MARCO LEGAL Y NORMATIVO DE LOS PP EN COLOMBIA

foCus of ReseARCh ANd developmeNT ACTiviTies

The Biotest Group’s R&D activities are aimed at strengthening its position as a provider of highly specific products for immunology and haematology. In plasma proteins our focus is on developing new indications for our products and making the products easier to handle, such as by providing simpler forms of application. Biotest has the competences and resources needed to take plasma protein devel- opment projects forward from the pre-clinical phase to approval with own teams.

In monoclonal antibodies the lead indications – serious autoimmune and haematological diseases – complement the therapeutical indications of our plasma proteins. For this reason Biotest already has extensive experience with these indications and is also very well linked to research institutions and hospitals that are active in this field.

The cooperation with a development and marketing partner that is planned from clinical phase III is intended to enable Biotest to give high priority to the continued development all three monoclonal antibodies. Proportionate to development progress, Biotest is continually expanding its own resources in the Biotherapeutic segment.

In the Microbiological Monitoring segment the focus of our research and development continues to be on developing solutions to increase the efficiency and safety of hygiene monitoring. These include both improved test media and further development of automation concepts.

ReseARCh ANd developmeNT iN fiNANCiAl yeAR 2009

In financial year 2009 Biotest spent €48.5 million on research and development, equivalent to 11.0% (2008: 11.0%) of Group sales. It was invested for the most part in personnel expenses and external costs for the outsourcing of pre-clinical, clinical and production activities.

Research and development expenditure by segment

The number of Biotest Group employees engaged in research and development rose by 14.5% to 173.4 (full-time equivalents) in the course of 2009. This figure corresponds to 9.5% of the total headcount.

€ million 2009 2008 Change in % Plasma Proteins 25.7 24.0 7.1 Biotherapeutics 20.7 16.6 24.7 Microbiological Monitoring 2.1 1.7 23.5 Total 48.5 42.3 14.7

Key ReseARCh ANd developmeNT ResulTs Plasma Proteins segment

In addition to approvals of Intratect®, Albiomin als well as of the hepatitis B immunoglobulins Hepatect® and Zutectra® already mentioned in the presentation of business development (cf. page 47), we achieved major progress in other R&D projects in financial year 2009.

New developments

IgM concentrate: In June 2009 we started the clinical development of IgM concentrate, a product

manufactured in Dreieich, Germany. In the phase I clinical trial the preparation was administered to 24 healthy volunteers. The aim of the trial was to investigate its tolerability and pharmacokinetics. No serious side effects occurred either during treatment or in the 13-week follow-up phase.

The product is being developed for a range of indications comparable with those for Pentaglobin®, which has already been approved. The new preparation has an even higher IgM content and could therefore exhibit an improved functional activity in the patient.

CivacirTM_{: BPC is developing this hyperimmunoglobulin for the hepatitis C virus reinfection prophylaxis}

indication after a liver transplantation with the aim of securing approval in the United States and the European Union. In financial year 2009 we collected additional pre-clinical data in order to achieve an optimal antibody concentration for this preparation. The results thus obtained on its virus-neutralising effect were very good.

Intravenous immunoglobulin (IVIG): In the phase III clinical trial, treatment of the last patient included

was completed in May 2009 at the end of the 12-month scheduled duration of treatment. Work on the final clinical report began after the end of the obligatory three-month follow-up phase in August 2009. This preparation is being developed solely for the US market. Approval is to be applied for in the third quarter of 2010.

Zutectra®: Along with the EU approval procedure, we prepared for the hepatitis immunoglobulin’s

market launch in the reporting year. After the approval was granted in December 2009, distribution commenced at the beginning of 2010.

Further development of existing products

Intratect®: A phase III clinical trial delivered highly promising data on the drug’s efficacy in treating

chronic pain syndrome/fibromyalgia. The pain level was successfully reduced to a statistically signifi- cant and clinically relevant extent. Further immunological tests are planned to show which groups of patients can benefit from immunoglobulin therapy.

Cytotect®: An international phase III trial was initiated to secure approval in the indication “avoiding

the transmission of a cytomegalovirus infection and preventing disablement of the unborn child during pregnancy”. By the end of 2009 about 4,000 pregnant women had been included in the trial.

As primary CMV infection occurs in about 1% of pregnancies, approximately 20,000 additional women need to be included in the trial. In the second half of the year additional large hospitals in further European countries were included in the trial. The aim of this measure is to speed up the project’s progress.

Biotherapeutic segment

In September 2009, clinical development of BT-063 began with the first administration of the antibody to a healthy volunteer. All three monoclonal antibodies in Biotest’s pipeline are now in their clinical phase.

Progress of clinical and pre-clinical trials

In financial year 2009, six clinical trials of Biotest’s three monoclonal antibodies were under way. The documentation for a further trial on the development of BT-061 was submitted in September 2009, and the documents for a further trial of BT-062 were submitted to the FDA in October 2009.

