Infectious diseases, including malaria, diarrheal disease, and neglected tropical infections kill over 8 million people each year, according to the Global Burden of Disease 2015 Study. In an effort to address this burden, the Novartis Institute for Tropical Diseases (NITD) is dedicated to finding new medicines that treat and, ultimately, contribute to the elimination of these pathogens.
“Some of these diseases have been around for thousands of years,” says Thierry Diagana, Global Head of NITD. “We now have the opportunity to apply modern drug discovery technologies and find new solutions to this ancient problem. Our vision is to create therapies that can be part of eradication programs for diseases like malaria and human African trypanosomiasis.”
As a small-molecule drug discovery research institute within the Novartis Institutes for BioMedical Research (NIBR), NITD works in collaboration with a number of academic and non-profit partners. NITD research currently focuses on parasitic diseases, such as malaria, cryptosporidiosis, and three major kinetoplastid diseases – human African trypanosomiasis (sleeping sickness), Chagas disease and leishmaniasis.
“I’m proud to work alongside a team of scientists committed daily to solving a very important problem that affects people who we don’t necessarily see every day,” says Diagana..
Malaria kills about half as many people as it did two decades ago, yet it remains one of the world’s most deadly infectious diseases. The World Health Organization (WHO) estimates 429,000 people die from malaria each year – mostly young children, pregnant women, and others with compromised immune systems.
Success in controlling infections by malaria parasites has been achieved through substantial investments in bed nets, insecticide campaigns, and artemisinin combination therapies. Now, rising artemisinin resistance threatens this progress.
New drugs with diverse modes of action are needed to combat resistance, as well as to block transmission, prevent infection, and reduce relapse. Such compounds will be used in combination to develop regimens that promote accessibility, compliance, and take into account the needs of particularly vulnerable patients.
In partnership with Wellcome Trust, Medicines for Malaria Venture, the Genomics Institute of the Novartis Research Foundation (GNF), and the Swiss Tropical Public Health Institute, NITD developed two antimalarial compounds that are now in clinical trials (KAF156 and KAE609). Notably, these are the first compounds with novel mechanisms in more than two decades. NITD continues research efforts to strengthen the global antimalarial portfolio.
Nearly 1.7 billion cases of childhood diarrheal disease occur each year, according to WHO. These diseases can cause dehydration, malnutrition, stunting, and cognitive defects, and contribute to more than half a million deaths annually.
Cryptosporidium is the second most common cause of diarrhea-related mortality in children under two years old. The parasite can cause weeks of watery diarrhea and sets up a vicious cycle of malnutrition and increased susceptibility to infection. Currently, there is no vaccine and the only available treatment is poorly efficacious in malnourished children.
In collaboration with the University of Georgia and Washington State University, NITD researchers have used transgenic parasites and novel disease models for Cryptosporidium drug discovery. These tools brought about the identification and validation of a potent and specific Cryptosporidium PI(4)K inhibitor, KDU731. NITD is expanding its drug discovery efforts to identify novel agents to fight cryptosporidiosis.
Kinetoplastid parasites include pathogens that cause human African trypanosomiasis (sleeping sickness), Chagas disease, and leishmaniasis. Together these diseases result in over 50,000 deaths each year worldwide. The kinetoplastids, including Trypanosoma and Leishmania species, are highly associated with poverty and have been severely neglected in the development of diagnostics, treatments, and vaccines. The challenges facing available drugs include toxicities, limited efficacy, and difficulties in administering them.
One possible opportunity for kinetoplastid drug discovery is that a single compound may have activity against more than one member of the group. Indeed, a collaborative effort led by GNF, supported by the Wellcome Trust, and in partnership with University of York, University of Washington, and University of Glasgow discovered an inhibitor of the kinetoplastid proteasome that has efficacy against Trypanosomacruzi, Trypanosoma brucei, and Leishmania donovani in preclinical models.
NITD scientists and collaborators are also in the early stages of developing a fast-acting, oral treatment specifically for human African trypanosomiasis. The goal is to replace existing drugs, which are dosed intravenously and show significant toxicities. An improved oral regimen may support elimination of this disease.
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 Jun 15;546(7658):376-380.
White NJ, Duong TT, Uthaisin C, Nosten F, Phyo AP, Hanboonkunupakarn B, Pukrittayakamee S, Jittamala P, Chuthasmit K, Cheung MS, Feng Y, Li R, Magnusson B, Sultan M, Wieser D, Xun X, Zhao R, Diagana TT, Pertel P, Leong FJ. Antimalarial Activity of KAF156 in Falciparum and Vivax Malaria. N Engl J Med. 2016 Sep 22;375(12):1152-60.
Khare S, Nagle AS, Biggart A, Lai YH, Liang F, Davis LC, Barnes SW, Mathison CJ, Myburgh E, Gao MY, Gillespie JR, Liu X, Tan JL, Stinson M, Rivera IC, Ballard J, Yeh V, Groessl T, Federe G, Koh HX, Venable JD, Bursulaya B, Shapiro M, Mishra PK, Spraggon G, Brock A, Mottram JC, Buckner FS, Rao SP, Wen BG, Walker JR, Tuntland T, Molteni V, Glynne RJ, Supek F. Proteasome inhibition for treatment of leishmaniasis, Chagas disease and sleeping sickness. Nature. 2016 Sep 8;537(7619):229-233.
Diagana TT. Supporting malaria elimination with 21st century antimalarial agent drug discovery. Drug Discov Today. 2015 Oct;20(10):1265-70.
White NJ, Pukrittayakamee S, Phyo AP, Rueangweerayut R, Nosten F, Jittamala P, Jeeyapant A, Jain JP, Lefèvre G, Li R, Magnusson B, Diagana TT, Leong FJ. Spiroindolone KAE609 for falciparum and vivax malaria. N Engl J Med. 2014 Jul 31;371(5):403-10.