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New drugs needed for tropical diseases
Newsdesk New drugs needed for tropical diseases
134
discovery of compounds that inhibit pathways necessary for their survival. Yet the potential of this work has not been exploited, as the expertise necessary to develop a promising compound into a drug is available only in industry.
Charles Bond
There is a desperate need for effective treatments for many diseases endemic in poor tropical countries. Over 1 billion people have seen no benefit from the huge investment in healthcare research in recent decades, simply because they suffer from the ruthless disease categorised Z59.5 in the WHO’s International Classification of Diseases: extreme poverty. The statistics speak for themselves. Research by charity Médecins sans Frontières has found that only 15 of the new drugs registered in the last 25 years were indicated for tropical infectious diseases. By contrast, 179 new cardiovascular drugs entered the clinic during that period. Yet the WHO estimates that these two categories contribute about the same amount to the world’s overall burden of disease. The increasingly globalised and competitive pharmaceutical industry is understandably reluctant to invest in diseases where there is no viable market. The cost of developing a single marketable drug can be as high as US$350 million. Philip Dean, of De Novo Pharmaceuticals, a drug design company based in Cambridge, UK, explains: “The risk/benefit analysis, as far as shareholders are concerned, is not in favour of research into tropical diseases”. Many of the most widespread and intractable of these diseases are caused by parasitic protozoa. This category includes sleeping sickness and leishmaniasis in Africa, Chagas disease in South America, and malaria. There is, however, an important distinction between malaria and other protozoal infections. There is viable market for antimalarials, in middle-income countries and for western travellers, and some pharmaceutical companies maintain a vague interest in it. Sleeping sickness and other trypanosomal diseases are endemic only in the poorest parts of the world. “The market will not bear any interest by pharmaceutical companies in these diseases”, says Alan Fairlamb (University of Dundee, UK). Work by academic parasitologists like Fairlamb and his collaborators has led to important insights into the biochemistry of these protozoa, and to the
Slipping between bench and bedside.
How can the gap between bench and bedside be narrowed? The genomic revolution may provide some answers. Barry Bloom predicted “Sequencing bacterial and parasitic pathogens . . . could buy the sequence of . . . every drug target for all time” (Nature 1995; 378: 236). Publicly funded parasite genome sequencing projects are now yielding a vast amount of information. Given the sequence of every gene in a parasite, it should be possible to identify the most suitable drug targets. Since drug development costs include investment in the large proportion of lead molecules that never reach the clinic, narrowing the choice of targets and inhibitors to the most promising must be cost-effective. Drug companies often talk about the need to “fail fast, fail cheap”; this is even more critical where the market is small. There are signs that the Plasmodium falciparum genome project is beginning to bear results in the development of promising antimalarial leads. Triclosan, an antiseptic present in mouthwash, has been found to bind to a Plasmodium enzyme, enoyl acyl carrier protein reductase (ENR), and to inhibit parasite growth. The discovery of the essential enzyme 1-deoxy-D-xylulose phosphate (DOXP) reductoisomerase has led to another promising lead: fosmidomycin. However, both these compounds would benefit from further optimisation to improve
their potential as antimalarials. Genome sequencing may be increasing the effectiveness of academic research in the early stages of drug discovery , but there is still a gap to bridge. The United Nations’ Special Programme for Research and Training in Tropical Diseases (TDR), created in 1974, provides a partial solution. Most of the antiprotozoal drugs that have entered the clinic since then have done so with TDR support and funding. More recently, TDR has had an important role in setting up publicprivate partnerships to address particular diseases. The Medicines for Malaria Venture, established in 1999, aims to bring one new antimalarial to market every 5 years; the Global Alliance for TB Drug Development seeks to develop new antituberculosis drugs. Expertise for these ventures comes from academia and industry; funding, from governments, industry, non-governmental organisations, and private philanthropy. The last-named is becoming increasingly important, particularly in the most neglected research areas. TDR’s Felix Kuzoe has described a US$15 million gift from the Bill and Melinda Gates Foundation as having “no precedence in the history of African trypanosomiasis research”. Improving research conditions in the developing world can also be effective. “In some third-world countries, clinical trials can now be done relatively cheaply, and to FDA standards,” says Fairlamb. Although public–private partnerships are making progress, it is painfully slow. The increasing trend to ring-fence funding for each specific disease is unwelcome. Furthermore, most recent efforts have been aimed at the more “popular” diseases, such as malaria. There is still no specialist public–private venture dedicated to any of the most neglected diseases. And not all drugs will be as effective in a tropical village as in a western teaching hospital. “Drugs for use in the developing world must be stable, very easy to use and very safe . . . for many diseases it is these issues that underlie the [current] medical need” says TDR’s Rob Ridley. Clare Sansom
THE LANCET Infectious Diseases Vol 2 March 2002
http://infection.thelancet.com
For personal use. Only reproduce with permission from The Lancet Publishing Group.
