Industrial

Roche (Switzerland)

ThromboGenics and BioInvent entered into a license agreement with Roche for their jointly developed anti-cancer agent TB-403. TB-403 is a novel monoclonal antibody which blocks Placental Growth Factor (PIGF), one of the growth factors responsible for the development of new blood vessels.

Under the terms of the agreement, ThromboGenics and BioInvent received an upfront payment of €50 million. In addition, ThromboGenics and BioInvent could potentially receive up to €450 million over the term of the collaboration based on the successful completion of a series of development and commercial milestones for multiple indications, as well as double digit royalties on potential product sales, including any backup antibodies based on inhibition of PlGF. ThromboGenics, which discovered TB-403, will receive 60% and BioInvent 40% of the revenue from the deal. Roche will have a worldwide, exclusive license to develop and commercialize TB-403. ThromboGenics and BioInvent will retain co-promotion rights for the product in the Benelux, Baltic and Nordic regions.

TB-403 has the potential to be a major advance in the treatment of cancer. It is a humanized monoclonal antibody that blocks the formation of the new blood vessels that are needed by solid tumours to support their growth. TB-403 has the potential to minimize both the growth and spread of cancer cells.

Rhein Minapharm (Egypt/Middle East)

ThromboGenics and Rhein Minapharm entered into a license agreement for manufacturing, clinical development and commercialization of THR-174, the next-generation derivative of Staphylokinase, in the Middle East, Africa and other countries comprising the MENA region. THR-174 is a recombinantly derived thrombolytic agent developed for treatment of acute myocardial infarction (heart attack). In return for granting this license, ThromboGenics will receive upfront and milestone payments, and will earn double digit royalties on net sales. Rhein Minapharm will assume responsibility for all future costs.

In preclinical studies, THR-174 has shown improved efficacy, safety and, most importantly, reduced immunogenic response compared to earlier versions of Staphylokinase, as well as to established thrombolytics, such as streptokinase. Unlike streptokinase and other therapies, THR-174 produces a lower antibody response or allergic reaction. This means that it could potentially be administered to most patients more than once, allowing treatment of subsequent cardiac events and improving quality of care, with minimal side effects and without the use of steroids.

The agreement between ThromboGenics and Rhein Minapharm is designed to develop and commercialize THR-174 as a replacement for established thrombolytics, such as streptokinase, in the Middle East, Africa and other countries. As part of this license deal, ThromboGenics will transfer its THR-174 technology to Rhein Minapharm, which will manufacture the finished drug. With input from ThromboGenics, Rhein Minapharm will be responsible for developing the commercial manufacturing process, implementing a clinical development plan, and gaining marketing authorization to commercialize THR-174 in the Middle East, Africa and other countries. THR-174 is expected to be launched by 2010.

Bharat Biotech International Limited (India)

ThromboGenics and Bharat Biotech International Limited entered into a license agreement for manufacturing, clinical development and commercialization of THR-100*, a novel variant of Recombinant Staphylokinase, in developing countries and certain industrialized countries. THR-100 is a thrombolytic agent developed for treatment of acute myocardial infarction (heart attack) and other vascular diseases based on its ability to dissolve blood clots. In return for granting this license, ThromboGenics will earn double digit royalties on net sales. Bharat Biotech will assume responsibility for all future costs.

THR-100 has completed Phase II clinical trials in Europe for treatment of AMI in over 140 patients. In the clinic, THR-100 has demonstrated efficacy equivalent to tPA, or tissue plasminogen activator (considered the “gold standard” for thrombolytic therapy), but at significantly lower patient cost than tPA. THR-100 has also shown superior efficacy to both streptokinase and urokinase, the most commonly used thrombolytic agents in the developing world for the treatment of AMI and other thrombotic conditions.

The objective of the agreement between ThromboGenics and Bharat Biotech is to develop and commercialize THR-100 as a replacement for established thrombolytics, such as streptokinase and urokinase, in developing markets. As part of this license deal, ThromboGenics will transfer its THR-100 technology to Bharat Biotech, which will become the global manufacturer for the finished drug. With input from ThromboGenics, Bharat Biotech will be responsible for developing the commercial manufacturing process, implementing a clinical development plan for Phase III trials, and gaining marketing authorization to commercialize THR-100, initially in India. Entry into markets outside of India is also planned as part of this alliance.

* formerly known as Sak42D

BioInvent International AB (Sweden)

ThromboGenics and BioInvent International AB entered into a collaborative research and licensing agreement in September 2004 to co-develop antibody-based drugs for vascular indications. Currently, the partners are jointly developing two candidates:

• TB-402 (Anti-Factor VIII) as an anticoagulant therapy for numerous indications, including prevention and treatment of deep vein thrombosis and treatment of atrial fibrillation; and

• TB-403 (Anti-PlGF) as an anti-angiogenic agent for potential treatment of various diseases, including cancer, age-related macular degeneration, retinopathies and inflammation.

The objective of this collaboration is to bring together a portfolio of expertise in the area of antibody discovery, development and manufacturing. BioInvent contributes its knowledge and experience in antibody discovery, production and immunology. ThromboGenics contributes its research and clinical development skills in the area of vascular medicine. Both parties provide core intellectual property based on specific therapeutic targets.

Millipore Corporation (USA)

ThromboGenics and Millipore Corporation entered into a license agreement under which ThromboGenics has licensed its technology for production of the proprietary stem cell culture medium marketed by Millipore as RESGRO(TM)*. The technology for producing RESGRO was originally developed by the ThromboGenics drug discovery team as part of its successful efforts to identify several of its drug discovery candidates currently in clinical trials.

Under this agreement, ThromboGenics has licensed to Millipore its patents, data and know-how for the manufacturing, development and evaluation of RESGRO. Millipore has assumed responsibility for the exclusive production and sales of the medium, as well as all future costs. ThromboGenics receives upfront and milestone payments, and will earn double digit royalties on Millipore's sales.

The success of RESGRO for worldwide use in stem cell research is the culmination of an extensive R&D effort at ThromboGenics. ThromboGenics has utilized this improved stem cell platform as a means to identify promising new drug candidates, several of which have now advanced into clinical trials.

* RESGRO and Chemicon are Milipore owned trademarks. RESGRO is also known as TX-WES Stem Cell Medium

Roche Diagnostics (Switzerland) and Biosite Inc. (USA)

ThromboGenics, along with its partner Geymonat, has entered into two co-exclusive licensing agreements, with Roche Diagnostics and Biosite Inc., for use of PlGF (Placental Growth Factor) in diagnostic applications. ThromboGenics and Geymonat have out-licensed the use of PlGF as a diagnostic marker for the prediction of major cardiac events, such as heart attack, and pre-eclampsia, a disease of pregnancy. ThromboGenics and Geymonat received upfront payments upon signing these agreements, and will receive milestone payments tied to submission to regulatory authorities and approval for commercialization, as well as royalties on net sales.

Geymonat SpA (Italy)

ThromboGenics and Geymonat SpA entered into a cooperation agreement for co-development of PlGF (Placental Growth Factor) in February 2004, as a pro-angiogenic growth factor which has shown potential in pre-clinical studies to treat conditions such as ischemic heart disease.

The objective of this collaboration is to bring together into a single intellectual property portfolio the patents covering both the composition-of-matter and use of PlGF. Geymonat owns the exclusive rights to the intellectual property characterising the protein sequence of PlGF. ThromboGenics owns the exclusive rights to the therapeutic applications of PlGF.