This is an open access article published under an ACS AuthorChoice License, which permits copying and redistribution of the article or any adaptations for non-commercial purposes. Viewpoint Cite This: ACS Infect. Dis. XXXX, XXX, XXX−XXX pubs.acs.org/journal/aidcbc Drug Discovery for Kinetoplastid Diseases: Future Directions † ‡ § ∥ Srinivasa P. S. Rao,*, Michael P. Barrett, Glenn Dranoff, Christopher J. Faraday, ⊥ # † ∇ ° Claudio R. Gimpelewicz, Asrat Hailu, Catherine L. Jones, John M. Kelly, Janis K. Lazdins-Helds, • ¶ × Pascal Maser,̈ Jose Mengel,$,@ Jeremy C. Mottram,+ Charles E. Mowbray, David L. Sacks, ∼ † † Phillip Scott,& Gerald F. Spath,̈ ^ Rick L. Tarleton, Jonathan M. Spector, and Thierry T. Diagana*, † Novartis Institute for Tropical Diseases (NITD), 5300 Chiron Way, Emeryville, California 94608, United States ‡ University of Glasgow, University Place, Glasgow G12 8TA, United Kingdom § Immuno-oncology, Novartis Institutes for Biomedical Research (NIBR), 250 Massachusetts Avenue, Cambridge, Massachusetts 02139, United States ∥ Autoimmunity, Transplantation and Inflammation, NIBR, Fabrikstrasse 2, CH-4056 Basel, Switzerland ⊥ Global Drug Development, Novartis Pharma, Forum 1, CH-4056 Basel, Switzerland # School of Medicine, Addis Ababa University, P.O. Box 28017 code 1000, Addis Ababa, Ethiopia ∇ London School of Hygiene and Tropical Medicine, Keppel Street, London WC1E 7HT, United Kingdom ° Independent Consultant, Chemic Des Tulipiers 9, 1208 Geneva, Switzerland • Swiss Tropical and Public Health Institute, Socinstrasse 57, 4501 Basel, Switzerland; University of Basel, CH 4000 Basel, Switzerland $Laboratory of Clinical Immunology, Oswaldo Cruz Institute, FIOCRUZ-RJ, Av. Brasil 4365, Cep: 21040-900, Rio de Janeiro-RJ, Brazil @Faculty of Medicine of Petropolis, University in Petropolis,̀ Av. Barao do Rio Branco 1003, Cep: 25680-120, Petropolis-RJ, Brazil +University of York, Wentworth Way Heslington, York YO10 5DD, United Kingdom ¶ Drugs for Neglected Diseases initiative, 15 Chemin Louis-Dunant, 1202 Geneva, Switzerland × National Institute of Allergy and Infectious Diseases, 4 Memorial Drive, Bethesda, Maryland 20892, United States &University of Pennsylvania, 380 South University Avenue, Philadelphia, Pennsylvania 19104, United States ^Institut Pasteur, 25 Rue du Docteur Roux, 75015 Paris, France ∼ University of Georgia, Coverdell Center, 500 DW Brooks Dr, Athens, Georgia 30602, United States ABSTRACT: Kinetoplastid parasites have caused human disease for millennia. Significant achievements have been made toward developing new treatments for leishmaniasis (particularly on the Indian subcontinent) and for human African trypanosomiasis (HAT). Moreover, the sustained decrease in the incidence of HAT has made the prospect of elimination a Downloaded via 188.63.101.230 on January 22, 2019 at 09:16:45 (UTC). tantalizing reality. Despite the gains, no new chemical or biological entities to treat kinetoplastid diseases have been registered in more than three decades, and more work is needed to discover safe and effective therapies for patients with Chagas disease and leishmaniasis. Advances in tools for drug discovery and novel insights into the biology of the host−parasite interaction may provide opportunities for accelerated progress. Here, we summarize the output from a gathering of scientists and physicians who See https://pubs.acs.org/sharingguidelines for options on how to legitimately share published articles. met to discuss the current status and future directions in drug discovery for kinetoplastid diseases. early a billion people are at risk from the group of vector- Neglected Diseases initiative (DNDi) directing global efforts N borne kinetoplastid diseases comprised of Chagas for new therapies. The introduction of nifurtimox-eflornithine disease, leishmaniasis, and human African trypanosomiasis therapy in 2009 was a pivotal milestone, which was followed (HAT, also known as sleeping sickness). These ancient recently by the demonstrated efficacy of oral fexinidazole2 for parasitic illnesses have burdened humans for thousands of late-stage disease. (Approval for use is now pending assessment years, as evidenced by Trypanosoma DNA sequences found in by medicine regulatory agencies.) Fewer than 1500 new cases South American mummies.1 In the current era, kinetoplastid were reported to WHO in 2017, making disease elimination a diseases cause an estimated 30 000 deaths annually and induce tangible goal. crippling morbidities in millions more. Successes in combating HAT are encouraging and contrast There is reason to be optimistic about trends concerning with slower progress in containing other kinetoplastid diseases. HAT. Public and private partners have jointly tackled the disease in recent decades, with the World