134
discovery of compounds that inhibit pathways necessary for their survival. Yet the potential of this work has not been exploited, as the expertise necessary to develop a promising compound into a drug is available only in industry.
Charles Bond
There is a desperate need for effective treatments for many diseases endemic in poor tropical countries. Over 1 billion people have seen no benefit from the huge investment in healthcare research in recent decades, simply because they suffer from the ruthless disease categorised Z59.5 in the WHO’s International Classification of Diseases: extreme poverty. The statistics speak for themselves. Research by charity Médecins sans Frontières has found that only 15 of the new drugs registered in the last 25 years were indicated for tropical infectious diseases. By contrast, 179 new cardiovascular drugs entered the clinic during that period. Yet the WHO estimates that these two categories contribute about the same amount to the world’s overall burden of disease. The increasingly globalised and competitive pharmaceutical industry is understandably reluctant to invest in diseases where there is no viable market. The cost of developing a single marketable drug can be as high as US$350 million. Philip Dean, of De Novo Pharmaceuticals, a drug design company based in Cambridge, UK, explains: “The risk/benefit analysis, as far as shareholders are concerned, is not in favour of research into tropical diseases”. Many of the most widespread and intractable of these diseases are caused by parasitic protozoa. This category includes sleeping sickness and leishmaniasis in Africa, Chagas disease in South America, and malaria. There is, however, an important distinction between malaria and other protozoal infections. There is viable market for antimalarials, in middle-income countries and for western travellers, and some pharmaceutical companies maintain a vague interest in it. Sleeping sickness and other trypanosomal diseases are endemic only in the poorest parts of the world. “The market will not bear any interest by pharmaceutical companies in these diseases”, says Alan Fairlamb (University of Dundee, UK). Work by academic parasitologists like Fairlamb and his collaborators has led to important insights into the biochemistry of these protozoa, and to the
Slipping between bench and bedside.
How can the gap between bench and bedside be narrowed? The genomic revolution may provide some answers. Barry Bloom predicted “Sequencing bacterial and parasitic pathogens . . . could buy the sequence of . . . every drug target for all time” (Nature 1995; 378: 236). Publicly funded parasite genome sequencing projects are now yielding a vast amount of information. Given the sequence of every gene in a parasite, it should be possible to identify the most suitable drug targets. Since drug development costs include investment in the large proportion of lead molecules that never reach the clinic, narrowing the choice of targets and inhibitors to the most promising must be cost-effective. Drug companies often talk about the need to “fail fast, fail cheap”; this is even more critical where the market is small. There are signs that the Plasmodium falciparum genome project is beginning to bear results in the development of promising antimalarial leads. Triclosan, an antiseptic present in mouthwash, has been found to bind to a Plasmodium enzyme, enoyl acyl carrier protein reductase (ENR), and to inhibit parasite growth. The discovery of the essential enzyme 1-deoxy-D-xylulose phosphate (DOXP) reductoisomerase has led to another promising lead: fosmidomycin. However, both these compounds would benefit from further optimisation to improve
their potential as antimalarials. Genome sequencing may be increasing the effectiveness of academic research in the early stages of drug discovery , but there is still a gap to bridge. The United Nations’ Special Programme for Research and Training in Tropical Diseases (TDR), created in 1974, provides a partial solution. Most of the antiprotozoal drugs that have entered the clinic since then have done so with TDR support and funding. More recently, TDR has had an important role in setting up publicprivate partnerships to address particular diseases. The Medicines for Malaria Venture, established in 1999, aims to bring one new antimalarial to market every 5 years; the Global Alliance for TB Drug Development seeks to develop new antituberculosis drugs. Expertise for these ventures comes from academia and industry; funding, from governments, industry, non-governmental organisations, and private philanthropy. The last-named is becoming increasingly important, particularly in the most neglected research areas. TDR’s Felix Kuzoe has described a US$15 million gift from the Bill and Melinda Gates Foundation as having “no precedence in the history of African trypanosomiasis research”. Improving research conditions in the developing world can also be effective. “In some third-world countries, clinical trials can now be done relatively cheaply, and to FDA standards,” says Fairlamb. Although public–private partnerships are making progress, it is painfully slow. The increasing trend to ring-fence funding for each specific disease is unwelcome. Furthermore, most recent efforts have been aimed at the more “popular” diseases, such as malaria. There is still no specialist public–private venture dedicated to any of the most neglected diseases. And not all drugs will be as effective in a tropical village as in a western teaching hospital. “Drugs for use in the developing world must be stable, very easy to use and very safe . . . for many diseases it is these issues that underlie the [current] medical need” says TDR’s Rob Ridley. Clare Sansom
THE LANCET Infectious Diseases Vol 2 March 2002
http://infection.thelancet.com
For personal use. Only reproduce with permission from The Lancet Publishing Group.