Future treatment options for human African trypanosomiasis

Abstract

Over the past 17 years, the number of reported cases of human African trypanosomiasis (HAT) has declined by over 90%, a significant result since the disease was highlighted as a public health problem by the WHO in 1995. However, if the goal of eliminating HAT by 2020 is to be achieved, then new treatments need to be identified and developed. A plethora of compound collections has been screened against Trypanosoma brucei spp, the etiological agents of HAT, resulting in three compounds progressing to clinical development. However, due to the high attrition rates in drug discovery, it is essential that research continues to identify novel molecules. Failure to do so, will result in the absence of molecules in the pipeline to fall back on should the current clinical trials be unsuccessful. This could seriously compromise control efforts to date, resulting in a resurgence in the number of HAT cases.

Keywords:

• drug discovery
• high-throughput screening
• human African trypanosomiasis

Human African trypanososmiasis

Human African trypanosomiasis (HAT) is a parasitic disease caused by the protozoan parasites Trypanosoma brucei gambiense and T.b. rhodesiense. The disease is restricted to the African subcontinent where the tsetse fly vector resides. In 2014, 3796 cases of HAT were reported, which is likely to represent only a fraction of the true number of cases due to a significant degree of under-reporting owing to the isolated regions in which the disease occurs and frequent civil unrest [1]. Over 95% of cases are attributed to T.b. gambiense that presents as a chronic infection with many months to years passing before the patient succumbs to the infection. In contrast, T.b. rhodesiense infections are acute, with death occurring in a matter of months [2]. Irrespective of the infecting subspecies, the disease progresses through two distinct stages: an early or hemolymphatic stage characterized by the presence of the parasites in the vascular and lymphatic systems followed by a second or CNS stage in which the parasites penetrate the blood–brain barrier (BBB) and invade the CNS. Symptoms in the early stage of the disease are often nondescript such as fever, headaches, general malaise and nausea [3]. CNS HAT is characterized by tremors, irritability, loss of coordination and characteristic disturbances of the sleep–wake cycle in which periods of day time somnolence alternate with night-time insomnia [4]. Without adequate treatment, the disease is almost always invariably fatal. However, the treatment options currently available are inadequate, with severe adverse reactions frequently observed, which is further complicated by the fact that different drugs are required depending on the infecting subspecies and disease stage.

Prospects for control

Elimination of HAT is considered by many to be achievable due to the rapid decline in the number of cases following the implementation of vigorous active surveillance and control programs. As a result, in 2012, the WHO Strategic and Technical Advisory Group on Neglected Tropical Diseases set the target of eliminating T.b. gambiense HAT as a public health problem (<1 case per 10,000 inhabitants) by 2020 and completely stopping transmission of the disease by 2030 [5]. A subsequent declaration was announced in 2014, to also eliminate rhodesiense HAT as a public health problem (<1 case per 10,000 people at risk) [6]. Elimination of gambiense and rhodesiense HAT requires different approaches, as T.b. rhodesiense is a zoonosis with wild and domestic animals being the main reservoirs that act as a source of human infection. A ‘one-health’ approach combining treatment of both humans and domestic animals along with vector control will therefore be required to achieve elimination of rhodesiense HAT. Addressing the wild animal reservoir of T.b. rhodesiense is more complex as direct treatment is not a viable option; therefore, widespread vector control and avoidance of the areas in which wild animals and tsetse flies reside are recommended. As humans are the main epidemiologically relevant reservoir of T.b. gambiense, the diagnosis and treatment of infected individuals is the primary method of control. Although humans are the main reservoir of T.b. gambiense, a number of domestic and game animals are susceptible to the parasite and previously the persistence of gambiense HAT, despite vigorous chemotherapy and control campaigns, has been linked to these animal reservoirs [7,8]. To achieve elimination of gambiense HAT, it may therefore be necessary to address the animal reservoir with vector control initiatives and the treatment of domestic animals.

The first report monitoring the progress of the gambiense elimination campaign indicated that the program was on track, with a progressive decrease in the number of cases reported over the two time periods studied and a 57% reduction in the population classified at high or very high risk of gambiense HAT [9]. Although progress has been made in achieving the goal of eliminating gambiense HAT as a public health problem by 2020, many challenges still lie ahead. Social unrest, changes in public health priorities, incomplete coverage of the population at risk and diminishing resources could all threaten and destabilize the elimination programs [10,11]. Furthermore, it is unlikely that the goal can be achieved with currently available therapeutics; therefore, new treatments need to be developed.

Current treatment options

Pentamidine and suramin are used in the treatment of hemolymphatic stage T.b. gambiense and T.b. rhodesiense infections, respectively. Hypotension, glucose perturbations and leucopenia are frequent adverse effects observed following the administration of pentamidine [12]. Adverse events associated with suramin treatment include nephrotoxicity, fever and nausea [3,12]. Once the disease has progressed to the CNS stage, the arsenical melarsoprol is the only drug effective against both subspecies. The drug is extremely toxic with up to 10% of all patients developing a post-treatment reactive encephalopathy (PTRE) that leads to death in 50% of cases [13]. Furthermore, pyrexia, headache and general malaise occur in nearly all patients and resistance has reached 30% in some regions [14]. An alternative to melarsoprol, eflornithine was introduced in 1990 for the treatment of CNS stage T.b. gambiense infections. Eflornithine is as efficacious as melarsoprol and has a superior safety profile [15]. However, the requirement for 56 intravenous (iv.) infusions over a 14-day period limited its widespread use and logistically, the transportation and storage of the volume of the required infusions further hampered the acceptance of eflornithine as a first-line treatment for CNS T.b. gambiense infections [16]. To address these problems, eflornithine was combined with nifurtimox in 2009 to produce a nifurtimox/eflornithine combination therapy (NECT) that reduced the administration schedule to 14 iv. eflornithine infusions over 7 days combined with nifurtimox orally for 10 days. NECT is as efficacious as eflornithine monotherapy and has a superior safety profile [17,18]. However, the requirement for iv. infusions still remains a major drawback of NECT. The search, therefore, continues for an orally available, rapidly acting drug preferably requiring once a day dosing which is active against both stages of the disease.

Drug discovery efforts for HAT

Over the past 10 years, a number of 96- and 384-well assay formats using either fluorescence- or luminescence-based technologies have been developed to enable the rapid screening of large compound collections against either the clinically relevant human infective subspecies (T.b. gambiense and T.b. rhodesiense) or the nonhuman infective model species, T.b. brucei (recently reviewed in [19]). This has led to the identification of thousands of molecules with trypanocidal activity. However, only a limited number of those identified have progressed past the initial hit identification stage, and to date only three, pafuramidine (DB289), fexinidazole and SCYX-7158, have progressed into clinical development. The diamidine prodrug, DB289, emerged from structure activity relationship (SAR) studies aimed at increasing the efficacy and tolerability of the stage 1 compound, pentamidine. Following oral administration, DB289 is converted in the liver to the active compound furamidine (DB75), which is >100,000-fold more active in vitro than DB289 [20]. DB289 produced 100% cures in murine models of HAT and also in a T.b. rhodesiense primate model following oral administration [20–22]. The absence of any toxicity led to the compound entering clinical development and in a Phase IIa trial, 95% of patients with early stage T.b. gambiense infections were cured with the remaining 5% of patients lost at follow-up [20]. Despite these promising initial results, the identification of acute renal toxicity led to the clinical development of DB289 being suspended. Fexinidazole was initially identified through the screening of a collection of nitroheterocyclic molecules by the Drugs for Neglected Disease initiative (DNDi). The compound is an orally available nitroimidazole prodrug with in vivo activity in both acute T.b. rhodesiense and T.b. brucei CNS murine models and is the second compound to enter clinical development for HAT [23,24]. In a Phase I, first-in-man trial to determine the optimum dosing schedule, fexinidazole was well tolerated at doses up to 3600 mg with headaches and vomiting, which resolved spontaneously, being the only adverse effects reported [25]. The optimal treatment regime required to obtain effective drug concentrations, while maintaining a good therapeutic index, was determined to be 1800 mg daily for 4 days followed by 1200 mg daily for 6 days [25]. A Phase II/III evaluating this treatment regime in patients with CNS infections commenced in 2012 but to date preliminary outcomes from this trial have not been reported.

In addition to fexinidazole, SCYX-7158 is also currently in the DNDi clinical development pipeline for HAT. The compound was identified through the HTS of a library of benzoxaboroles and a subsequent lead optimization program. The compound is orally efficacious in both acute and CNS murine models of HAT, and pharmacokinetic studies suggest that once a day dosing would be feasible due to the maintenance of drug concentrations above the minimum trypanocidal concentration for 14 to 20 h [26]. A Phase I, first-in-human study commenced in 2012 but had to be temporarily suspended in 2013 for additional studies to be completed in canines due to the half-life in human plasma being longer than expected [27]. The trial recommenced later in 2013 and safety profiling in additional subjects is ongoing.

Expert opinion

The implementation of NECT was a significant step forward in the treatment of T.b. gambiense HAT providing a simple and more safe chemotherapy regime compared with those for melarsoprol or eflornithine alone. However, as discussed above, NECT is far from ideal. To improve the treatment of HAT, an orally available drug with minimal adverse effects, efficacious against both the hemolymphatic and CNS stage is required. This would dramatically simplify the treatment of HAT, as the need for medical personnel to perform painful lumbar punctures to stage the disease would be eliminated, as treatment regimes would be the same, irrespective of stage. This would facilitate patients receiving treatment within their own communities, thus alleviating the pressure on extremely resource-poor healthcare facilities. The lack of a financial incentive for commercial partners requires that any new compound developed for HAT must be relatively cheap and easy to manufacture. Identifying one compound that fulfills all criteria is a major challenge, which, as a result of extensive efforts by research institutes around the globe, and the will and support of not-for-profit organizations, has been met with two compounds being identified.

Fexinidazole and SCYX-7158 represent a breakthrough in the search for new, safe and efficacious oral drugs for the treatment of HAT and the results from the clinical trials are eagerly awaited. However, even if successful, it will still be a number of years before either drug makes it to the market. The Phase II/III clinical trial of fexinidazole is expected to take 4 years to complete as the elimination campaigns have resulted in a dramatic reduction in the number of cases of HAT, meaning it is becoming increasingly difficult to recruit sufficient numbers of patients to complete a statistically relevant clinical trial. This needs to be taken into account, as clinical trials will only become more difficult to undertake as cases continue to fall. It is therefore essential that agencies work together and only the most promising molecules are progressed into clinical development to prevent competition for cases arising and all clinical trials being compromised.

It is anticipated that the fexinidazole clinical trial will be completed by late 2017/early 2018, thus drug availability to patients will only occur after this date.

Even with two candidate molecules currently in clinical development for HAT, the continued identification of new molecules and their progression is required to combat the high attrition rates frequently observed in drug discovery. If the clinical trials of fexinidazole and SCYX-7158 are unsuccessful, there are currently no other molecules in preclinical development for HAT, raising the question why out of the thousands of trypanocidal molecules identified, only a limited number are progressing beyond the initial identification stage? We have previously questioned whether the lack of compound progression is due to the libraries being screened or the assay formats that we currently use, or a combination of both [19]. Would the identification of new validated targets for trypanosomes provide more opportunities or will we be faced yet again with the issue of lack of translation in the whole organism? Clearly, a review of common practice and a decision criteria going forward is needed or we run the real risk of finding ourselves back where we started, with no potential candidates in the pipeline. This could derail the elimination program and once again, as in the 1990s, we could see a resurgence in the number of HAT cases.

Financial & competing interests disclosure

CI Avery is supported by an Australian NHMRC Project Grant APP1067728. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.