Few drugs are available for soil-transmitted helminthiasis (STH); the benzimidazoles albendazole and mebendazole are the only drugs being used for preventive chemotherapy as they can be given in one single dose with no weight adjustment. While generally safe and effective in reducing intensity of infection, they are contra-indicated in first-trimester pregnancy and have suboptimal efficacy against Trichuris trichiura. In addition, drug resistance is a threat. It is therefore important to find alternatives.
We searched the literature and the animal health marketed products and pipeline for potential drug development candidates. Recently registered veterinary products offer advantages in that they have undergone extensive and rigorous animal testing, thus reducing the risk, cost and time to approval for human trials. For selected compounds, we retrieved and summarised publicly available information (through US Freedom of Information (FoI) statements, European Public Assessment Reports (EPAR) and published literature). Concomitantly, we developed a target product profile (TPP) against which the products were compared.
The paper summarizes the general findings including various classes of compounds, and more specific information on two veterinary anthelmintics (monepantel, emodepside) and nitazoxanide, an antiprotozoal drug, compiled from the EMA EPAR and FDA registration files.
Few of the compounds already approved for use in human or animal medicine qualify for development track decision. Fast-tracking to approval for human studies may be possible for veterinary compounds like emodepside and monepantel, but additional information remains to be acquired before an informed decision can be made.
There are few drugs - none ideal - for the treatment and control of gastrointestinal helminths (soil-transmitted nematodes) which, as chronic infections jeopardize children's growth, learning and ultimately individual, community and country development. Drugs for helminths are not attractive in human medicine, but are lucrative in animal health. Traditionally, investment in veterinary medicines has benefited humans for these diseases. With modern regulations an approved veterinary medicine can be tested in humans with little adaptation, reducing time and cost of development. We searched for products that could easily be transitioned into humans, having the necessary characteristics for use in communities exposed to these infections. A limited number of candidates met the main criteria for selection. We provide here a detailed analysis of two veterinary products, emodepside and monepantel, and nitazoxanide, which is approved for human use. In addition we include a less detailed analysis of all products examined, and the criteria on which the analysis was based. It is clear that the pipeline of easily obtainable human anthelminthics remains extremely limited, and further efforts are needed to find replacements for the inadequate number of products available today.
Citation: Olliaro P, Seiler J, Kuesel A, Horton J, Clark JN, Don R, et al. (2011) Potential Drug Development Candidates for Human Soil-Transmitted Helminthiases. PLoS Negl Trop Dis 5(6): e1138. https://doi.org/10.1371/journal.pntd.0001138
Editor: Timothy G. Geary, McGill University, Canada
Received: December 8, 2010; Accepted: February 19, 2011; Published: June 7, 2011
Copyright: © 2011 Olliaro et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Funding: The originators and funders of this work are the UNICEF/UNDP/World Bank/WHO Special Programme on Research and Training in Tropical Diseases (TDR) and DNDi. PLO and AK are employed by TDR and RN is employed by DNDi. For the purpose of this study, JS was supported by a grant of the UNICEF/UNDP/World Bank/WHO Special Programme on Research and Training in Tropical Diseases (TDR) and JNC was contracted by DNDi. JK is grateful to the Swiss National Science Foundation (project no. PPOOA-114941) for financial support. This funder had no role in the design, data collection and analysis, decision to publish, or preparation of the manuscript.
Competing interests: The authors have declared that no competing interests exist.
Soil-transmitted helminthiasis (STH) is caused primarily by four species of nematode worms, Ancylostoma duodenale and Necator americanus (hookworms), Ascaris lumbricoides (roundworm), and Trichuris trichiura (whipworm), that parasitize the human gastrointestinal tract . Some 2–3 billion people are thought to have active infections and billions more are at risk of infection –. STH is estimated to be responsible for the loss of 39 million disability adjusted life years (DALYs) annually  but the burden of disease is currently being re-evaluated .
There are only four drugs recommended by the World Health Organization (WHO) for STH, and they have been in use for several decades: the two benzimidazole carbamates (BZs) albendazole and mebendazole, levamisole, and pyrantel pamoate , . While STH related morbidity can be controlled through chemotherapy, various problems need to be faced as anthelmintics are increasingly deployed in mass drug administration (MDA) programs . For practical reasons MDA requires a single drug administration to all subjects without prior diagnosis or checking for contra-indications.
For this reason, the BZs are preferred over levamisole and pyrantel (which require weight-based dosing and are also intrinsically less potent). However, the BZs are not perfect drugs either: first, the efficacy against some of the STHs (especially T. trichiura) is suboptimal when delivered as a single dose ; second the BZs are contra-indicated in early pregnancy, which may go unnoticed or unreported in the first trimester; and finally, the wide-spread coverage with a single class of compounds exposes parasites to selective pressure potentially leading to resistance, which has already occurred widely in veterinary practice , . Therefore, there is a pressing need for concerted efforts to discover and develop the next generation of anthelmintic drugs and for drug combinations. The main drivers are risk of emerging BZ resistance, the limited spectrum of activity and the contraindications of the current drugs.
Discovering and developing new drugs (Research & Development, R&D) is a complicated, expensive, risky and time-consuming endeavour. For a new drug to be granted marketing authorization in humans, it must be developed following strict regulatory requirements . Clinical development is also the most expensive part of R&D . Therefore, the decision to move a compound from the discovery into the development stage must be carefully considered and based on sound science and cost considerations.
Our goal is to identify and evaluate potential development candidates for STHs to assess whether all data required to inform the decision to initiate development are available or what additional data are needed. Compounds registered for veterinary medical use by the US Food and Drug Administration (FDA), European Medicines Agency (EMA) and other regulatory bodies have extensive safety, pharmacokinetics (in some cases) and efficacy data derived in animals. Therefore, these should have the potential for accelerated transition into human use.
Almost all products currently available for human helminth diseases have been transitioned from veterinary/animal health companies since the 1950's , . The average transition time was 3 years, but for older veterinary drugs, this was longer because of the need to conduct additional studies (e.g. safety, pharmacology) to satisfy modern requirements.
