CHEM21 method could dramatically cut production costs of essential anti-fungal medicine

Press release: CHEM21 method could dramatically cut production costs of essential anti-fungal medicine

http://www.imi.europa.eu/content/chem21-flucytosine

Brussels, Belgium, 1 February 2017 – Scientists from the Innovative Medicines Initiative (IMI) project CHEM21 have developed a new, more efficient way of producing flucytosine, a medicine used to treat a common and often deadly fungal form of meningitis in people with HIV / AIDS. The new method, which is described in a paper in Organic Process Research & Development (OPR&D), is expected to decrease drastically costs of production, and so make the medicine more affordable for the many people with HIV/AIDS who live in low income countries. The CHEM21 team is now working to scale up the method to the industrial scale.

People with HIV / AIDS have weakened immune systems and so are particularly susceptible to fungal infections such as cryptococcal meningitis (CM), which is caused by the fungus Cryptococcus neoformans. There are 950 000 cases of CM worldwide every year, and 625 000 deaths, making CM the leading fungal cause of death for people with HIV / AIDS. The majority of cases are in sub-Saharan Africa.

The recommended treatment for CM is a combination of flucytosine and another drug called amphotericin B, both of which feature in the World Health Organization (WHO) List of Essential Medicines. However, flucytosine is not registered for use in any African country and so cannot be prescribed as a treatment there. Flucytosine is also very expensive, as its patented manufacture involves carrying out a sequence of four chemical reactions.

That could now change thanks to the work of the CHEM21 team, who have cut the number of reactions needed from four to one. The story starts at the University of Durham in the UK, where Professor Graham Sandford and PhD student Antal Harsanyi devised a way of making flucytosine via a one-step ‘continuous flow’ method that uses the readily-available natural product cytosine as its starting point. In this technique, fluorine gas is passed through a steel tube together with a solution of cytosine in acid and, in the tube, fluorine atoms react with the cytosine molecules to make flucytosine. Because it involves just one selective reaction instead of four, the new method uses significantly less energy and raw materials and produces less waste than conventional techniques to manufacture flucytosine. It is also less expensive.

Pharmaceutical company Sanofi, which is also part of CHEM21, saw the potential of the technique and contracted MEPI, a French non-profit association, to investigate ways to scale up the process. With input from scientists from Durham and Sanofi, MEPI succeeded in setting up a small reactor capable of producing 1 kg per day of raw material. The next challenge will be for the team at Sanofi to transform the raw material into an active medicine that meets international standards. The University of Durham and Sanofi will also work on a technical and economic evaluation of the process. Meanwhile, the University of Durham has applied for a patent for the technique.

The hopes of the team are summed up in the closing paragraph of the paper published in the American Chemical Society’s Organic Process Research and Development journal: ‘This operationally simple procedure from inexpensive starting materials offers the only alternative manufacturing procedure for flucytosine to the currently operated expensive four-step process,’ they write. ‘We envisage that this one-step low cost synthesis of flucytosine will help to raise awareness of the neglected CM health epidemic and ultimately contribute to meeting the urgent requirement for large quantities of flucytosine for low income nations.’

‘This is an excellent example of how through IMI, universities and pharmaceutical companies can work together to deliver a promising discovery that addresses an unmet medical need, and then rapidly progress it to a larger scale,’ said IMI Executive Director Pierre Meulien.

The new technique could also have wider implications as flucytosine is used in the synthesis of two other important medicines: the cancer drug capecitabine and the HIV treatment emtricitabine.

CHEM21 is funded by the Innovative Medicines Initiative, a €5 billion public-private partnership between the European Union (through the European Commission’s research framework programmes) and the European pharmaceutical industry (through EFPIA, the European Federation of Pharmaceutical Industries and Associations).

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