Schistosomiasis therapeutics: whats in the pipeline?

Abstract

Schistosomiasis is a debilitating neglected tropical disease caused by schistosome worms. Global efforts to control schistosomiasis rely predominantly on mass drug administration of the drug praziquantel to populations at risk of infection. We review the history of schistosome drug development and the current position of schistosome drug research. We conclude that with no additional candidates currently in the anti-schistosome drug clinical trial pipeline, a practical and necessary approach is to optimise the health benefits from praziquantel. We offer suggestions of where and how this can be achieved. We also highlight knowledge gaps in the utility of praziquantel particularly in the treatment of chronic schistosomiasis, which includes fibrosis, organomegaly and cervical lesions associated with female genital schistosomiasis.

Keywords:

• antimony potassium tartrate
• artesunate
• metrifonate
• mirazid
• oxamniquine
• pediatric formulation
• praziquantel
• schistosomiasis
• Schistosoma
• therapeutics

In 2011, there were an estimated 207 million people infected with schistosomes and a further 779 million at risk of infection in Africa, Asia and South America.[1] People become infected with schistosomes following contact with freshwater containing the infective stage of the parasite (cercariae) which are released by the intermediate snail hosts and actively penetrate the human skin. Following human infection, eggs are produced by mated females which are released into freshwater via urine or feces to infect the intermediate host snails, thereby continuing the vicious cycle. Current schistosome control is dominated by the treatment of exposed people with the anti-helminthic drug praziquantel (PZQ), for reduction of both infection and morbidity.[2] PZQ is safe, efficacious and cheap. The current operational disadvantages of PZQ are the bitter taste and large tablet size making it unpalatable and difficult to swallow especially for young children. Due to the widespread availability and safety of PZQ, control programs utilize mass drug administration (MDA) targeted at populations/communities for preventative chemotherapy and transmission control.

Several countries are now implementing national schistosome control programs through MDA. However, reliance on PZQ alone is concerning should resistance develop. Such a situation occurred following the use of oxamniquine (OXAM) to treat around 10 million people in Brazil during the national S. mansoni control program,[2] which was eventually discontinued in 2010 due to large-scale drug resistance in the schistosomes.[3] It is widely recognized that chemotherapy alone cannot eliminate schistosome transmission and that improved provision of safe water and sanitation such as the UNICEF ‘WASH’ strategies are vital to interrupt the parasite’s life cycle.[4] This review focuses on schistosome therapeutics. To improve on the current status of schistosome therapeutics, much can be learnt from examining historical schistosome anti-helminthics.

The oldest recorded anti-schistosome drug is antimony potassium tartrate (APT) dating back to 1605.[5] APT acts against adult S. mansoni and S. haematobium worms and is more efficacious against the females due to higher drug uptake. APT induces muscular paralysis in females causing them to dislodge from the males and from the blood vessels. APT also suppresses ovulation in the worms.[6] APT is no longer used for schistosome treatment due to its toxic side effects in humans, difficulty in its administration (injection) and availability of PZQ. However, APT is still used as an anti-microbial, an emetic in poison sufferers and for the treatment of other parasitic diseases leishmaniasis and trypanosomiasis.[5]

In 1952, Bayer developed the insecticide metrifonate which was subsequently discovered to be active against adult S. haematobium worms.[1,7] Metrifonate is an organophosphorus cholinesterase inhibitor,[8] targeting the schistosome nervous system by attacking the synaptic connections and disrupting nerve signals, thereby inducing muscular spasms. Metrifonate was used only against S. haematobium; indirect studies in humans suggest that metrifonate may also be effective against S. mansoni, but that the physical location of S. mansoni worms may preclude the worms from the drug.[9] Another possible reason for differential action of metrifonate on different schistosome species may be the differences in cholinoceptors amongst the schistosome species.[7] Metrifonate is no longer commercially available as an anti-schistosome agent due to the need for multiple doses [8] and reduced efficacy compared to PZQ.[10] However, it is still used widely as an insecticide and as a veterinary anti-helminthic.[11] Due to its effect on the acetylcholine receptor, metrifonate is currently under investigation as a potential Alzheimer’s therapeutic.[11]

OXAM, first produced by Pfizer in the late 1960s,[12] is effective against only S. mansoni, killing schistosomula and adult worms,[13] and is more efficacious against male parasites. A sulfotransferase enzyme converts the drug to a sulfate ester which dissociates and binds schistosome DNA covalently. This causes nucleic acid alkylation disrupting cell division and protein synthesis eventually damaging and killing the parasites.[14] Molecular and genetic analyses recently showed that OXAM resistance in schistosomes was due to a resistance locus on the schistosome chromosome 6 which coded for the sulfotransferase.[3] Worms not initially killed undergo morphological changes expressing antigens resulting in immune-mediated damage.[13] However, unlike other anti-schistosome drugs, OXAM is not used to treat any other diseases or other human or animal parasites and remains on the WHO List of Essential Medicines. In the 1970s, a novel artensunate-derived anti-malarial drug was produced from a chemical extracted from sweet worm wood. In the 1980s, this was shown to possess anti-schistosome properties.[1] Although the drug targets the post-infection larvae, schistosomula and liver stage parasites of all three human schistosome species,[10] artesunate is less efficacious than PZQ.[13] Artesunate derivatives act synergistically with blood hemin to produce free radicals toxic to schistosomes.[2] They are also effective against trypanosomes, human liver flukes Faschiola hepatica and Clonorchis sinensis and also mammalian intestinal flukes.[15] Currently, artesunate derivatives are administered only to people co-infected with Plasmodium and schistosome parasites.[1] However, their use is declining due to the spread of artesunate resistant Plasmodium strains [16] and they are not recommended for use as anti-schistosome drugs by the WHO.

The anti-helminth properties of PZQ were first discovered in 1972 by Bayer and at the same time synthesized by Merck (Germany) whilst researching potential tranquilizers. The two companies combined efforts to study the drug’s anti-schistosome properties and subsequently human trials commenced in 1978.[1] PZQ is thought to alter the schistosome calcium transport channels in the tegument increasing cellular ion permeability thus inducing muscular paralysis.[17] It also stimulates morphological changes in the schistosome tegument allowing greater expression of antigens stimulating of the development of an immune response protective against re-infection. PZQ is effective against adults (not juveniles/infective stages [18]) of all three human schistosomes as well as helminth infections in domestic and companion animal schistosomiasis.[19] It is also used to treat other human parasitic diseases such as hydatid disease.[20] Experimental studies show that PZQ is more effective against bisexual compared to single-sex infections and that the adult worms can survive low drug doses. The relevance of this in human infections remains to be investigated.[18] In addition, reports from experimental studies of schistosome PZQ resistance remain to be validated and differentiated from differential drug sensitivity in human populations and simulation studies in S. haematobium demonstrate that the variation in PZQ efficacy reported in human studies does not support the development of PZQ resistance.[21]

The newest anti-schistosome drug is Mirazid which targets early stages of the parasite.[22] Developed from myrrh, it is used almost exclusively in Egypt where it is produced by Pharco Pharmaceuticals. Its efficacy against S. mansoni and S. haematobium is still controversial (lack of efficacy shown in experimental studies [23]) and has only recently been mass analyzed. In addition its pharmacokinetics in humans and mode of action against trematodes remain unclear.[22]

Currently, there are no schistosome drug candidates under human clinical trials. However, there is a lot of research being conducted to identify new drug targets as well as repurpose current drugs as comprehensively reviewed by El Ridi and Tallima.[24] In particular, schistosome extracellular and transmembrane protein kinases (PKs) have been suggested as potential targets for anti-schistosome drugs. The kinases are conserved essential proteins involved in signal transduction, and several schistosome PKs have been characterized in terms of location and function. Due to their central roles in various physiological functions and role of anti-PK inhibitors as anti-cancer drugs, PKs are seen as potential schistosome drug candidates, particularly since schistosome parasites and the other flukes, C. sinensis and Opisthorchis viverrini, are carcinogens.[25] Another group of physiologically essential proteins being researched as potential schistosome drugs are antioxidant enzymes as some aspects of the schistosome detoxification pathways differ from those in humans.[26] Finally, experimental studies have shown the anti-malarial drug mefloquine to be efficacious against juvenile and adult parasites from the three main schistosome species affecting man. Mefloquine has also been shown to act synergistically with PZQ, as combination therapy, against schistosomes in experimental studies,[27] but this effect could not be reproduced in recent human trials of people infected with S. haematobium parasites.[28] Combination therapy has the advantage of delaying/averting the development of drug resistance parasites when the drugs have different pharmacokinetcis.

Taken together, these historical and current anti-schistosome drugs illustrate the challenge of developing anti-schistosome therapeutics, and the combination of stage-specific, sex-specific and species-specific efficacy enhances the challenge for drug development. However, these drugs provide models for drug discovery and repurposing. The lack of schistosome drugs in the clinical trial pipeline is also of concern and is representative of the drug discovery/development landscape for helminth parasites in general.[15] Comparative genotype studies of the three human schistosome species are now possible due to sequencing of the genomes. Current molecular and genetic studies characterizing the schistosome pharmacophore provide potential for redesigning new anti-schistosome drugs using the old drugs as proposed for OXAM.[3] Advances in high-throughput platforms allowing phenotypic and target-based screening of drug candidates alongside the novel genetics now provide tools for drug discovery that were previously unavailable. Meanwhile, the establishment of public–private partnerships (e.g., TI Pharma, Merck KGaA (Darmstadt, Germany), Astellas Pharma Inc. and the Swiss Tropical and Public Health Institute for the formulation of pediatric PZQ) provides an economic model and platform for drug production and clinical trials. The remaining challenge is identifying potential drug targets, particularly for producing evolution proof drugs. There is a need for a clear scientific framework within which to conduct screening studies. Merck KGaA has a library of molecules available for screening for schistosome drug targets, and the recent identification of 121 compounds active against the schistosomula and 36 compounds active against the adult schistosome stage, from a library screen of 1,600 FDA-approved compounds supported by the Gates-funded drug discovery project, overseen by the Drugs for Neglected Diseases initiative offers some hope for discovering potential drug candidates.[29] In the current climate, where there are no schistosome drugs on the horizon, we are proposing a paradigm shift for the future of anti-schistosome therapeutics, optimizing the benefits of PZQ in four ways:

• Making PZQ available and accessible to all people exposed to schistosome infection, including pre-school children. We have succeeded along with others [30] in having the WHO recommend that these children be treated against schistosomiasis with PZQ.[19] Although this recommendation was made in 2010, it has largely remained unimplemented due to the lack of a pediatric formulation of PZQ to overcome the bitter taste and risk of choking on the large tablets currently available. The pediatric formulation has now been developed and awaits clinical trials.[19]

• Optimizing the timing of treatment with PZQ. Our studies and those of others [31,32] have shown that PZQ alters host immune responses accelerating the development of responses protective against reinfection [19] as well as reversing schistosome-related pathology.[33] Thus, there is a need to determine a strategy to maximize longer-term effects of PZQ beyond the transient reduction of infection and morbidity.

• Researching the treatment and clinical management of chronic schistosome pathology. Much focus has been made on controlling schistosome infection and early morbidity and relatively little on the control of pathology in chronic infection such as liver fibrosis, lesions in female genital schistosomiasis and bladder cancer. There are still no systemic mechanistic or clinical studies of the effect of PZQ on these.

• Understanding the pharmacogenetics of PZQ. PZQ undergoes first-pass metabolism in the liver by the CYP system.[34] Differential expression of these enzymes makes its pharmacokinetics susceptible to variability due to individual pharmacogenetic heterogeneity; interactions with drugs/substances that induce/inhibit specific isoenzymes of the CYP system taken concomitantly with PZQ and liver function, particularly important in chronic schistosome pathology. To date, no extensive studies have been conducted to ascertain the relative contribution of host genetics in the metabolism and efficacy of PZQ.

Financial & competing interests disclosure

The authors have no 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. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Additional information

Notes on contributors

Santiago Trainor-Moss

Francisca Mutapi