Modern rules for veterinary medicine licensure means that data available now are essentially equivalent to those required for human medicines; therefore transitioning can be achieved earlier. However, criteria for veterinary medicine anthelmintic efficacy are much more stringent than current human requirements, e.g. generally require an efficacy defined as 90% or greater clearance of the target organism , .
The underlying approach for this analysis was first to assess candidates based on publicly available information (through US Freedom of Information (FoI) statements, European Public Assessment Reports (EPAR), scientific meetings, publications, patents, etc) that could be summarized and shared. For the compounds that emerge as promising from this initial assessment, further information will be sought by directly contacting the relevant data owner for additional confidential data as appropriate. This will allow identification and analysis of the missing elements to permit an informed decision to be made on taking the compound forward and for planning the additional experiments that are required for human registration.
This paper summarizes the general findings and more specific information on two veterinary anthelmintics (monepantel, emodepside) and on nitazoxanide, a licensed antiprotozoal drug with evidence for anthelminthic activity, compiled from an analysis of publicly available information in the EMA EPAR and FDA registration files. Complete reviews with these data are provided as supplementary data (see below). None of these has been assessed for STH from a human drug development perspective. These summaries are made available to help define and stimulate decisions by potential researchers and drug developers, identify additional investigations that may be needed for an informed decision, as well as creating development partnerships.
Materials and Methods
Two searches were performed in parallel:
- We searched PubMed (http://www.ncbi.nlm.nih.gov) up to March 1, 2010 and contacted experts to identify potential drug development candidates for treating infections with soil transmitted helminths. For the electronic search the terms “chemotherapy”, “drug” or “anthelmintic”, in combination with “in vivo” and “ascariasis”, “Ascaris lumbricoides”, “hookworm”, “Ancylostoma duodenale”, “Necator americanus”, “trichuriasis”, “Trichuris trichiura”, “soil-transmitted helminths”, “soil-transmitted helminthiases”, or “nematode” were used. The search was restricted to publications over the past 20 years.
- Marketed veterinary drugs (U.S. and/or ex-U.S.) were also examined and categorized by the various chemical classes. Documents reviewed for this exercise included the U.S. FoI statements prepared by the veterinary drug companies and approved by the FDA, EMEA and other ex-U.S. regulatory body registration files, company product information, patents, scientific meeting abstracts and published literature and knowledge gathered by one of the authors (JNC) over 30 years in the animal health drug industry.
The candidate compounds for the searches were assessed against a product profile that had been previously generated following discussions at several meetings of experts at WHO and elsewhere (see proposed target product profile (TPP) which is provided in detail in Appendix S1). The assessment criteria used for the analysis contain the key points of the TPP and required the drug to be potentially:
- Safe for mass drug administration (MDA)
- - as well tolerated as in-use BZs albendazole and mebendazole
- - ideally capable of being given to pregnant women (ensuring maximum use in affected populations)
- Affordable in the context of MDA in endemic countries
- Achieving desired effect in a single dose (maximum two doses in one day)
- Simple to dose (not requiring complex measurements to deliver the drug)
- And additionally:
- - Spectrum to cover A. lumbricoides, both N. americanus and A. duodenale, T. trichiura (and also possibly S. stercoralis)
- - Minimally or not absorbed (if significantly absorbed, safety margins must be high)
- - No cross-resistance to existing drugs
To identify compounds amenable to rapid development, we aimed for compounds that are already in human or veterinary use or that had gone through extensive animal testing in their development as veterinary drugs.
Searches and assessment of potential drug candidates identified
The electronic search on PubMed yielded 299 hits. After discarding duplicate publications and studies outside our scope (e.g. molecular papers) and veterinary drugs (as these were already identified in our parallel search as described below), 25 potential drug candidates remained. The majority of these were natural product compounds and with the exception of tribendimidine, none of these had undergone extensive animal testing, and hence were not considered further. Through expert consultation an additional compound was identified (nitazoxanide).
In addition, we identified several primary anthelmintics used in veterinary medicine today. These include various representatives from the macrocyclic lactones (MLs, avermectins and milbemycins, including some experimental compounds that did not reach the market), BZs, depsipeptides, paraherquamides, hexahydropyrazines, tetrahydropyrimidines, imidathiazoles, amino-acetonitriles, salicylanilides, phenylsulfonamides, biphenylsulfides and miscellaneous compounds. Although there are some compounds (e.g. phenothiazines) that have been used in veterinary medicine, these are very old drugs and were not thought to be worth including here. A representative of each class is summarized in Table 1; details are provided in Appendix S2. Additional details on approved animal health compounds identified, including compound class, generic name, chemical structure, current supplier, patent approval, U.S. approval, mode of action, more specifics on parasite claims and efficacy/resistance, dose rates, more on safety and toxicity issues and an overall assessment of current use in veterinary medicine.
We did not further consider the avermectin class (which comprise a large number of animal health registered compounds, such as doramectin, eprinomectin, ivermectin and selamectin and agrochemical-registered compounds such as abamectin and emamectin) to be potentially interesting drug development candidates, as these drugs would likely be cross resistant to ivermectin-resistant parasites. In addition, ivermectin is characterized by low efficacy against hookworms , . The aforementioned compounds are all very similar structurally and act by the same mode of action, and therefore are unlikely to offer a clear advantage over ivermectin in terms of efficacy or resistance. No further search was undertaken for moxidectin, a milbemycin macrocyclic lactone, as this drug is under development for systemic helminths (onchocerciasis) in humans. The physico-chemical characteristics of this molecule result in pharmacokinetic advantages over ivermectin (longer residence time, larger volume of distribution). Though milbemycin oxime, another compound in this class, was effective in the treatment of ascarids and hookworms in naturally infected cats  and in dogs (Interceptor® product label) and is approved for Trichuris vulpis in dogs (Interceptor® product label), only moderate egg reduction rates were observed in baboons infected with T. trichiura . Further, this compound is only registered for use in companion animals so much of the data generated for a food producing animal that would accelerate any human health program would not be readily available.
