect any organ or tissue; the skin, stomach, intestines, liver and the immune system are most frequently attacked. One of the strategies for GVHD reduction is T-cell depletion. ATG-Fresenius S depletes T-cells and consequently represents an important therapeutic advance in GVHD prevention.

At the 47th Annual Meeting of the American Society of Clinical Oncology (ASCO) in Chicago (June 3-7, 2011), Fresenius Biotech presented new data on the trifunctional antibody Removab® with 11 contributions.

Significant overall survival benefit in patients with higher relative lymphocyte count
Follow-up results for the pivotal study in patients with malignant ascites show a statistically significant benefit in overall survival for Removab®-treated patients (p=0.0219, HR=0.649). The six-month survival rate in Removab®-treated patients was more than four times higher compared to control patients (28.9% vs. 6.7%). A higher baseline-relative lymphocyte count (RLC) had a significant impact on overall survival. In patients with a RLC >13%, the six-month survival rate with Removab® was more than seven times higher than in control patients (37.0% vs. 5.2%), leading to a mean overall survival benefit of 131 days (p=0.0072, HR=0.518). The RLC was previously identified as a biomarker in an independent hypothesis-generating study.

Removab® improves quality of life in patients with malignant ascites
In addition to improving overall survival, Removab®-treated patients were shown to have an improved quality of life (QoL). Analysis of pivotal trial data using the EORTC QLQ-C30 questionnaire showed a significantly higher percentage of patients with improvement in QoL scores at day 30. This effect appeared consistently across multiple scores. While nearly all (97%) patients treated with Removab® at least maintained their QoL level ("Global QoL score"), 30% of patients in the control group had a rapid deterioration in QoL within the first 30 days.

Integrated safety analysis supports shorter infusion time
A shorter infusion time of 3 hours for Removab® is supported by new results from an integrated safety analysis. Based on this analysis, the safety profile of Removab® after a more tolerable and convenient 3-hour infusion was largely comparable to the currently approved 6-hour infusion time.

# # #

About Removab® (catumaxomab)
Removab®, with its trifunctional mode of action, represents the first antibody of a new generation. The therapeutic objective of Removab® is to generate a stronger immune response to cancer cells that are the main cause of ascites. Removab® binds to three different cell types simultaneously: One arm of the antibody binds to the EpCAM (epithelial cell adhesion molecule) antigen on carcinoma cells, another arm binds to CD3 on T cells. Thirdly, the intact Fc region of Removab® binds to Fc-gamma receptors on accessory cells (such as macrophages, monocytes, dendritic cells and natural killer cells). This simultaneous binding subsequently results in the mutual stimulation and activation of T cells and accessory cells, enabling the generation of a stronger immune response and destruction of cancer cells. Data from animal studies with trifunctional antibodies also suggest a potential long-lasting effect to prevent cancer recurrence. Removab® is under further development for new indications. Catumaxomab (Removab®) is a trifunctional antibody developed by TRION Pharma GmbH.

Removab® has been approved in the European Union since April 2009 for intraperitoneal treatment of malignant ascites in patients with EpCAM-positive carcinomas where standard therapy is not available or no longer feasible.
Fresenius Biotech is responsible for the clinical development and commercialization of Removab®.

For more information, please visit www.removab.com.

About the pivotal study
The study involved 258 patients with malignant ascites due to various carcinomas. Of those, 129 suffered from ovarian cancer, while another 129 had other types of cancer. Patients received paracentesis followed by four intraperitoneal infusions of Removab®, or paracentesis alone (control group). Details of the study results are published by Heiss et al, Int J Cancer 2010;127:2209–21

About Biomarker
A characteristic that is objectively measured and evaluated as an indicator of normal biological processes, a pathogenic process, or pharmacologic responses to a therapeutic intervention.

About relative lymphocyte count (RLC)
The relative lymphocyte count describes the percentage of lymphocytes among the total of leukocytes in the peripheral blood.

About epithelial cell-adhesion molecule (EpCAM)
EpCAM is a tumor-associated antigen expressed on the vast majority of epithelial tumors. EpCAM is expressed on tumor cells in the ascites fluid of patients with EpCAM-positive tumors.

About malignant ascites
Malignant ascites can be caused by various kinds of tumors. The peritoneal spread of tumor cells leads to an accumulation of fluid in the peritoneal cavity and is associated with an unfavorable prognosis for the patient. The most common method of treatment is paracentesis, which generally must be repeated at intervals of one to two weeks and can lead to complications such as infections or elevated losses of fluids and proteins. Removab® destroys the peritoneal cancer cells and thus directly attacks the cause of malignant ascites.

About EORTC QLQ-C30
The EORTC QLQ-C30 is a quality of life questionnaire designed for use in a wide range of cancer patients. It is an accepted and valid measure of QoL in cancer patients. The EORTC QLQ-C30 has been translated into and validated in more than 80 different languages.

