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How to bolster the antifungal pipeline

April 07 2015

No new antifungal drug has been licensed since 2006, and the last new class of antifungal emerged in 2002. With an estimated 300 million people worldwide with serious fungal disease and 1.3 to 2 million deaths, new agents are desperately needed.

Just published in Perspectives  in Science, Manchester academics Professor David Denning and Dr Mike Bromley, highlight the problems for doctors. Prof Denning, who is a Professor of Infectious Diseases in Global Health at The University of Manchester, said: ‘In our clinics, we have large numbers of untreatable patients – going down hill, and current therapy ineffective or impossible to take for some patients. Many are really desperate and some die years earlier than they should through lack of treatment.’
Dr Mike Bromley, Lecturer at the Manchester Fungal Infection Group, is trying to identify new antifungals and define how they work on fungal cells. He declared: ‘New antifungals are tough to find, partly because the human cell machinery is quite similar to fungi, so killing a fungal cell without damaging a human cell is tricky. We have several promising leads however, which we are working on as fast as resources allow.’
The authors point out the very low numbers of funded positions in this area in the UK and USA (few grants awarded), which greatly impedes research in the area. High resistance rates in Candida and Aspergillus are very concerning. 

Microscopic picture of Aspergillus fumigatusLast week the US Food and Drug Administration approved isavuconazole a new azole antifungal, from Basilea. This is welcome, but existing problems are not being addressed.
Poor patient responses to antifungal medicines, antifungal resistance, drug-drug  interactions and toxicity to many of the existing drugs figure highly amongst the problems. Difficulties in identifying new broadspectrum compounds and a chronic lack of investment in novel antifungal agents are both responsible for the limited drug development pipeline.

Most major pharmaceutical companies are not investing in antifungals, preferring to focus on other, more lucrative areas.
EU (New Drugs 4 Bad Bugs) and U.S. (BARDA Broad Spectrum Antimicrobials) initiatives have stimulated investment in the development of antibiotics, but no similar initiatives exist for the development of antifungals. Attempts to address the lack of investment include the U.S. Food and Drug Administration’s (FDA’s) Generating Antibiotics Incentives Now (GAIN) Act, which allows a 5-year extension of market exclusivity for anti-infectives and specifically names Aspergillus, Candida, and Cryptococcus species as qualifying diseases. In some ways, the challenges to the development of antifungals are more pronounced than those faced by antibacterial development. Because fungi, like mammals, are eukaryotes, many proteins that are potential targets for therapy are also found in humans, with substantial drug toxicity risk. 

The focus has to be on novel, alternative pathways, utilizing molecular and genetic techniques to focus the search for effective treatments. The FDA’s “orphan status” for new antifungal agents has helped to a degree, by lowering clinical trial barriers clinical trials to bring improved regimens to patients. As our understanding of the risk factors for developing fungal diseases improves, so will the targetting of patient groups and therefore clinical trials, which will lead to improved treatment regimens. Nevertheless, in the short term, the burden of serious fungal diseases such as cryptococcal meningitis, chronic pulmonary Aspergillosis and allergic fungal disease continues to cause large-scale death and morbidity. Intense and sustained research into new classes of drugs is essential to help this growing group of patients.

Article: Denning and Bromley, Perspectives in Science, 27 March 2015.