Clinical trials in the Biotherapeutic segment

Type of trial

and indication Trial no. Dosage / trial design

Planned number of

participants Status*

BT-061

Phase I

Tests on healthy volunteers

961 Up to 60 mg intravenously, up to 180 mg

subcutaneously, single dose

57 Administration to

healthy volunteers completed, final evalution available Phase IIa

Rheumatoid arthritis 962 Up to 100 mg subcu-taneously and 25 mg intravenously, multidose, treatment duration six weeks, placebo-controlled

96 Patient recruitment ongoing (final group for treatment), positive results of interim analysis available Phase II Rheumatoid arthritis (BT-061 + MTX**, placebo-controlled) 971 0.5 mg and 2.0 mg intravenously, 50 mg subcutaneously, multidose, treatment duration eight weeks

110 Intravenous administra- tion: treatment of patients completed, results of interim analysis available

Subcutaneous administra- tion: patient recruitment under way

Phase I/IIa Psoriasis

967 Up to 20 mg intravenously, up to 25 mg subcutane- ously, single dose, placebo- controlled

56 Treatment of patients completed, final evalution available by March 2010 Phase II Psoriasis 973 Multidose, intravenous and subcutaneous, placebo-controlled, treat- ment duration eight weeks

48 First patients enrolled in February 2010

BT-062

Phase I

Multiple myeloma 969 Repeated single dose, intravenously, every 21 days, 10-200 mg/m2

34 Trial in progress, presentation of interim results in December 2009 (ASH) Phase I/IIa

Multiple myeloma 975 Repeated multidose (split dose), intravenously 60 Protocol approved by FDA in November 2009

BT-063

Phase I

Tests on healthy subjects 977 Single dose, intravenously, up to 100 mg 24 First administration to healthy volunteers in September 2009

*) Status as of 31 December 2009 unless otherwise stated

BT-061 development:

Trial 961 on healthy subjects, which was scheduled to have been completed in the fourth quarter of 2008, was extended. Further dosages were tested to provide additional data about the safety and tole- rability of the antibody in higher doses, which were administered subcutaneously. The final evaluation of this trial is available.

In trial 971 the antibody was originally to be administered intravenously (IV) only. After already having reached the optimal effective level with low intravenous doses, we added subcutaneous administra- tion to the trial design. That has brought us a step closer to our development target of taking BT-061 to approval as a preparation for subcutaneous administration. In October 2009 Biotest presented the results of data analysis from a first, unblinded part of the trial.

For the indication psoriasis a phase II clinical trial has been initiated based on the positive data from phase I/IIa.

BT-062 development:

The phase I clinical trial went on according to plan in financial year 2009. As multiple myeloma is an oncological disease, we were already able to test the immunoconjugate consisting of a monoclonal antibody and a highly effective cytotoxic agent for this indication in patients in clinical phase I. In December 2009, Biotest presented preliminary data from the trial at the American Society of Hema- tology (ASH) meeting in New Orleans, in which 25 patients had been involved up to that date. Based on encouraging results in respect of efficacy and the good tolerability observed to date, Biotest continued with the development of BT-062 and initiated a trial with a more intensive dosage schedule. With a view to the planned clinical development in Europe we established a Scientific Advisory Board with European oncologists. Clinical development of BT-062 in Europe will probably begin in 2011 once a dosage schedule has been agreed upon.

BT-063 development:

After approval of the phase I clinical trial by the relevant authority and the ethics commission, BT-063 was administered to first healthy volunteers in September 2009. So far, the antibody has proved very tolerable.

Results to date

All clinical development data available so far has been very satisfactory. The monoclonal antibodies have generally proved to be highly tolerable. Signs of clinical efficacy were found for both indications. The phase I BT-062 trial also revealed initial indications of efficacy. In 53% of patients progress of the tumour was arrested for more than six weeks, and in one case for as long as 30 weeks.

Microbiological Monitoring segment

The focus of R&D activities in 2009 was on solutions to shorten the process on the basis of the polymerase chain reaction (PCR), reducing the time required between taking samples and achieving results.

In July 2009 we launched newly developed real-time PCR test kits to demonstrate the existence of bacterial pathogens, such as salmonella, in food. These test kits are used for quality assurance in the food sector to comply with statutory standards and requirements in a wide range of areas, such as baby food or milk products.

In September 2009 a real-time rapid PCR test was launched for hygiene monitoring in pharmaceutical industry cleanrooms. This innovative test to identify swiftly and easily microorganisms that occur frequently is based on molecular genetic methods and is a good addition to our culture medium programme for this target group. Further PCR-based products are under development.

Patent protection

By submitting an additional seven patent applications in the Biotherapeutic segment Biotest continued its strategy of seeking wide-ranging protection of in-house developments in the financial year. The patents relate both to clinical application of the antibodies and to their mechanism of action.