Health Organization Received: November 1, 2018 (WHO) coordinating public health activities and the Drugs for © XXXX American Chemical Society A DOI: 10.1021/acsinfecdis.8b00298 ACS Infect. Dis. XXXX, XXX, XXX−XXX ACS Infectious Diseases Viewpoint Figure 1. Clinical manifestations of kinetoplastid diseases and opportunities for intervention. Most of the current kinetoplastid drugs are repurposed and are 15−30% patients are unable to finish the standard 60-day often not potent enough to render a sterile cure (i.e., to course, mainly because of skin and nervous system eliminate all parasites). Safe, effective, short-course practical complications. In children, nifurtimox is better tolerated than therapies are urgently needed for Chagas disease and benznidazole. leishmaniasis yet remain elusive. In both acute and chronic T. cruzi infection, treatment To understand the present-day challenges and opportunities reduces the parasite load and can yield clearance from blood related to new medicines for Chagas disease, visceral using available assays (e.g., PCR). Even so, in some cases, leishmaniasis (VL), and cutaneous leishmaniasis (CL), the parasites presumably may persist intracellularly, and it is Novartis Institute for Tropical Diseases convened a multi- unclear in adults how the reductions in the parasite load disciplinary group of scientific and medical specialists in modulate the severity of chronic disease in the absence of parasitology, immunology, and drug discovery in June 2018. complete parasite clearance. Current drugs are inadequate The scope of the discussion encompassed unmet medical because they fail too often and are not dependable. However, needs, the global pipeline of preclinical drug candidates, WHO recommends off-label use of benznidazole for the parasite biology, assays, models, and the potential use of novel treatment of chronically infected patients, even though its immunomodulatory and adjunct therapies to target disease efficacy in later stages of the disease is debatable. A large study sequelae. This Viewpoint summarizes key workshop learnings. of patients with chronic Chagas cardiomyopathy (the BENEFIT trial) demonstrated that benznidazole treatment ■ CURRENT DRUGS: OLD, TOXIC, AND OFTEN reduced the parasite burden but did not significantly reduce INEFFECTIVE disease progression. However, most subjects had New York Chagas disease, which is endemic in the Americas, is caused by Heart Association class I (largely asymptomatic) heart disease, Trypanosoma cruzi. Inoculation typically occurs through which may have confounded the findings.3 Some non- infected feces from the triatomine bug, which is scratched or randomized, unblinded studies using benznidazole in inde- rubbed into the skin or mucosa. Transmission also takes place terminate patients without heart failure showed reduced through blood transfusion and congenital and oral routes. The disease progression, emphasizing the need for controlled pathogenesis of Chagas disease is not fully understood, and it is randomized studies for indeterminate patients.4 currently impossible to predict which fraction of the patient Similarly, the approved therapeutic arsenal for leishmaniasis population (approximately 30%) will develop the serious has important limitations. Leishmaniasis is distributed across cardiac or gastrointestinal sequelae that appear years after the the tropics and subtropics, though a majority of VL cases are initial infection (Figure 1). Sudden death from chronic Chagas reported in only seven countries: Brazil, Ethiopia, Kenya, cardiomyopathy is an all too common outcome. Two drugs, Somalia, Sudan, South Sudan, and India. Patients succumb to nitroheterocyclic agents benznidazole and nifurtimox, are used VL gradually over a period of 2 years. Anorexia and for the treatment of Chagas disease; both were developed pancytopenia give rise to wasting and increased susceptibility decades ago, are contraindicated during pregnancy, and can to bacterial superinfections. VL is fatal without treatment, and have serious adverse effects that substantially restrict their use. even those who undergo therapy remain at risk of a disfiguring Benznidazole is the better-tolerated option in adults, although dermal form of relapsing disease called post kala-azar dermal B DOI: 10.1021/acsinfecdis.8b00298 ACS Infect. Dis. XXXX, XXX, XXX−XXX ACS Infectious Diseases Viewpoint leishmaniasis (PKDL) that may also contribute to continued disease transmission (Figure 1). CL has a higher global burden than VL, with the greatest prevalence in Africa, the Mediterranean, and South America. It does not cause systemic morbidities or death but can result in grievous disfiguration and stigma. Drugs targeting Leishmania parasites have generally been repurposed from other indications.