The BZs represent a wide variety of molecules developed by several animal health companies and launched mostly in the 1960's and early 1970's for livestock, horses and companion animals. As mentioned above, albendazole and mebendazole are the most widely used drugs against STH today. The BZs act as inhibitors of tubulin formation, affecting cell synthesis and function , . The main disadvantage is that, as a class, the BZs are teratogens in animals and are contraindicated for use in the first trimester of pregnancy. Additionally, there is concern that their widespread use in public health programmes in highly endemic countries will result in helminth resistance, just as seen in the veterinary field a few years after their introduction. Before selecting any of the other BZs identified (fenbendazole, flubendazole, oxfendazole, oxibendazole, thiabendazole and netobimin) for development for STHs, any advantage over albendazole or mebendazole in terms of potential cross-resistance, improved efficacy profile or contraindications, would have to carefully considered. For example, fenbendazole given at doses of 30–50 mg/kg only achieved a cure rate of 28.6% in 28 Korean patients with T. trichiura respectively . Finally, oxfendazole and flubendazole are currently being investigated for treatment of systemic helminth infections in humans by the NIH and BMGF, and no publicly available information in humans exists for oxibendazole, which had been in clinical development for STH by SmithKlineBeecham/GlaxoSmithKline until about 2003.
Paraherquamide A is a natural product produced by Penicillium paraherquei which was discovered in 1981 . It was evaluated by Merck in the late 1980's and a small chemistry effort was conducted to produce analogs . Paraherquamide A was found to have outstanding broad spectrum nematocidal activity against various sheep gastro-intestinal nematodes . It is a nicotinic antagonist that blocks depolarization in muscles and induces a rapid paralysis of the mid-body of the parasite . However, it was severely toxic in mice and dogs, which prevented its development , as these species are the standard models for safety studies. In addition, poor activity was observed against T. vulpis in dogs . UpJohn, later Pfizer, conducted semi-synthetic medicinal chemistry on Paraherquamide A  and eventually identified derquantel as a safer but still effective compound against sheep gastrointestinal parasites. Derquantel was noted, however, to cause lethality in horses  and was not pursued for this species. This product is being developed as a sheep product in Australia and New Zealand in combination with abamectin . It remains to be confirmed whether derquantel offers improved efficacy against Trichuris spp. In addition, a thorough evaluation of potential toxicity of derquantel or any metabolites will have to be done prior to any administration to humans, acknowledging the history of this compound class. This issue lowered the priority for this compound in our evaluation.
No new compounds were identified within the hexahydropyrazine and imidazothiazole classes. Many of the hexahydropyrazines (DEC, piperazine, praziquantel and epsiprantel) and the imidazothiazole levamisole have been used for many years in human health. Similarly, the tetrahydropyrimidine class of neuromuscular blocking agents, such as pyrantel, has been used for decades in human health , , and the related molecule morantel would not offer any advantage over pyrantel.
Amidantel (BAY d 8815), a precursor of tribendimidine, was evaluated by Bayer in late 1970's. It showed efficacy against hookworms and ascarids in dogs with a single oral dose of 25 mg/kg , including Toxacara canis, which was completely eliminated by a single 10 mg/kg oral treatment. Early studies showed the compound acted as an acetylcholine agonist . The compound was not marketed as a veterinary product as the drug had to be given twice on two consecutive days, which was a great disadvantage in the face of other existing anthelmintics for companion animals . As tribendimidine, a symmetrical diamidine derivative of amidantel, is marketed in China for STH  and being pursued for human use, amidantel was not considered as a candidate from our analysis.
The salicylanilides (closantel, niclosamide, oxyclozanide, rafoxanide), the phenylsulfonamide clorsulon, the biphenylsulfides bithionol and febantel, and nitroscanate and nitroxynil are structurally similar with all containing one or more phenyl groups with halide or phenolic hydroxyls and/or nitro group substitutions. They are among the older anthelmintics developed for veterinary medicine and are still used, although safer and broader spectrum parasiticides take precedence except where price is more of a priority. They generally act as uncouplers of oxidative phosphorylation and so would not be prime candidates for human development without a thorough toxicology evaluation. In addition, several of these drugs (e.g. bithionol, clorsulon, rafoxanide) are only active against the trematode Fasciola hepatica ,  and do not possess nematocidal activity.
Hence, from our initial assessment we selected 4 compounds, which fulfilled further progression criteria (no cross resistance to already available drugs, excellent activity and toxicity profile). These four drugs are already marketed for either human (nitazoxanide, tribendimidine) or veterinary (the depsipeptide, emodepside and the aminoacetonitrile, monepantel) use. We did not compile a dossier on tribendimidine, which is registered for human use in China and is being developed for regulatory approval by a consortium composed of XPC China, Swiss Tropical and Public Health Institute (Swiss TPH), and Institute for One World Health (iOWH.) The structures of emodepside, monepantel and nitazoxanide are depicted in Figure 1.
Drug profiles of emodepside, monepantel and nitazoxanide
Information was available through documentation in the EMA and FDA registration files (EPAR and FOI summaries, respectively) and from available Material Safety Data Sheets as well as scientific publications. Complete dossiers with these data are provided as supplementary data and a brief summary of each of the drugs is provided below. The physico-chemical characteristics of these compounds are summarized in Appendix S3.
Emodepside is a semi-synthetic derivative of the cyclooctadepsipeptide PF1022A, a natural product compound produced by fermentation of the fungus Mycelia sterilia . Anthelmintic activities of emodepside have been demonstrated in several in vitro and in vivo studies against various nematodes , . Bayer Animal Health developed emodepside for use in cats and registered a topically administered product in combination with praziquantel to treat hookworms and ascarids (emodepside) and tapeworms (praziquantel) in Europe in 2005 and in the U.S. in 2007. The compound has a unique dual mechanism of action at the neuromuscular junction that involves on the one hand binding to a presynaptic latrophilin-like receptor and on the other hand pre- and post-synaptic interactions with a Ca2+-activated K+ ion channel (SLO-1). Binding of emodepside to the latrophilin receptor and the SLO-1 ion channel in the parasite leads to inhibition of pharyngeal pumping, paralysis and death , . Emodepside appears to be of low general toxicity and exhibits no genotoxic properties. Although some adverse effects were noted in embryotoxicity/teratogenicity studies in rats and rabbits, the use of the compound in pregnant cats has not been associated with any teratogenic findings. This compound represents a new class of anthelmintic, which could potentially be useful to treat helminthiasis in humans. The primary issue will be cost and to our knowledge, no studies have been published to date on the efficacy of the drug against specific soil-transmitted helminths (For detailed information see Appendix 4). In addition, some safety aspects (notably safety pharmacology, reproductive toxicity and neurotoxicity) remain to be elucidated. Of note, PF1022A, the emodepside precursor should also be considered, since the drug has a broad spectrum of activity ,  and might have lower production costs.
