Company history

A research and development company

Isofol Medical is based on a co-operation between its founder Prof. Bengt Gustavsson and Merck Eprova, the world's leading supplier of reduced folates. Gustavsson in 1978 co-discovered that the folate Leucovorin (LV) could significantly increase efficacy and decrease side effects the cytotoxic 5-FU. After establishing that the active metabolite in LV was MTHF (Methylene-Tetrahydrofolate) and that only around 30% of patients treated could transform Leucovorin into MTHF, Gustavsson started to collaborate with researchers at Merck Eprova. 15 years ago, their collaboration resulted in a stable racemic form of MTHF, which Gustavsson in clinical phase I and II trials found to be significantly more effective in combination with 5-FU compared to Leucovorin.

Gustavsson has since continued his research and he has, together with his skilled research team, succeeded in identifying the biologically active isomer in MTHF. In 2005 Merck Eprova managed to do what scientists up until then considered impossible; to synthesize a stable, non-racemic form of MTHF. The novel pharmaceutical substance has been given the name Modufolin®. Modufolin® opens up great possibilities for increasing the efficacy and decreasing the side effects of several cytotoxics used in various cancer treatments.

Merck Eprova has recently signed an exclusive agreement with Isofol Medical for the development and commercialization of Modufolin® and Isofol Medical now has ongoing combined phase I and II clinical trials to verify the benefits of using Modufolin® as a co-therapy in the treatment of cancer.

Folates were discovered in the 1930’s

The history of research into the effects of folates, which are derivatives of folic acid or vitamin B9, goes back almost 80 years to 1931 when a scientist by name of Lucy Wills identified folates as a nutrient was needed to prevent anemia during pregnancy. Dr. Wills demonstrated that anemia could be reversed with brewer’s yeast and in the late 1930s scientists indentified folates as the corrective substance. The crystalline form of folates was first isolated in spinach leaves in 1941, and in 1943 folates was isolated in a pure crystalline form. It was early recognized that the active metabolites of folates were essential for numerous bodily functions such as the ability to stimulate cell growth.

Folates as a co-therapy in cancer treatment

In 1957, the world renowned scientist Dr. Charles Heidelberger synthesized the cytotoxic 5-fluororacil (5-FU). 5-FU is still today a dominating component of several treatment protocols of cancer, including colorectal cancer which is the second most commonly diagnosed type of cancer today. As the side effects of 5-FU were severe, Heidelberger started work on trying to mitigate these effects without lowering the anti-tumor effect of the cytotoxic. 21 years later, in 1978, two young scientists working for Heidelberger, discovered that by mixing 5-FU with a reduced folic acid called Leucovorin (LV), one could decrease the adverse events of 5-FU and at the same time increase the tumor-reducing effect of 5-FU. This discovery, based on combining 5-FU with a folate, was contrary to what scientific expertise believed possible at the time and therefore became the subject of much dispute. The combination gradually gained acceptance however and it became a worldwide dominating combination treatment against colorectal cancer. 5-FU-LV is still selling for USD 700 million in the US and EU markets alone and it is selling for an estimated USD 2 billion worldwide. Sales of LV alone, in combination with several cytotoxics for various indications, are estimated to USD 2 billion annually.

Bengt Gustavsson co-discovered 5-FU-LV

The pair that made the discovery of the synergistic effects by combining LV with 5-FU in 1978 was Bengt Gustavsson, a cancer surgeon and scientist working at the University Hospital of Sahlgrenska in Sweden, and Paul Spears, a scientist at the University of Southern California. Paul Spears later left the work on the effects of folates on cytotoxics to concentrate on cancer mathematics. Bengt Gustavsson however continued his research on the possibility of combining folates with cytotoxics to reduce their side effects and to increase their efficacy.