The Italian Medicines Agency, AIFA, has added Fresenius Biotech's antibody Removab® to its list of reimbursable medications. As of June 25, 2011, use of Removab® for the treatment of malignant ascites in patients with EpCAM-positive carcinomas will be fully reimbursed. Removab® is a trifunctional monoclonal antibody approved throughout the European Union. It has been launched in Austria, France, Germany, Scandinavia and the UK.

"The positive decision concerning reimbursement is another step in the successful implementation of our European marketing strategy for Removab®," said Dr. Christian Schetter, CEO of Fresenius Biotech. "It enables patients in Italy to benefit from treatment with Removab® quickly and without bureaucratic hurdles."

Follow-up results for the pivotal study, recently presented at the 47th Annual Meeting of the American Society of Clinical Oncology (ASCO), showed a statistically significant benefit in overall survival for Removab®-treated patients. After six months, nearly 30% of all patients treated with Removab® were still alive, which is a fourfold increase compared to the control group (around 7%). In addition, Removab®-treated patients were shown to have an improved quality of life.

###

About Removab® (catumaxomab)
Removab®, with its trifunctional mode of action, represents the first antibody of a new generation. The therapeutic objective of Removab® is to generate a stronger immune response to cancer cells that are the main cause of ascites. Removab® binds to three different cell types simultaneously: One arm of the antibody binds to the EpCAM (epithelial cell adhesion molecule) antigen on carcinoma cells, another arm binds to CD3 on T cells. Thirdly, the intact Fc region of Removab® binds to Fc receptors on accessory cells (such as macrophages, monocytes, dendritic cells and natural killer cells). This simultaneous binding subsequently results in the mutual stimulation and activation of T cells and accessory cells, enabling the generation of a stronger immune response and destruction of cancer cells. Data from animal studies with trifunctional antibodies also suggest a potential long-lasting effect to prevent cancer recurrence. Removab® is under further development for new indications. Catumaxomab (Removab®) is a trifunctional antibody developed by TRION Pharma GmbH.
Removab® has been approved in the European Union since April 2009 for intraperitoneal treatment of malignant ascites in patients with EpCAM-positive carcinomas where standard therapy is not available or no longer feasible.
Fresenius Biotech is responsible for the clinical development and commercialization of Removab®.
For more information, please visit www.removab.com.

About the pivotal study
The study involved 258 patients with malignant ascites due to various carcinomas. Of those, 129 suffered from ovarian cancer, while another 129 had other types of cancer. Patients received paracentesis followed by four intraperitoneal infusions of Removab®, or paracentesis alone (control group). Details of the study results are published by Heiss et al, Int J Cancer 2010;127:2209–21

About epithelial cell-adhesion molecule (EpCAM)
EpCAM is a tumor-associated antigen expressed on the vast majority of epithelial tumors. EpCAM is expressed on tumor cells in the ascites fluid of patients with EpCAM-positive tumors.

About malignant ascites
Malignant ascites can be caused by various kinds of tumors. The peritoneal spread of tumor cells leads to an accumulation of fluid in the peritoneal cavity and is associated with an unfavorable prognosis for the patient. The most common method of treatment is paracentesis, which generally must be repeated at intervals of one to two weeks and can lead to complications such as infections or elevated losses of fluids and proteins. Removab® destroys the peritoneal cancer cells and thus directly attacks the cause of malignant ascites.

The European Commission has broadened the existing approval of Fresenius Biotech's antibody Removab^® (catumaxomab) to treat malignant ascites by allowing a shorter infusion time. The infusion time for Removab^® can now be halved, from six to three hours. Moreover, the approval allows marketing of follow-up results for the pivotal study in patients with malignant ascites showing that the one-year survival rate in Removab^®-treated patients was more than four times higher than in the control group (11.4% Removab group vs. 2.6% control group). The summary of product characteristics for Removab^® will include the overall survival data from the pivotal study with immediate effect. The broadened approval follows on the recommendation of the Committee for Medicinal Products for Human Use (CHMP), part of the European Medicines Agency (EMA). It is valid in all EU countries and also confirms the safety profile of the trifunctional antibody.

The European Commission's decision is based on the results of an analysis of pooled safety data. In clinical studies, Removab^® was administered intraperitoneally as three or six-hour infusions. The safety profiles for both administrations were comparable.

Thanks to the shortened infusion time, Removab^® will be easier to use in out-patient settings. "Treatment options for patients with malignant ascites must not only be effective, but also minimize the burden for the patient," said Prof. Dr. Barbara Schmalfeldt from the obstetrics and gynecology department at Technical University of Munich. "A shorter infusion time means patients spend less time at their physician's office or day clinic. The new application time for Removab^® addresses this frequent patient request. It also makes applications in day-to-day practice much easier and more efficient."