The amino-acetonitrile derivatives (AAD) represent a novel class of anthelmintic drugs developed by Novartis Animal Health for use in sheep and potentially in cattle . Monepantel, a member of this family, was registered in New Zealand as Zolvix® in 2009 for sheep abomasal parasites (Haemonchus contortus, Trichostrongylus colubriformis, and Teladorsagia circumcincta) and certain intestinal parasites (Oesphagostomum spp., Nematodirus spp., and Chabertia spp. but not T. ovis). As of January 2011 the product has been registered in a total of 32 countries in Australasia, Europe and Latin America. It is an agonist of a helminth-specific subfamily (DEG-3) of the nicotinic acetylcholine receptor, specifically attacking its subunit Hco-MPTL-1. Activation of the receptor through this agonist action causes hyper-contraction of the parasite body and spasmodic contraction of the pharynx . It has been reported to be effective against veterinary parasites resistant to known anthelmintics including macrocylic lactones, benzimidazoles and levamisole , a characteristic which could potentially give it an advantage as a human health drug. As the product was just recently launched there has been no field resistance reported as yet. It has recently been demonstrated that monepantel is not active against Strongyloides ratti in vitro, which lacks such a MPTL-1 homolog . A complete program of safety pharmacology and toxicology studies has been conducted. The compound appears to be of adequate safety with only adaptive effects noted in general toxicity studies and with no adverse effects in reproductive toxicity (paternal and embryo-foetal) observed in different animal species , . Monepantel is also without mutagenic activity . Hence, in conclusion, monepantel (i) has a clean safety profile and is reportedly not contraindicated in pregnancy; (ii) is not cross-resistant with the BZ family; and (iii) has a contemporary state-of-the-art regulatory dossier for veterinary use. The efficacy of the drug against some of the soil-transmitted helminths is not yet known. Specifically, there is no information on its activity on Necator americanus and Trichuris trichiura. Since the genomes of these two species are not published yet, and since predicting sensitivity on the basis of genomic information (such as whether the receptors conferring sensitivity to monepantel are present in Trichuris) might be inaccurate or insufficient, in vitro and in vivo experiments will be needed to complete its efficacy profile. Hence, we have started in vitro and in vivo studies with monepantel against T. muris and hookworms in our laboratories. For detailed information on monepantel see Appendix S5.
Nitazoxanide is an antiprotozoal drug used for the treatment of infections with Cryptosporidium parvum and Giardia intestinalis. The drug (trade name: Alinia®) is commonly given in six divided doses (500 mg bid for 3 days for adults and 200 mg bid for 3 days for children aged 4–11 years). The safety and tolerability of nitazoxanide in humans has been documented by >10 years of commercial use, during which more than 20 million people have been treated with this drug (Romark Laboratories, pers. commun.), most of them for relatively short durations ranging from 3 to 10 days. Three studies carried out in Mexico have shown that nitazoxanide achieved high cure rates against T. trichiura and A. lumbricoides –. For example, in Mexico cure rates of 78 and 56% were achieved against light and moderate infections with T. trichiura . However, studies against hookworms and using single doses remain to be done. Its mode of action involves inhibition of enzymes relevant for the survival of the parasites in an anaerobic environment, such as pyruvate:ferredoxin/flavodoxin oxidoreductases, nitroreductases and/or protein disulphide isomerases. Nitazoxanide appears to be a drug with no major safety issues emerging from non-clinical safety pharmacology and toxicology studies. Specifically, reproductive toxicity was not significantly affected due to the low absorption from the gastrointestinal tract, thus allowing its use in pregnancy. Although the haematotoxicity observed in rats and dogs might warrant special consideration for the use of nitazoxanide in G6PD-deficient patients, there was no evidence from the post-marketing experience for any major safety problems associated with the human use of nitazoxanide at recommended doses. For detailed information see Appendix S6.
The main objective of this work was to identify potential drug candidates that would be eligible for rapid transitioning into development for human STH infections. We have not considered possible drug combinations in the present work, as this strategy has already been discussed in recent reviews .
Several elements have to be taken into consideration when deciding whether a compound deserves further investigation and before investment is made to provide sufficient data for an informed development track decision. Examples are: cost of goods, suitability of formulation for human use, additional non-clinical pharmacology data such as efficacy against the target human helminths, safety, including potential drug∶drug interactions, and pharmacology. Many of these issues have yet to be addressed in detail and may result in further reduction in the already sparse list of candidates.
It is clear from these searches that the majority of compounds that could be developed still come from animal health. While this analysis has focussed on single drug candidates, it is important to recognise that there may not be one simple solution to the problem, especially since humans, like their animal counterparts, may be infected with several species of helminth at one time. Thus drugs may be identified that, taken together in combination, may also enhance efficacy and also reduce the risk of generating resistance. This strategy is followed in the chemotherapy of HIV, tuberculosis and malaria, and there is no reason to suppose that it would not also be effective for STHs. Indeed, for example a recent study has shown that a combination of mebendazole and ivermectin has enhanced efficacy against trichuriasis, while protecting from the poor efficacy of ivermectin against hookworm .
Although drugs registered for animal health could be rapidly transitioned into humans, it is essential to conduct discussions with the relevant regulatory authorities to ensure that all the necessary pre-clinical studies have been or can be conducted to permit human studies. The examination of data compiled in analyses such as presented here, together with expertise on regulatory process, should enable to identify the most suitable candidates, requiring the lowest progression investment. While this can accelerate the transition into humans, it should also be recognised that the most expensive phase of development is yet to be faced, and not all potential candidates will make it through human efficacy testing.
Finally, it is one thing to register a drug (difficult though it may be), but getting it into use is a challenge of a different level of complexity, especially in the case of STH or other helminthic diseases. Here, the product is not chosen by the individual customer or prescriber, but is rather selected by control programmes or even internationally for procurement and distribution through MDA. With all their limitations, displacing the current BZs will be complex even for a very good drug. After all, BZs are capable of reducing infection intensity (and thus morbidity), are generally safe, are given in a single dose and the same dose for all, and are donated to a large extent. Cost-effectiveness will be an issue and will include consideration of the cost of changing policy as well, against the prospective advantages of the new drug.
We believe it was important both to conduct this analysis and to share and make the results publicly available. STH and helminthiasis in general are among the most neglected diseases in terms of drug R&D, even compared to other tropical diseases, such as those caused by kinetoplastids (leishmaniasis, African trypanosomiasis, Chagas disease) or malaria . Today there are few dedicated funds for anthelmintic, particularly STH, R&D for human use; there are some potential but scattered initiatives and little or no cohesive approach thus far. With scarce resources, and the high costs and long development times for new drugs, developing the wrong candidate or a “me-too” drug (drugs that will offer no significant public health advantage over existing interventions) is not an option.
Making the results of this search publicly available will hopefully assist decision making for R&D in the community of developers and funders. However, this will only be the beginning, as more needs to be done. Based on our assessment, we will endeavour to access proprietary information through confidentiality agreements with the respective companies and to generate the data that we feel will be required to make a development track decision.
Recently, TDR, BIO Ventures for Global Health (BVGH) and the Sabin Vaccine Institute initiated discussions with a number of public and not-for-profit organizations potentially interested in drug development for helminths including developers, researchers and funding agencies. The objective is to favour an enabling environment for anthelmintic R&D, consistency and openness (with sharing of information). Hopefully a degree of cohesion can be reached. In the case of STH (and helminths at large) R&D, the situation is such (little resources, few candidate drugs, few development partners) that it must be approached considering the global R&D pipeline rather than individual initiatives by single organizations. This will hopefully provide consistency and consolidate development efforts. And this is the spirit underlying this paper.
Proposed Target Product Profile for drugs for STH.
Additional details on approved animal health compounds identified, including compound class, generic name, chemical structure, current supplier, patent approval, U.S. approval, mode of action, more specifics on parasite claims and efficacy/resistance, dose rates, more on safety and toxicity issues and an overall assessment of current use in veterinary medicine.
Physico-chemical data for emodepside, monepantel and nitazoxanide.
Detailed information on emodepside.
Detailed information on monepantel.
Thanks are addressed to Carla Kirchhofer for the systematic review.
P. Olliaro and A. Kuesel are staff members of the WHO; J. Keiser is a member of a WHO/TDR scientific advisory committee; J. Horton serves as an adviser to various programmes of the WHO, including TDR. The authors alone are responsible for the views expressed in this publication and they do not necessarily represent the decisions, policy or views of the WHO.
Conceived and designed the experiments: PLO JK. Performed the experiments: JS JNC JK. Analyzed the data: PLO JK RD AK JH. Wrote the paper: PLO JK JH.
- 1. Bethony J, Brooker S, Albonico M, Geiger SM, Loukas A, et al. (2006) Soil-transmitted helminth infections: ascariasis, trichuriasis, and hookworm. Lancet 367: 1521–1532.J. BethonyS. BrookerM. AlbonicoSM GeigerA. Loukas2006Soil-transmitted helminth infections: ascariasis, trichuriasis, and hookworm.Lancet36715211532
- 2. Chan MS (1997) The global burden of intestinal nematode infections–fifty years on. Parasitol Today 13: 438–443.MS Chan1997The global burden of intestinal nematode infections–fifty years on.Parasitol Today13438443
- 3. de Silva N, Brooker S, Hotez PJ, Montresor A, Engels D, et al. (2003) Soil-transmitted helminth infections: updating the global picture. Trends Parasitol 19: 547–551.N. de SilvaS. BrookerPJ HotezA. MontresorD. Engels2003Soil-transmitted helminth infections: updating the global picture.Trends Parasitol19547551
- 4. Hotez PJ, Molyneux DH, Fenwick A, Kumaresan J, Sachs SE, et al. (2007) Control of neglected tropical diseases. N Engl J Med 357: 1018–1027.PJ HotezDH MolyneuxA. FenwickJ. KumaresanSE Sachs2007Control of neglected tropical diseases.N Engl J Med35710181027
- 5. Brooker S (2010) Estimating the global distribution and disease burden of intestinal nematode infections: adding up the numbers–a review. Int J Parasitol 40: 1137–1144.S. Brooker2010Estimating the global distribution and disease burden of intestinal nematode infections: adding up the numbers–a review.Int J Parasitol4011371144
- 6. WHO (2006) Preventive chemotherapy in human helminthiasis: coordinated use of anthelminthic drugs in control interventions: a manual for health professionals and programme managers. WHO2006Preventive chemotherapy in human helminthiasis: coordinated use of anthelminthic drugs in control interventions: a manual for health professionals and programme managers.World Health Organization, Geneva. World Health Organization, Geneva.
- 7. Keiser J, Utzinger J (2010) The drugs we have and the drugs we need against major helminth infections. Adv Parasitol 73: 197–230.J. KeiserJ. Utzinger2010The drugs we have and the drugs we need against major helminth infections.Adv Parasitol73197230
- 8. Keiser J, Utzinger J (2008) Efficacy of current drugs against soil-transmitted helminth infections: systematic review and meta-analysis. Jama 299: 1937–1948.J. KeiserJ. Utzinger2008Efficacy of current drugs against soil-transmitted helminth infections: systematic review and meta-analysis.Jama29919371948
- 9. Geerts S, Gryseels B (2000) Drug resistance in human helminths: current situation and lessons from livestock. Clin Microbiol Rev 13: 207–222.S. GeertsB. Gryseels2000Drug resistance in human helminths: current situation and lessons from livestock.Clin Microbiol Rev13207222
- 10. Kaplan RM (2004) Drug resistance in nematodes of veterinary importance: a status report. Trends Parasitol 20: 477–481.RM Kaplan2004Drug resistance in nematodes of veterinary importance: a status report.Trends Parasitol20477481
- 11. Dickson M, Gagnon JP (2004) Key factors in the rising cost of new drug discovery and development. Nat Rev Drug Discov 3: 417–429.M. DicksonJP Gagnon2004Key factors in the rising cost of new drug discovery and development.Nat Rev Drug Discov3417429
- 12. Geary TG, Woo K, McCarthy JS, Mackenzie CD, Horton J, et al. (2010) Unresolved issues in anthelmintic pharmacology for helminthiases of humans. Int J Parasitol 40: 1–13.TG GearyK. WooJS McCarthyCD MackenzieJ. Horton2010Unresolved issues in anthelmintic pharmacology for helminthiases of humans.Int J Parasitol40113
- 13. Wood IB, Amaral NK, Bairden K, Duncan JL, Kassai T, et al. (1995) World Association for the Advancement of Veterinary Parasitology (W.A.A.V.P.) second edition of guidelines for evaluating the efficacy of anthelmintics in ruminants (bovine, ovine, caprine). Vet Parasitol 58: 181–213.IB WoodNK AmaralK. BairdenJL DuncanT. Kassai1995World Association for the Advancement of Veterinary Parasitology (W.A.A.V.P.) second edition of guidelines for evaluating the efficacy of anthelmintics in ruminants (bovine, ovine, caprine).Vet Parasitol58181213
- 14. Gutman J, Emukah E, Okpala N, Okoro C, Obasi A, et al. (2010) Effects of annual mass treatment with ivermectin for onchocerciasis on the prevalence of intestinal helminths. Am J Trop Med Hyg 83: 534–541.J. GutmanE. EmukahN. OkpalaC. OkoroA. Obasi2010Effects of annual mass treatment with ivermectin for onchocerciasis on the prevalence of intestinal helminths.Am J Trop Med Hyg83534541
- 15. Wen LY, Yan XL, Sun FH, Fang YY, Yang MJ, et al. (2008) A randomized, double-blind, multicenter clinical trial on the efficacy of ivermectin against intestinal nematode infections in China. Acta Trop 106: 190–194.LY WenXL YanFH SunYY FangMJ Yang2008A randomized, double-blind, multicenter clinical trial on the efficacy of ivermectin against intestinal nematode infections in China.Acta Trop106190194
- 16. Catton DG, Van Schalkwyk PC (2003) The efficacy of two anthelmintics against ascarids and hookworms in naturally infected cats. Parasitol Res 90: Suppl 3S144–145.DG CattonPC Van Schalkwyk2003The efficacy of two anthelmintics against ascarids and hookworms in naturally infected cats.Parasitol Res90Suppl 3S144145
- 17. Reichard MV, Wolf RF, Carey DW, Garrett JJ, Briscoe HA (2007) Efficacy of fenbendazole and milbemycin oxime for treating baboons (Papio cynocephalus anubis) infected with Trichuris trichiura. J Am Assoc Lab Anim Sci 46: 42–45.MV ReichardRF WolfDW CareyJJ GarrettHA Briscoe2007Efficacy of fenbendazole and milbemycin oxime for treating baboons (Papio cynocephalus anubis) infected with Trichuris trichiura.J Am Assoc Lab Anim Sci464245
- 18. Lacey E (1988) The role of the cytoskeletal protein, tubulin, in the mode of action and mechanism of drug resistance to benzimidazoles. Int J Parasitol 18: 885–936.E. Lacey1988The role of the cytoskeletal protein, tubulin, in the mode of action and mechanism of drug resistance to benzimidazoles.Int J Parasitol18885936
- 19. Lacey E, Gill JH (1994) Biochemistry of benzimidazole resistance. Acta Trop 56: 245–262.E. LaceyJH Gill1994Biochemistry of benzimidazole resistance.Acta Trop56245262
- 20. Rim HJ, Lee JS, Joo KH, Kim YS (1981) Anthelmintic effects of single doses of fenbendazole and oxantel-pyrantel pamoate to the intestinal nematodes. Kisaengchunghak Chapchi 19: 95–100.HJ RimJS LeeKH JooYS Kim1981Anthelmintic effects of single doses of fenbendazole and oxantel-pyrantel pamoate to the intestinal nematodes.Kisaengchunghak Chapchi1995100
- 21. Yamazaki M, Okuvama E (1981) The structure of paraherquamide, a toxid metabolite from Penicillum Paraherquei. Tetrahedron Letters 22: 135–136.M. YamazakiE. Okuvama1981The structure of paraherquamide, a toxid metabolite from Penicillum Paraherquei.Tetrahedron Letters22135136
- 22. Blizzard TA, Margiatto G, Mrozik H, Schaeffer JM, Fisher MH (1991) Chemical modification of paraherquamide. 4. 1-N-substituted analogs. Tetrahedron Lett 32: 2441–2444.TA BlizzardG. MargiattoH. MrozikJM SchaefferMH Fisher1991Chemical modification of paraherquamide. 4. 1-N-substituted analogs.Tetrahedron Lett3224412444
- 23. Shoop WL, Michael BF, Haines HW, Eary CH (1992) Anthelmintic activity of paraherquamide in calves. Vet Parasitol 43: 259–263.WL ShoopBF MichaelHW HainesCH Eary1992Anthelmintic activity of paraherquamide in calves.Vet Parasitol43259263
- 24. Zinser EW, Wolf ML, Alexander-Bowman SJ, Thomas EM, Davis JP, et al. (2002) Anthelmintic paraherquamides are cholinergic antagonists in gastrointestinal nematodes and mammals. J Vet Pharmacol Ther 25: 241–250.EW ZinserML WolfSJ Alexander-BowmanEM ThomasJP Davis2002Anthelmintic paraherquamides are cholinergic antagonists in gastrointestinal nematodes and mammals.J Vet Pharmacol Ther25241250
- 25. Shoop WL, Eary CH, Michael BF, Haines HW, Seward RL (1991) Anthelmintic activity of paraherquamide in dogs. Vet Parasitol 40: 339–341.WL ShoopCH EaryBF MichaelHW HainesRL Seward1991Anthelmintic activity of paraherquamide in dogs.Vet Parasitol40339341
- 26. Lee BH, Clothier MF, Dutton FE, Nelson SJ, Johnson SS, et al. (2002) Marcfortine and paraherquamide class of anthelmintics: discovery of PNU-141962. Curr Top Med Chem 2: 779–793.BH LeeMF ClothierFE DuttonSJ NelsonSS Johnson2002Marcfortine and paraherquamide class of anthelmintics: discovery of PNU-141962.Curr Top Med Chem2779793
- 27. European Medicines Agency. Committee for Medicinal Products for Veterinary Use (2010) European public MRL assessment report (EPMAR). Derquantel. European Medicines Agency. Committee for Medicinal Products for Veterinary Use2010European public MRL assessment report (EPMAR).Derquantel(ovine species). (ovine species).
- 28. Little PR, Hodges A, Watson TG, Seed JA, Maeder SJ (2010) Field efficacy and safety of an oral formulation of the novel combination anthelmintic, derquantel-abamectin, in sheep in New Zealand. N Z Vet J 58: 121–129.PR LittleA. HodgesTG WatsonJA SeedSJ Maeder2010Field efficacy and safety of an oral formulation of the novel combination anthelmintic, derquantel-abamectin, in sheep in New Zealand.N Z Vet J58121129
- 29. Urbani C, Albonico M (2003) Anthelminthic drug safety and drug administration in the control of soil-transmitted helminthiasis in community campaigns. Acta Trop 86: 215–221.C. UrbaniM. Albonico2003Anthelminthic drug safety and drug administration in the control of soil-transmitted helminthiasis in community campaigns.Acta Trop86215221
- 30. Thomas H (1979) The efficacy of amidantel, a new anthelmintic, on hookworms and ascarids in dogs. Tropenmed Parasitol 30: 404–408.H. Thomas1979The efficacy of amidantel, a new anthelmintic, on hookworms and ascarids in dogs.Tropenmed Parasitol30404408
- 31. Tomlinson G, Albuquerque CA, Woods RA (1985) The effects of amidantel (BAY d 8815) and its deacylated derivative (BAY d 9216) on Caenorhabditis elegans. Eur J Pharmacol 113: 255–262.G. TomlinsonCA AlbuquerqueRA Woods1985The effects of amidantel (BAY d 8815) and its deacylated derivative (BAY d 9216) on Caenorhabditis elegans.Eur J Pharmacol113255262
- 32. Harder A (2002) Milestones of helmintic research at Bayer. Parasitol Res 88: 477–480.A. Harder2002Milestones of helmintic research at Bayer.Parasitol Res88477480
- 33. Xiao SH, Wu HM, Tanner M, Utzinger J, Chong W (2005) Tribendimidine: a promising, safe and broad-spectrum anthelmintic agent from China. Acta Trop 94: 1–14.SH XiaoHM WuM. TannerJ. UtzingerW. Chong2005Tribendimidine: a promising, safe and broad-spectrum anthelmintic agent from China.Acta Trop94114
- 34. Keiser J, Utzinger J (2007) Food-borne trematodiasis: current chemotherapy and advances with artemisinins and synthetic trioxolanes. Trends Parasitol 23: 555–562.J. KeiserJ. Utzinger2007Food-borne trematodiasis: current chemotherapy and advances with artemisinins and synthetic trioxolanes.Trends Parasitol23555562
- 35. Elitok B, Elitok OM, Kabu M (2006) Field trial on comparative efficacy of four fasciolicides against natural liver fluke infection in cattle. Vet Parasitol 135: 279–285.B. ElitokOM ElitokM. Kabu2006Field trial on comparative efficacy of four fasciolicides against natural liver fluke infection in cattle.Vet Parasitol135279285
- 36. Sasaki T, Takagi M, Yaguchi T, Miyadoh S, Okada T, et al. (1992) A new anthelmintic cyclodepsipeptide, PF1022A. J Antibiot (Tokyo) 45: 692–697.T. SasakiM. TakagiT. YaguchiS. MiyadohT. Okada1992A new anthelmintic cyclodepsipeptide, PF1022A.J Antibiot (Tokyo)45692697
- 37. Harder A, von Samson-Himmelstjerna G (2002) Cyclooctadepsipeptides–a new class of anthelmintically active compounds. Parasitol Res 88: 481–488.A. HarderG. von Samson-Himmelstjerna2002Cyclooctadepsipeptides–a new class of anthelmintically active compounds.Parasitol Res88481488
- 38. von Samson-Himmelstjerna G, Harder A, Sangster NC, Coles GC (2005) Efficacy of two cyclooctadepsipeptides, PF1022A and emodepside, against anthelmintic-resistant nematodes in sheep and cattle. Parasitology 130: 343–347.G. von Samson-HimmelstjernaA. HarderNC SangsterGC Coles2005Efficacy of two cyclooctadepsipeptides, PF1022A and emodepside, against anthelmintic-resistant nematodes in sheep and cattle.Parasitology130343347
- 39. Harder A, Schmitt-Wrede HP, Krucken J, Marinovski P, Wunderlich F, et al. (2003) Cyclooctadepsipeptides - an anthelmintically active class of compounds exhibiting a novel mode of action. Int J Antimicrob Agents 22: 318–331.A. HarderHP Schmitt-WredeJ. KruckenP. MarinovskiF. Wunderlich2003Cyclooctadepsipeptides - an anthelmintically active class of compounds exhibiting a novel mode of action.Int J Antimicrob Agents22318331
- 40. Guest M, Bull K, Walker RJ, Amliwala K, O'Connor V, et al. (2007) The calcium-activated potassium channel, SLO-1, is required for the action of the novel cyclo-octadepsipeptide anthelmintic, emodepside, in Caenorhabditis elegans. Int J Parasitol 37: 1577–1588.M. GuestK. BullRJ WalkerK. AmliwalaV. O'Connor2007The calcium-activated potassium channel, SLO-1, is required for the action of the novel cyclo-octadepsipeptide anthelmintic, emodepside, in Caenorhabditis elegans.Int J Parasitol3715771588