MTHF is a key metabolite of Leucovorin

Gustavsson’s continued research, carried out together with several skilled researchers at Sahlgrensa University, showed that the 5-FU-LV combination was only effective on about 30% of the patients treated. The team managed to identify the biologically active key metabolite of LV, which is Methylene-Tetrahydrofolate (MTHF). MTHF facilitates the synthesis of DNA in human cells and it is generated from LV through three enzymatic reactions. Variations among individuals in the structure of these enzymes are believed to be the reason why LV only has an effect on about 30% of all patients. The remainder cannot simply transform LV into MTHF, hence no positive effect in 5-FU-LV treatment is experienced. Gustavsson also found that even in the patients that did react positively to LV, the metabolic processes strongly decreased the effect of the compound. His conclusion was therefore that if one could synthetically produce and administrate MTHF directly, one would not only be able to provide a combination treatment with 5-FU for all those who cannot metabolize LV, but also strengthen the effect in the 30% that could make use of LV.

Racemic MTHF was synthesized in 1993

To successfully synthesize MTHF, Gustavsson started collaborating with a small company producing folates in Lugano, Switzerland. This later lead to a close research collaboration with the world leader in folate synthesis, Merck Eprova located in Shaffhausen, Switzerland. This close collaboration has been ongoing for over 15 years and it forms one of the cornerstones in Isofol Medical’s development. Early in the 90’s, the collaboration resulted in the production of a so called racemic form of MTHF. This racemic form comprised of equal amounts (50/50) of two compounds which were mirror images of each other, i.e. they were optical stereoisomers. Pre-clinical studies made by Gustavsson showed that the racemic form of MTHF in certain cases proved to increase toxicity of 5-FU. Overall however, the racemic form substantially increased the positive effects on 5-FU when compared with LV. Gustavsson was thereafter allowed by regulatory authorities to conduct phase one and phase two clinical trials which proved a significantly increased positive effect on humans.

A decade of research resulted in Modufolin®

A non-racemic form of MTHF was now strongly desired. After intensive research, Gustavsson identified the isomer which had a positive biological effect in humans and wanted to exclude the other, less effective and potentially toxic, isomer. Until a few years ago, it was considered impossible to generate a stable isomer of MTHF due to the compound’s high sensitivity to oxidation by air. Having spent over a decade of research and 35 million USD in total development costs, a breakthrough was finally reached in 2005. Almost 30 years after Gustavsson participated in the discovery of the positive effects on 5-FU by LV, the collaboration between Merck Eprova and Gustavsson resulted in a synthetically produced non-racemic form of MTHF. The novel pharmaceutical substance was given the name Modufolin®.

Isofol Medical was founded in 2008

Bengt Gustavsson founded Isofol Medical in 2008 and Isofol Medical today holds pending patent protection for Modufolin® across all major markets. In 2009, Isofol Medical entered into an exclusive global license-, production- and cooperation agreement with Merck Eprova to develop the use of Modufolin® for a wide range of cancer treatments. Merck Eprova also holds the trademark and the intellectual property rights for the production process of Modufolin®.

Modufolin® improves efficacy and reduces side effects

Pre-clinical trials have demonstrated that Modufolin® makes 5-FU significantly more effective both in comparison with 5-FU-LV and in comparison with racemic MTHF combined with 5-FU. Early studies also show the same synergistic effects when combining Modufolin® with antifolates, another class of cytotoxics frequently used in cancer treatment. Isofol Medical now has ongoing combined phase I and II clinical trials to verify the great benefits of using Modufolin in combination with cytotoxics. The trials will be ongoing during 2010 and the first half of 2011.



5FU-LV treatment regimen co-discovered by Prof. Bengt Gustavsson.


Racemic MTHF synthesized by Merck & Cie.


Modufolin® manufactured as a stable pharmaceutical composition by Merck & Cie.


Isofol Medical founded.


Exclusive agreement established between Merck & Cie and Isofol for the use of Modufolin® in cancer treatment.


Swedish MPA approves Isofol's first clinical trial. Isofol's first patent family granted in Europe.


Isofol Medical initiates phase I and II clinical trials with Modufolin®, its lead clinical candidate.
Isofol Medical AB, Biotech Center, Arvid Wallgrens Backe 20, SE-413 46 Gothenburg, Sweden
Phone: +46 (0) 707 64 65 00 / +46 (0) 739 89 55 28 E-mail: