RESEARCH AND DEVELOPMENT

We place great importance on research and development at Fresenius, where we develop products and therapies for severely and chronically ill patients. High quality is crucial for providing patients with optimal care, improving their quality of life, and thus increasing their life expectancy. As an integral part of our corporate strategy, research and development also serves to secure the Company’s economic development and success. 

DIALYSIS

Research and development at Fresenius Medical Care is focused on products and therapies for dialysis and other extracorporeal blood therapies. Fresenius Medical Care benefits from its unique position as a vertically integrated company, covering both dialysis products and dialysis care. The experience we gain daily from treating around 174,000 patients provides important insights for the development of new products and therapies, and is therefore of enormous value. It also fosters the development of holistic therapies.

Hemodialysis

In 2007, the Body Composition Monitor (BCM) was introduced to the market. The BCM is a device that can be used to determine the dialysis patient’s body composition, i.e. body water, fat-free body mass and fat. Exact knowledge of this data, especially the percentage of body water, is important for assessing the patient’s condition and deciding on the therapy. In the treatment of dialysis patients it is equally crucial to prevent hyperhydration as well as dehydration. Hyperhydration burdens and damages the cardiovascular system, while dehydration frequently leads to complications during the dialysis treatment that further impair the patient’s already restricted quality of life. Studies of current practice all indicate that a sufficiently accurate knowledge of this important patient data is generally not provided. With the BCM, we have developed a suitable, easy-to-use and low-cost state-of-the-art measuring device. And even more important – for the first time the user is provided with a comprehensive, clinically validated evaluation program for the data obtained.

In 2007, much of our development work was again linked to the launch of the 5008 hemodialysis machine. We are continuing to monitor its reliability and performance in practice in the clinic and under different operating conditions internationally. The feedback from our own dialysis clinics and from clients is taken into account in the process of continuous product improvement.

With the development of the 5008, we have upgraded online hemodiafiltration (Online HDF) from an exclusive process for a few users into a standard feature included in the basic version of the machine. In online HDF the machine produces the required amount of sterile and pyrogen-free dialysis solution from standard bicarbonate dialysate, without changing bags of liquid. Our conceptual decision has proven to be correct. A growing number of clinical studies on the advantages of hemodiafiltration indicate that this application can lead to a reduction of more than 30 - 35% in the mortality rate for patients. Few other individual measures in kidney replacement therapy have had such a significant influence on patients’ rate of survival. Fresenius Medical Care, as one of the first providers of commercially available Online HDF devices, sees this as confirmation of its long-term innovation and product development policy.

Membrane technology was another focus of our development work in 2007. All the activities in the area of hemodialysis depend on the availability of dialyzers or membrane types required for a given treatment procedure or for a given patient group. With our various types of Fresenius Polysulfone membrane we have been global market leaders for many years. Today, modern hollow fiber dialyzers have achieved a level of efficacy and technical reliability that only recently was undreamt of. Despite this already advanced stage of development, it is still possible to adapt membranes and complete dialyzers to special new therapy variants, further improving their effectiveness. Today, there are still gaps in medical science’s knowledge of the biochemical causes of acute and chronic uremia as a result of kidney failure. However, the recent advances that have been achieved in research into so-called uremic toxins suggest that membranes with specific properties can be developed, able to filter targeted substances from the patient’s blood.

The acquisition of the US company Renal Solutions, Inc. (RSI) in 2007 also promises synergies between development departments in this field. RSI is active in the area of dialysate regeneration using enzyme-based sorbent systems. RSI’s SORB technology enables ordinary tap water to be prepared for dialysis and for the dialysis solution to be reused. The SORB filter has proved successful in the hemodialysis market, and six million have already been sold. Only six liters of tap water are required per dialysis treatment, instead of the approximately 120 liters of ultra-pure water from reverse osmosis systems previously. This space and water-saving technology is therefore particularly suitable for home hemodialysis. These features – in addition to ecological and financial considerations – allow a substantial reduction in the size of the hemodialysis machine. An aspect of this technology of particular long-term interest to us is that it points to still further-reaching possibilities for selective toxin removal from the patient’s blood in addition to the selective properties of future hemodialysis membranes.

We are also working on membranes that can release pharmaceutical agents into the patient’s blood. The membranes take on special characteristics by attaching appropriate ligands – special molecules – to the surface of the membranes. This research is still at an early stage, and its general medical application has still to be investigated. However, we are confident that future membranes will incorporate such functional properties.

Peritoneal dialysis

In peritoneal dialysis, our portfolio of individually tailored, biocompatible dialysis solutions in toxicologically and ecologically compatible packaging systems traditionally covers a broad spectrum of products for all applications. We are therefore excellently positioned in the market. We also have high-performance machines for automated peritoneal dialysis (APD) – so-called cyclers. Currently working on a global cycler, the R & D department’s goal is to offer high-quality APDs worldwide at optimized cost. Developing a common technical platform for this cycler is an important step along this path.

Extracorporeal blood treatment is one of Fresenius Medical Care’s core competencies. In addition to its widespread application in the area of chronic hemodialysis, this technology is of essential importance for the treatment of acute kidney failure, liver failure, sepsis and multiple organ failure. Fresenius Medical Care has been developing methods, devices and disposable products for the treatment of such diseases for many years. We see our primary mission as developing equipment and processes that help to reduce the still dramatically high mortality rates of these diseases.

There are already promising approaches for treating liver failure which reconstruct the complex functions of the liver using living cells in an extracorporeal system. The challenge here is the availability of living cells of suitable quality and in appropriate volumes rather than development of the extracorporeal systems. We are therefore currently focusing our development activities on cell production with the aid of appropriate stem cell technologies; we only use adult stem cells. This work is being conducted in close cooperation with internationally recognized academic institutions.

INFUSION THERAPY AND CLINICAL NUTRITION

Fresenius Kabi’s research and development efforts are focused on infusion therapy and clinical nutrition. Our development competence spans all product-relevant components: the primary packaging, pharmaceutical solutions for infusion therapy and clinical nutrition, medical devices for application and the manufacturing technology for their production.

The research and development strategy is built on two pillars:

In this way we are making an important contribution toward achieving medical advancements in the therapy of critically and chronically ill patients and for improving their quality of life.

Infusion therapy

The use of blood volume substitution products in emergency and intensive care medicine has been a focus of research and development at Fresenius Kabi for decades. Our blood volume substitution products contain hydroxyethyl starch (HES) based on waxy maize starch. The HES molecules adhere to the fluid in a blood vessel, thus insuring that the fluid remains in the vessel and does not pass rapidly into the surrounding cells and tissue.

In 2007, we successfully completed the development of a new blood volume substitution solution and have already launched the product in Switzerland, the first market. During operations or in an intensive care unit, large quantities of blood volume substitution products may be required. The electrolyte composition of the new product is matched to blood plasma. This reduces chloride stress and thus prevents hyperacidity.

In 2007, in our clinical research activities in blood volume therapy, we also started a controlled, double-blind, multicentric study involving our Voluven® 6% product for sepsis patients. In December 2007, we received regulatory approval for Voluven® 6% from the U.S. Food and Drug Administration (FDA).

HESylation technology is another focus of our research and development work. This technology platform enables an active pharmaceutical substance to be coupled to specific hydroxyethyl starch molecules, decisively modifying a drug’s profile. Such coupled products usually have a longer half life and a better safety profile than unmodified drugs. We are working in partnership with pharmaceutical companies to further develop the potential of this technology. 

In the field of intravenously administered generic drugs (I.V. drugs) we focus on antiinfectants, anesthetics, analgesics and drugs that are used in oncological diseases. In our development portfolio we have an extensive range of active substances which will be ready for market launch in the near future. We are working on the registration dossiers for their marketing authorization in Europe and outside Europe.

In 2007, we submitted the certification documents for six I.V. drugs to the responsible regulatory authorities and expect to launch these products on the market in 2008. We plan, for instance, to introduce antibiotics that can be used for particularly severe infections.

We also continued with preparations for an international rollout of the I.V. drugs obtained with the Filaxis acquisition. These are cytostatic drugs used in oncological diseases. We submitted the documents for regulatory approval for the first product to the relevant authorities in 2007.

The level of technology and manufacturing capacity at our production site in Campo de Besteiros in Portugal makes it our center of competence for the production of I.V. drugs. To expand production capacity at this site, we have brought into operation an additional sterile unit for the manufacture of antibiotics.

Clinical nutrition

In parenteral nutrition our focus is on the development of innovative pharmaceuticals that have a high therapeutic effect in the care of critically and chronically ill patients. Sufficient energy and an appropriate combination of nutrients are crucial for maintaining body mass and are also important for a patient’s immune system, for maintaining and improving organ functions and for rapid wound healing. For parenteral nutrition we offer single component nutrients and nutrient combinations in two and three-chamber bags.

Our product SMOFlipid® is used specifically for the parenteral nutrition therapy of intensive care patients. We believe the high therapeutic relevance of SMOFlipid® can also play an important role in the parenteral nutrition of critically ill children. In 2007, we successfully completed a further clinical study of this product in pediatric care, and will be submitting the registration files for approval of its use in this medical field.