- 41. von Samson-Himmelstjerna G, Harder A, Schnieder T, Kalbe J, Mencke N (2000) In vivo activities of the new anthelmintic depsipeptide PF 1022A. Parasitol Res 86: 194–199.G. von Samson-HimmelstjernaA. HarderT. SchniederJ. KalbeN. Mencke2000In vivo activities of the new anthelmintic depsipeptide PF 1022A.Parasitol Res86194199
- 42. Ducray P, Gauvry N, Pautrat F, Goebel T, Fruechtel J, et al. (2008) Discovery of amino-acetonitrile derivatives, a new class of synthetic anthelmintic compounds. Bioorg Med Chem Lett 18: 2935–2938.P. DucrayN. GauvryF. PautratT. GoebelJ. Fruechtel2008Discovery of amino-acetonitrile derivatives, a new class of synthetic anthelmintic compounds.Bioorg Med Chem Lett1829352938
- 43. Kaminsky R, Ducray P, Jung M, Clover R, Rufener L, et al. (2008) A new class of anthelmintics effective against drug-resistant nematodes. Nature 452: 176–180.R. KaminskyP. DucrayM. JungR. CloverL. Rufener2008A new class of anthelmintics effective against drug-resistant nematodes.Nature452176180
- 44. Rufener L, Keiser J, Kaminsky R, Mäser P, Nilsson D (2010) Phylogenomics of Ligand-Gated Ion Channels Predicts Monepantel Effect. PLoS Pathog 6: e1001091.L. RufenerJ. KeiserR. KaminskyP. MäserD. Nilsson2010Phylogenomics of Ligand-Gated Ion Channels Predicts Monepantel Effect.PLoS Pathog6e1001091
- 45. Hosking BC, Griffiths TM, Woodgate RG, Besier RB, Le Feuvre AS, et al. (2009) Clinical field study to evaluate the efficacy and safety of the amino-acetonitrile derivative, monepantel, compared with registered anthelmintics against gastrointestinal nematodes of sheep in Australia. Aust Vet J 87: 455–462.BC HoskingTM GriffithsRG WoodgateRB BesierAS Le Feuvre2009Clinical field study to evaluate the efficacy and safety of the amino-acetonitrile derivative, monepantel, compared with registered anthelmintics against gastrointestinal nematodes of sheep in Australia.Aust Vet J87455462
- 46. Malikides N, Spencer K, Mahoney R, Baker K, Vanhoff K, et al. (2009) Safety of an amino-acetonitrile derivative (AAD), monepantel, in ewes and their offspring following repeated oral administration. N Z Vet J 57: 193–202.N. MalikidesK. SpencerR. MahoneyK. BakerK. Vanhoff2009Safety of an amino-acetonitrile derivative (AAD), monepantel, in ewes and their offspring following repeated oral administration.N Z Vet J57193202
- 47. Kaminsky R, Gauvry N, Schorderet Weber S, Skripsky T, Bouvier J, et al. (2008) Identification of the amino-acetonitrile derivative monepantel (AAD 1566) as a new anthelmintic drug development candidate. Parasitol Res 103: 931–939.R. KaminskyN. GauvryS. Schorderet WeberT. SkripskyJ. Bouvier2008Identification of the amino-acetonitrile derivative monepantel (AAD 1566) as a new anthelmintic drug development candidate.Parasitol Res103931939
- 48. Romero Cabello R, Guerrero LR, Munoz Garcia MR, Geyne Cruz A (1997) Nitazoxanide for the treatment of intestinal protozoan and helminthic infections in Mexico. Trans R Soc Trop Med Hyg 91: 701–703.R. Romero CabelloLR GuerreroMR Munoz GarciaA. Geyne Cruz1997Nitazoxanide for the treatment of intestinal protozoan and helminthic infections in Mexico.Trans R Soc Trop Med Hyg91701703
- 49. Juan JO, Lopez Chegne N, Gargala G, Favennec L (2002) Comparative clinical studies of nitazoxanide, albendazole and praziquantel in the treatment of ascariasis, trichuriasis and hymenolepiasis in children from Peru. Trans R Soc Trop Med Hyg 96: 193–196.JO JuanN. Lopez ChegneG. GargalaL. Favennec2002Comparative clinical studies of nitazoxanide, albendazole and praziquantel in the treatment of ascariasis, trichuriasis and hymenolepiasis in children from Peru.Trans R Soc Trop Med Hyg96193196
- 50. Diaz E, Mondragon J, Ramirez E, Bernal R (2003) Epidemiology and control of intestinal parasites with nitazoxanide in children in Mexico. Am J Trop Med Hyg 68: 384–385.E. DiazJ. MondragonE. RamirezR. Bernal2003Epidemiology and control of intestinal parasites with nitazoxanide in children in Mexico.Am J Trop Med Hyg68384385
- 51. Knopp S, Mohammed KA, Speich B, Hattendorf J, Khamis IS, et al. (2010) Albendazole and mebendazole administered alone or in combination with ivermectin against Trichuris trichiura: a randomized controlled trial. Clin Infect Dis 51: 1420–1428.S. KnoppKA MohammedB. SpeichJ. HattendorfIS Khamis2010Albendazole and mebendazole administered alone or in combination with ivermectin against Trichuris trichiura: a randomized controlled trial.Clin Infect Dis5114201428
- 52. Cohen J, Dibner MS, Wilson A (2010) Development of and access to products for neglected diseases. PLoS One 5: e10610.J. CohenMS DibnerA. Wilson2010Development of and access to products for neglected diseases.PLoS One5e10610