Merck Eprova and Isofol Medical Enter Exclusive Agreement for Merck Eprova’s Modufolin® in oncology

• Leucovorin has been a mainstay of colorectal cancer treatment for 50 years
• Modufolin® may offer an improved profile over leucovorin in cancer therapy
• New licensing deal will allow clinical trials to begin later this year

Schaffhausen/ Switzerland, November 11, 2009 – Today Merck Eprova AG announced that the company has signed an exclusive license agreement with Isofol Medical AB of Sweden to utilize Merck Eprova’s proprietary folate compound Modufolin® in oncology. The use of Modufolin® is expected to enhance effectiveness compared to currently used folate compounds in cancer treatment. Merck Eprova AG will be providing Modufolin®, the active metabolite of LV (Leucovorin), for use in clinical trials and commercial drug products.

After years of intensive research, Merck Eprova AG has succeeded in developing a stable form of the reduced folate Modufolin® ([6R]-5,10-methylenetetrahydrofolate). This breakthrough opens an avenue for testing novel folate-based drug combinations in cancer treatment.

Modufolin® is a biomodulator originally designed to replace LV as the preferred folate to enhance the activity and reduce associated toxicity of 5-FU (5-fluorouracil), a widely used anti-cancer drug. The active form of 5-FU is an inhibitor of the key enzyme TS (thymidylate synthase). Blocking the synthesis of the nucleotide thymidine leads to inhibition of DNA replication and cell death. The effectiveness of 5-FU/LV in combination therapy may be limited due to several metabolic conversions of LV required to generate the pharmacologically active folate compound Modufolin®. In contrast Modufolin® does not need any further metabolic activation. In the tumour tissue this specific form of folate is directly usable by the target enzyme TS, potentially allowing 5-FU to work more effectively.

Isofol Medical AB ( is a medical development company, based in Sahlgrenska Science Park, Gothenburg, Sweden. The company specializes in the use of Modufolin® in combination with chemotherapeutic agents to increase efficacy and decrease side effects when treating cancer. The founder of Isofol, Prof. Bengt Gustavsson at Sahlgrenska University Hospital in Gothenburg, started research on the effects of reduced folates in combination with chemotherapeutic agents 30 years ago under the world renowned scientist Charles Heidelberger who first synthesized 5-FU. The work led to the discovery of the positive effects of the reduced folate LV in combination with 5-FU in the treatment of cancer. The combination 5-FU/LV has become a standard co-therapy of colorectal cancer, with annual sales of over USD 700 million in US/EU markets. For more than 15 years the research collaboration between Prof. Gustavsson and Merck Eprova AG has been ongoing in the research on effects in combining folates with antifolates in oncology treatment. In pre-clinical and early clinical studies using Modufolin® in combination with chemotherapeutic agents the companies have achieved proof of concept with increased efficacy and decreased side effects vs. LV. Isofol Medical AB has filed for patent protection in all major markets.

Isofol Medical AB will conduct phase I and II studies using a combination of Modufolin® and antifolates starting in autumn 2009 and expected to be finished by the end of 2010.

Merck Eprova AG . Switzerland
Im Laternenacker 5 . CH-8200 Schaffhausen
Tel. +41 (0)52 6307 272
Fax +41 (0)52 6307 255

Merck Eprova AG (, located in Schaffhausen, Switzerland, is a wholly owned subsidiary of Merck KGaA located in Darmstadt, Germany. In the pharmaceutical and nutritional field Merck Eprova AG is recognized as a centre of excellence for reduced folates. Merck Eprova AG is the world’s leading supplier of reduced folates such as Leucovorin and Metafolin®. In addition to this focus, Merck Eprova AG specializes in the development and production of cGMP grade, highly purified and characterized drug delivery compounds such as cationic lipids, PEGs, PEG-lipids, and phospholipids.

Merck is a global pharmaceutical and chemical company with total revenues of € 7.6 billion in 2008, a history that began in 1668, and a future shaped by approximately 33,000 employees in 60 countries. Its success is characterized by innovations from entrepreneurial employees. Merck’s operating activities come under the umbrella of Merck KGaA, in which the Merck family holds an approximately 70% interest and free shareholders own the remaining approximately 30%. In 1917 the U.S. subsidiary Merck & Co. was expropriated and has been an independent company ever since.

Modufolin® is a registered trademark of Merck KGaA, Darmstadt, Germany
Metafolin® is a registered trademark of Merck KGaA, Darmstadt, Germany