So far we have been offering SMOFlipid® as an individual product. In 2007, we received regulatory approval for SMOFlipid® as the lipid component in our three-chamber bag for the Swedish market. Market launches in other countries are planned.

Extensive data from studies document the positive effect of the amino acid glutamine on metabolism and immune competence. Our product Dipeptiven® is a concentrate of the dipeptide alanyl glutamine that can be added to all parenteral nutrition regimes according to compatibility. The amino acid glutamine is conditionally essential – not vital for healthy people but necessary for severely ill patients in a catabolic metabolic condition, for instance following trauma, surgery, or with sepsis. Glutamine is required in large amounts as a source of energy and nitrogen by the intestinal and immune cells of these patients, serving to maintain the structure and functioning of the intestine. If these patients are not supplied with glutamine, they can suffer a glutamine deficiency and associated functional disorders. In 2007, we continued to support a clinical study with Dipeptiven®. The aim of this study is to demonstrate the clinical therapeutic benefit of high doses of glutamine dipeptide.

In the development of enteral nutrition products we apply a comprehensive catalogue of criteria: We consider the patients’ illness, their nutritional condition, the probable length of the illness and the patients’ age. From this we determine the composition, the optimal quantity and the preferred form of administration – sip feed or tube feed nutrition. With enteral sip feed nutrition products we consider not only a formulation matched to the patient’s needs but also the flavor of the product. To prevent so-called taste fatigue in patients who take enteral sip feed nutrition products over a long period of time, a wide range of varieties and flavors is important.

In 2007, we therefore continued to work intensively on the further development of our sip feed nutrition products. Our product lines Fresubin® energy DRINK and Fresubin® energy fibre DRINK are suitable for use as supplemental or total nutrition. With 1.5 kilocalories per milliliter they are especially rich in calories. The products are characterized by their high nutrient-density and just three 200 ml Tetras-Brik packs are sufficient to supply patients with all vitamins and trace elements they require each day. To offer tasty sip feed nutrition products and at the same time more variety in the choice of products, especially for chronically ill patients, we have further improved the flavor of Fresubin® energy DRINK and Fresubin® energy fibre DRINK and have added new flavors to the range. 

In 2007, we worked on a further variant in the sip feed nutrition line Fresubin® for patients in convalescence with indications of nutritional deficiencies who require a higher intake of energy and protein, or whose fluid intake is restricted. Fresubin® 2kcal Drink is a sip feed nutrition product with a high energy density (400 kcal per Tetra-Brik), high in protein (10 g/100 ml) and excellent flavor. We will be launching this product internationally in 2008. Fresubin® 2kcal Drink is available with prebiotic fiber or without fiber. For many patients the high nutrient density is very important since even a small drink volume of only 200 - 400 ml can assure a balanced supply of nutrients. Moreover, with small volumes, patients tend to ingest the required intake of nutrients far more reliably.

We have successfully completed our multi-centric clinical research study on Diben. Diben is a tube feed nutrition which improves the blood sugar level of diabetes patients in longterm enteral nutrition. The results of the study have confirmed the high therapeutic benefits of this product for patients with diabetes who require long-term tube feed nutrition, for instance after a stroke resulting in a permanent inability to swallow. The study revealed a significantly better blood sugar level with a decreased demand for insulin. This suggests that Diben can reduce the risk of fatal sugar deficiencies.

In 2007, we started working on the development of a new line of enteral products for patients who have difficulty swallowing. For healthy people swallowing is a natural, unconscious process. We only become conscious of this swallowing process when it is impaired due to a restriction or lack of coordination between the mouth and throat muscles. Dysphagia is the term used to refer to difficulties in controlling the swallowing process, which can have a wide range of causes, for instance stroke, cancer diseases, neurological ailments and Morbus Parkinson. In patients with dysphagia the swallowing reflex is delayed or does not function at all. This can cause aspiration if, as a result of the lack of muscle coordination, solid or liquid matter enters the respiratory tract. If an aspiration goes undetected, there is a heightened risk of pneumonia. Often quite unconsciously, dysphagia patients tend to avoid eating and drinking for fear of swallowing and choking. Resulting nutritional deficiencies and dehydration can be effectively remedied with a product line specially tailored for this group of patients.

At our center of competence for packaging technology in Friedberg, Germany, we worked on the development of a new container for enteral sip feed nutrition products in 2007. Employing a new packaging concept, the aim is make extraction of the fluid easier, and thus improve the convenience for the user.

