New Drugs for Human African Trypanosomiasis: a Twenty First Century Success Story
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Tropical Medicine and Infectious Disease Review New Drugs for Human African Trypanosomiasis: A Twenty First Century Success Story Emily A. Dickie 1, Federica Giordani 1, Matthew K. Gould 1, Pascal Mäser 2, Christian Burri 2,3, Jeremy C. Mottram 4 , Srinivasa P. S. Rao 5 and Michael P. Barrett 1,* 1 Wellcome Centre for Integrative Parasitology, Institute of Infection, Immunity and Inflammation, University of Glasgow, Glasgow G12 8TA, UK; [email protected] (E.A.D.); [email protected] (F.G.); [email protected] (M.K.G.) 2 Swiss Tropical and Public Health Institute, Socinstrasse 57, 4002 Basel, Switzerland; [email protected] (P.M.); [email protected] (C.B.) 3 University of Basel, Petersplatz 1, 4000 Basel, Switzerland 4 York Biomedical Research Institute, Department of Biology, University of York, Wentworth Way, Heslington, York YO10 5DD, UK; [email protected] 5 Novartis Institute for Tropical Diseases, 5300 Chiron Way, Emeryville, CA 94608, USA; [email protected] * Correspondence: [email protected] Received: 16 January 2020; Accepted: 14 February 2020; Published: 19 February 2020 Abstract: The twentieth century ended with human African trypanosomiasis (HAT) epidemics raging across many parts of Africa. Resistance to existing drugs was emerging, and many programs aiming to contain the disease had ground to a halt, given previous success against HAT and the competing priorities associated with other medical crises ravaging the continent. A series of dedicated interventions and the introduction of innovative routes to develop drugs, involving Product Development Partnerships, has led to a dramatic turnaround in the fight against HAT caused by Trypanosoma brucei gambiense. The World Health Organization have been able to optimize the use of existing tools to monitor and intervene in the disease. A promising new oral medication for stage 1 HAT, pafuramidine maleate, ultimately failed due to unforeseen toxicity issues. However, the clinical trials for this compound demonstrated the possibility of conducting such trials in the resource-poor settings of rural Africa. The Drugs for Neglected Disease initiative (DNDi), founded in 2003, has developed the first all oral therapy for both stage 1 and stage 2 HAT in fexinidazole. DNDi has also brought forward another oral therapy, acoziborole, potentially capable of curing both stage 1 and stage 2 disease in a single dosing. In this review article, we describe the remarkable successes in combating HAT through the twenty first century, bringing the prospect of the elimination of this disease into sight. Keywords: human African trypanosomiasis; sleeping sickness; elimination; chemotherapy; fexinidazole; pafuramidine; acoziborole 1. Introduction The current drugs used for human African trypanosomiasis (HAT) (Figure1) have served their purpose for many years. The incidence of HAT is now at a historic low (fewer than 1000 cases reported in 2018 [1]). Two forms of the disease occur. The one found in West and Central Africa is caused by Trypanosoma brucei gambiense, and the other, found in East and Southern Africa, is caused by Trypanosoma brucei rhodesiense. The former causes a chronic disease, taking years between infection and death, while the latter may kill within weeks to months. Parasites injected into the bloodstream cause a stage 1 infection, where replication is primarily associated with blood and lymph. However, Trop. Med. Infect. Dis. 2020, 5, 29; doi:10.3390/tropicalmed5010029 www.mdpi.com/journal/tropicalmed Trop. Med. Infect. Dis. 2020, 5, 29 2 of 15 the parasites then invade other organs, including the central nervous system (CNS). Once replicating in the CNS, the disease progresses to stage 2, where many of the symptoms of sleeping sickness become manifest. The current drugs suffer many drawbacks [2]. For stage 1 disease, either suramin or pentamidine is used for HAT caused by T. b. rhodesiense and T. b. gambiense, respectively. Both drugs must be given by injection for a prolonged period, and both carry a risk of adverse events. For stage 2 disease, the highly toxic melarsoprol is still the treatment of choice for rhodesiense HAT. Melarsoprol causes an encephalopathic syndrome that is fatal in up to one in twenty people taking the drug [3]. For gambiense HAT, the past decade has seen the introduction of a combination therapy. Intravenous eflornithineTrop. Med. Infect. is givenDis. 2020 for, 5,10 x FOR days PEER alongside REVIEW oral nifurtimox for 14 days [4]. 