The Novartis Institute for Tropical Diseases (NITD), one of the institutes of the Novartis Institutes for BioMedical Research (NIBR), is dedicated to finding new medicines to treat neglected, infectious diseases. As a small-molecule drug discovery research institute, it combines the drug-discovery expertise and cutting-edge technologies of Novartis to fight infectious tropical diseases, including Malaria, Kinetoplastid diseases (Human African Trypanosomiasis, Leishmaniases, Chagas) and Cryptosporidiosis.
In developing countries where these diseases are endemic, Novartis will make treatments accessible to the communities that need them. NITD was set up in 2002 and is part of the Novartis Institutes for BioMedical Research. NITD`s international team of scientists are engaged in neglected disease research efforts, from target discovery and screening development to compound optimization and preparation for clinical testing. As a major center of excellence for drug discovery, NITD will offer exceptional teaching and training opportunities for post-doctoral fellows and graduate students.
Contact NITD Novartis Institutes for BioMedical Research NITD 5300 Chiron Way Emeryville, CA 94608-2916
Progress in global fight against diarrheal disease cryptosporidiosis
One of the challenges of discovering drugs for diseases of the developing world is the lack of basic research into the underlying causes of these diseases – an example of this is cryptosporidiosis.
Infectious disease scientists from Novartis, the University of Georgia and Washington State University have reported the discovery and early validation of a drug candidate for treating cryptosporidiosis, a diarrheal disease which is a major cause of child mortality in lower-income countries. Currently there are no vaccines or effective treatments.
Diarrheal diseases cause more than 800,000 deaths annually1. Epidemiological studies have highlighted the vital need for new treatment options against the protozoan parasite Cryptosporidium, which often infects its victims from exposure to contaminated water supplies. Nitazoxanide, the only approved treatment for cryptosporidiosis, has shown poor results in vulnerable infants and immune-compromised patients2,3.
Yet there are obstacles to finding new treatments. The parasite perishes relatively quickly in labs and scientists have lacked research tools to identify drug candidates. The team developed a novel drug discovery process using transgenic parasites and novel disease models, leading to the identification and validation of the Cryptosporidium PI(4)K inhibitor candidate KDU731. They reported the discovery and preclinical findings in a recent issue of Nature.
Novartis is advancing research of cryptosporidiosis through collaborations with the global health community and its scientists at NITD.
Program funders include the Novartis Institutes for BioMedical Research (NIBR), the Wellcome Trust, and the National Institutes of Health. In addition to the Wellcome Trust, the Medicines for Malaria Venture (MMV) supported discovery of Plasmodium PI(4)K.
Medicinal Chemistry – making new and better drugs through chemistry
Drugs developed for developing world diseases need to meet additional challenges aside from efficacy and safety such as stability under tropical conditions and low cost of goods to enable access for patients living in poverty. In endemic areas, people often travel long distances to get to clinics and require medicines that can work quickly with only a few inexpensive doses and don’t require follow-up visits. NITD has focused on developing small molecule based medicines that can meet these requirements by leveraging their expertise in medicinal chemistry with the goal of designing of molecules with the best possible safety and efficacy. Medicinal chemistry combines organic chemistry, pharmacology, and other specialized fields for the design, synthesis, and development of new drugs.
In South East Asia, the first signs of drug resistance against the malaria parasite have been reported and new drugs different from the current arsenal of antimalarials are needed to fight the resistant parasites.
To meet the need for next-generation compounds with new mechanisms of action, in 2016, MMV and Novartis announced the expansion of a long-standing collaboration, backed by several funders and partners, to develop a novel antimalarial compound, KAF156, in combination with the currently available antimalarial compound lumefantrine. In early studies, KAF156 worked against both types of malaria parasite, known as P. vivax and P. falciparum, including in patients infected with artemisinin-resistant parasites. The combination is in mid-stage of drug development. If it progresses according to plan, this new treatment could help address the problem of multi-drug resistant malaria.
MMV and Novartis are also collaborating to develop another compound, KAE609, which attacks parasites via a novel mechanism of action. If we have a variety of medicines that work in different ways, we will be all the more prepared for emerging resistance.
Screening drugs – finding drugs that are effective against neglected diseases
Screening for drugs effective in infectious diseases is challenging because of the often limited understanding of the pathophysiology of the disease. The best way to screen is thus to use the whole organism and look for compounds that cause cell death – Human African trypanosomiasis is one example. An estimated 70 million people, in sub-Saharan Africa are at risk of contracting Human African trypanosomiasis or sleeping sickness, a parasitic disease caused by the protozoan Trypanosoma brucei, which is transmitted by the bite of the tsetse fly. 7197 new cases were reported in 2012, however it is acknowledged that cases are under-reported and that WHO estimates the number of actual cases to be 30000 (Ref. World Health Organization Factsheet No.259:http://www.who.int/mediacentre/factsheets/fs259/en/index.html). Current treatments have complicated administration regimes and have serious adverse side-effects.
Training scientists from developing world in drug discovery
Many of developing countries currently do not have the capability or the capacity to carry out biomedical research and development activities. Basic infrastructure such as laboratory equipment, computers, and laboratory spaces are sorely lacking and proper training for scientists and physicians is often inadequate. NITD is contributing to the efforts of Novartis to build the capabilities that is essential to enable the discovery and development of new medicines for the people in the environment where they will be used. We have been providing training for drug discovery to PhD students (both internal Novartis and external attachment) and Postdocs since 2003, and the majority of the benefited students were from disease endemic countries.
Liu, L. et al. Global, regional, and national causes of under-5 mortality in 2000-15: an updated systematic analysis with implications for the Sustainable Development Goals. The Lancet. 2016.
Amadi, B. et al. High dose prolonged treatment with nitazoxanide is not effective for cryptosporidiosis in HIV positive Zambian children: a randomised controlled trial. BMC infectious diseases. 2009.
Amadi, B. et al. Effect of nitazoxanide on morbidity and mortality in Zambian children with cryptosporidiosis: a randomised controlled trial. The Lancet. 2002.
Manjunatha UH, Vinayak S, Zambriski JA, Chao AT, Sy T, Noble CG, Bonamy GMC, Kondreddi RR, Zou B, Gedeck P, Brooks CF, Herbert GT, Sateriale A, Tandel J, Noh S, Lakshminarayana SB, Lim SH, Goodman LB, Bodenreider C, Feng G, Zhang L, Blasco F, Wagner J, Leong FJ, Striepen B, Diagana TT. A Cryptosporidium PI(4)K inhibitor is a drug candidate for cryptosporidiosis. Nature. 2017 May 31. doi: 10.1038/nature22337. [Epub ahead of print]
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