ANTIBODY THERAPIES

Fresenius Biotech develops innovative therapies with trifunctional antibodies for the treatment of cancer. For many years Fresenius Biotech has been successfully marketing ATG-Fresenius S, a polyclonal antibody. This is an immunosuppressive agent used to suppress graft rejection following organ transplantation.

Trifunctional antibodies

The results of the phase II/III pivotal trial using the trifunctional antibody Removab® (INN: catumaxomab) for malignant ascites were published in 2007. They show a clear advantage of Removab® over the standard therapy in primary as well as secondary endpoints. In the study 258 patients who had developed malignant ascites as a result of different epithelial tumors, such as ovarian cancer or gastric cancer, were treated either with Removab® or, in the control group, only employing peritoneal puncture. The primary endpoint of the study was the median puncture-free survival period, in other words the time until the first puncture was required or death. With Removab®, this period of time was prolonged more than fourfold compared to the standard therapy (46 as compared to 11 days). In the secondary endpoint – median time to the first therapeutic puncture –, the treatment with Removab® was also found to be clearly superior, with 77 days as compared to 13 days in the control group.

Further results in the secondary endpoints of the study indicate that the trifunctional antibody has a direct influence on the underlying tumor. The median time until the tumor disease progressed again was 111 days with Removab® as compared to 35 days in the control group. This is further significant indication of its efficacy. A positive trend was also observed for overall survival. The safety profile of Removab® in the study was good.

The results of this study were presented in 2007 at the American Society of Clinical Oncology (ASCO) Annual Meeting in Chicago and at the European CanCer Organisation (ECCO) Congress in Barcelona. In light of the statistically significant results of the phase II/III study, Fresenius Biotech dispatched an application to the European Medicines Agency (EMEA) at the end of 2007 for approval of Removab® for the intraperitoneal treatment of malignant ascites following epithelial tumors in cases where standard therapies are not available or are no longer feasible. The application documents contain not only the results of the clinical study but also data from preclinical studies as well as information about production and product quality.

Parallel with the authorization process, Fresenius Biotech began preparations for marketing Removab® in Europe. Fresenius Biotech is currently also offering Removab® to potential development and marketing partners for the United States and Japan.

The effectiveness and safety of Removab® in the indication of malignant ascites are currently also being tested in a US phase II study. This study is largely pursuing the same aims as the successful European authorization study.

Two phase II studies have been initiated on the effectiveness and safety of Removab® for advanced ovarian cancer. One has since been completed. In the European study, the safety, tolerance and effectiveness of the intraperitoneal administration of the trifunctional antibody during and after removal of the tumor by surgery were compared with treatment by surgery alone.

Other phase II studies – in the United States and in Europe – are testing the effectiveness and safety of Removab® on patients with ovarian cancer. In the US study, patients who no longer reacted to a platinum-based standard chemotherapy, and who therefore had no further therapy options, were treated with Removab®. The European study is examining whether early therapy with Removab® is compatible and whether it has an effect on the recurrence of the tumor.

The development program for the antibody Rexomun® (INN: ertumaxomab) is continuing as planned with phase II studies on patients with advanced breast cancer. Two European studies are investigating the effectiveness of Rexomun® on patients who, following the failure of a hormone therapy, are not suitable for other antibody therapies and for whom there is no standard therapy.

Further information on the clinical studies can be found on our website at http://www.fresenius.com/ Fresenius Biotech.

Immunosuppressive agent ATG-Fresenius S

In the field of polyclonal antibodies, we generated sales of ATG-Fresenius S of around € 19 million (2006: €19 million). The clinical development of ATG-Fresenius S for other applications and distribution in new markets was continued. An important project is the clinical trial for the use of ATG-Fresenius S in stem cell transplantation. The study examines the effect of ATG-Fresenius S on the prophylaxis of acute Graft-versus-Host Disease. The standard therapy (Cyclosporin A and methotrexate) is being compared with the standard therapy plus the additional administration of ATG-Fresenius S. The recruitment of patients was completed in the first quarter of 2007. Two intermediate analyses have confirmed that ATG-Fresenius S is safe at the selected dosage. A final report will be published in 2009, at the end of the two-year observation period.

In our development program for the United States, we took over a study from our former cooperation partner Nabi Biopharmaceuticals at the end of 2007. This study, currently in progress, uses ATG-Fresenius S in lung transplantation. The study compares the effects of two different ATG dosage regimes and a placebo (double-blind and placebo controlled) on organ rejection and mortality rates on patients six months after transplantation.

R & D financial figures can be found in the Management Report.