# # #

About Removab^® (catumaxomab)
Removab^®, with its trifunctional mode of action, represents the first antibody of a new generation. The therapeutic objective of Removab^® is to generate a stronger immune response to cancer cells that are the main cause of ascites. Removab^® binds to three different cell types simultaneously: One arm of the antibody binds to the EpCAM (epithelial cell adhesion molecule) antigen on carcinoma cells, another arm binds to CD3 on T cells. Thirdly, the intact Fc region of Removab^® binds to Fc-gamma-receptors on accessory cells (such as macrophages, monocytes, dendritic cells and natural killer cells). This simultaneous binding subsequently results in the mutual stimulation and activation of T cells and accessory cells, enabling the generation of a stronger immune response and destruction of cancer cells. Data from animal studies with trifunctional antibodies also suggest a potential long-lasting effect to prevent cancer recurrence. Removab^® is under further development for new indications. Catumaxomab (Removab^®) is a trifunctional antibody developed by TRION Pharma GmbH.
Removab^® has been approved in the European Union since April 2009 for intraperitoneal treatment of malignant ascites in patients with EpCAM-positive carcinomas where standard therapy is not available or no longer feasible.
Fresenius Biotech is responsible for the clinical development and commercialization of Removab^®.
For more information, please visit www.removab.com.

About the pivotal study
The study involved 258 patients with malignant ascites due to various carcinomas. Of those, 129 suffered from ovarian cancer, while another 129 had other types of cancer. Patients received paracentesis followed by four intraperitoneal infusions of Removab®, or paracentesis alone (control group). Details of the study results are published by Heiss et al, Int J Cancer 2010;127:2209–21

About epithelial cell-adhesion molecule (EpCAM)
EpCAM is a tumor-associated antigen expressed on the vast majority of epithelial tumors. EpCAM is expressed on tumor cells in the ascites fluid of patients with EpCAM-positive tumors.

About malignant ascites
Malignant ascites can be caused by various kinds of tumors. The peritoneal spread of tumor cells leads to an accumulation of fluid in the peritoneal cavity and is associated with an unfavorable prognosis for the patient. The most common method of treatment is paracentesis, which generally must be repeated at intervals of one to two weeks and can lead to complications such as infections or elevated losses of fluids and proteins. Removab® destroys the peritoneal cancer cells and thus directly attacks the cause of malignant ascites.

The Belgian Ministry of Social Affairs and Public Health has added the trifunctional antibody Removab® (catumaxomab) from Fresenius Biotech to its list of reimbursable medications. As of October 1, 2011, use of Removab® for the intraperitoneal treatment of patients with malignant ascites due to EpCAM-positive ovarian carcinoma will be reimbursed, if the eligible patients also fulfill defined additional clinical inclusion criteria. Removab® is a trifunctional monoclonal antibody approved throughout the European Union. It has already been launched in Austria, France, Germany, Scandinavia and the UK. Removab® was also approved for reimbursement in Italy in June. The positive reimbursement decision in Belgium follows a comprehensive appraisal process that thoroughly assessed both the clinical value as well as the cost-effectiveness of Removab®.

###

About Removab® (catumaxomab)
Removab®, with its trifunctional mode of action, represents the first antibody of a new generation. The therapeutic objective of Removab® is to generate a stronger immune response to cancer cells that are the main cause of ascites. Removab® binds to three different cell types simultaneously: One arm of the antibody binds to the EpCAM (epithelial cell adhesion molecule) antigen on carcinoma cells, another arm binds to CD3 on T cells. Thirdly, the intact Fc region of Removab® binds to Fc-gamma receptors on accessory cells (such as macrophages, monocytes, dendritic cells and natural killer cells). This simultaneous binding subsequently results in the mutual stimulation and activation of T cells and accessory cells, enabling the generation of a stronger immune response and destruction of cancer cells. Data from animal studies with trifunctional antibodies also suggest a potential long-lasting effect to prevent cancer recurrence. Removab® is under further development for new indications. Catumaxomab (Removab®) is a trifunctional antibody developed by TRION Pharma GmbH.
Removab® has been approved in the European Union since April 2009 for intraperitoneal treatment of malignant ascites in patients with EpCAM-positive carcinomas where standard therapy is not available or no longer feasible.
Fresenius Biotech is responsible for the clinical development and commercialization of Removab®.
For more information, please visit www.removab.com.

About the pivotal study
The study involved 258 patients with malignant ascites due to various carcinomas. Of those, 129 suffered from ovarian cancer, while another 129 had other types of cancer. Patients received paracentesis followed by four intraperitoneal infusions of Removab®, or paracentesis alone (control group). Details of the study results are published by Heiss et al, Int J Cancer 2010;127:2209–21

About epithelial cell-adhesion molecule (EpCAM)
EpCAM is a tumor-associated antigen expressed on the vast majority of epithelial tumors. EpCAM is expressed on tumor cells in the ascites fluid of patients with EpCAM-positive tumors.

About malignant ascites
Malignant ascites can be caused by various kinds of tumors. The peritoneal spread of tumor cells leads to an accumulation of fluid in the peritoneal cavity and is associated with an unfavorable prognosis for the patient. The most common method of treatment is paracentesis, which generally must be repeated at intervals of one to two weeks and can lead to complications such as infections or elevated losses of fluids and proteins. Removab® destroys the peritoneal cancer cells and thus directly attacks the cause of malignant ascites.