3 of 15 . Figure 1. Different drugs have been used to treat HAT depending on the trypanosome subspecies Figure 1. Different drugs have been used to treat HAT depending on the trypanosome subspecies causing the disease, and whether progression is at stage 1 or 2. For the past decade nifurtimox and causing the disease, and whether progression is at stage 1 or 2. For the past decade nifurtimox and eflornithine combination therapy has been the treatment of choice for stage 2 T. b. gambiense disease, eflornithine combination therapy has been the treatment of choice for stage 2 T. b. gambiense disease, and pentamidine for stage 1. For rhodesiense HAT, stage 2 is treated with melarsoprol and stage 1 withand suramin.pentamidine for stage 1. For rhodesiense HAT, stage 2 is treated with melarsoprol and stage 1 with suramin. The combination is relatively safe and efficacious. However, the delivery of kilogram quantities of2. eflornithinePafuramidine and— manyA New liters Paradigm of sterile in saline Anti-Trypanosomal brings substantial Drug logistical Development difficulty. For melarsoprol, resistanceAmong was the a growingcurrently problem used drugs in the for early HAT 2000s is pentamidine, [5], and for a eflornithine diamidine that [6] and was nifurtimox introduced [7 in] independently,the 1940s, and resistancehas been the can mainstay be readily in selected the treatment in the laboratory. of stage 1 gambiense There is no HAT doubt for that nearly better 80 drugs years for[26]. use Another against HATdiamidine, are required diminazene, [8]. is used in treating veterinary trypanosomiasis [27]. The diamidinesThe first are two di decades-cations, of with the twentypositive first charges century at caneither be seenend, aswhich a major renders success them story highly in regards polar, toprecluding intervention bioavailabili against thisty neglectedif taken orally tropical [28]. disease. Pentamidine HAT was is runningtypically outgiven of controlby intramuscular in the late twentiethinjection for century, seven with days. an Das estimated and Boykin 300,000 showed people in infectedthe 1970s [9 ].that In methoxy response,-derivatives the international of other communitydiamidines launchedacted as severalorally available key initiatives, prodrugs, which and can the be seenmethoxy as having group converged metaboliz toed turn back the to tide. the Consequently,amidine systemically the twenty [29]. first century has witnessed a dramatic change in the trajectory of HAT. InThe 1999, Bill Mandédecins Melinda Sans Gates Fronti Foundationères (MSF) was initiated founded their in “Access”2000, a time campaign when the to resurgence encourage of a re-engagementHAT was at its ofpinnacle. the pharmaceutical Among the Foundation’s industry with earliest neglected supported diseases, projects including was HATthe development [10]. A key studyof the [diamidine11] revisited methoxy the administration-prodrug appro regimenach towards of melarsoprol new drugs for based HAT on through pharmacokinetic the CPDD. data. DB289 (Figure 2) (pafuramidine maleate; 2,5-bis(4-amidinophenyl)-furan-bis-O- methylamidoxime), the methoxy product of furamidine (2,5-bis(4-amidinophenyl)-furan), in which the benzamidine moieties are separated by a furan ring, emerged as the lead compound for progression. Furamidine is highly polar and unable to traverse lipid bilayers without the assistance of transporters (see later). Pafuramidine, however, has much greater capacity to diffuse across membranes [30], including the intestinal epithelium, giving it considerable oral bioavailability. Once systemic, it is metabolized via various cytochrome P450 enzymes and cytochrome b5 reductase [31– 36] to furamidine. Preclinical safety and efficacy results [37,38] were sufficient to enable the passage to clinical trials. Trop. Med. Infect. Dis. 2020, 5, 29 3 of 15 An effective 10-day administration protocol, which diminished hospitalization time for patients [12], albeit without increasing safety, was introduced to great effect [13]. This IMPAMEL program (“improved application of melarsoprol”) was crucial in implementing the first modern clinical trials on HAT, and also in demonstrating the feasibility of conducting trials in extremely resource-limited conditions according to Good Clinical Practice, laying the foundation for future developments. Eflornithine had been shown to be far safer than melarsoprol as treatment for stage 2 disease [14]. Yet, by the late 1990s, no pharmaceutical company was prepared to make this compound for HAT treatment. However, when it was discovered that the same compound could prevent the growth of unwanted facial hair in women, a number of drug companies saw an opportunity to market the compound for this purpose [15]. MSF, already campaigning for access to essential medicines, were able to make a compelling case that society needed to rethink drug discovery paradigms for neglected diseases [16]. Aventis (now Sanofi) were persuaded to develop the drug and donate it at no cost to the World Health