Scientific articles on the HELP Consortium project
Onchocerciasis drug development: from preclinical models to humans
by Ngwewondo A, Scandale I, Specht S. Parasitology Research 2021. doi: 10.1007/s00436-021-07307-4
Summary: Control programmes have made tremendous efforts in the management of onchocerciasis by mass drug administration and aerial larviciding; however, disease elimination is not yet achieved. In the new WHO roadmap, it is recognized that new macrofilaricidal drugs or drug regimens (that kill or permanently sterilize adult filarial worms) would significantly improve elimination timelines and accelerate the achievement of the program goal of disease elimination. In this review, the authors summarize recent advances in the late preclinical or early clinical stage in the search for a potent macrofilaricide, including drugs against the nematode and against its endosymbiont, Wolbachia pipientis.
Preclinical and clinical characteristics of the trichuricidal drug oxantel pamoate and clinical development plans: A review
by Palmeirim MS, Specht S, Scandale I, Gander-Meisterernst I, Chabicovsky M, Keiser J. Drugs 2021. doi: 10.1007/s40265-021-01505-1
Summary: Soil-transmitted helminths (Ascaris lumbricoides, hookworm and Trichuris trichiura) infect about one-fifth of the world’s population, however, the currently used drugs are poorly efficacious against T. trichiura. Oxantel pamoate is a tetrahydropyrimidine derivative discovered in the 1970s which is safe and efficacious against Trichuris trichiura. Within the framework of the Helminth Drug Development Platform, the authors conducted a literature review to determine whether any existing data could be used to support clinical development of oxantel pamoate for T. trichiura.
Scientific articles by institution members of the HELP Consortium
Comparison of the macrofilaricidal efficacy of oxfendazole and its isomers against the rodent filaria Litomosoides sigmodontis
by Risch F, Koschel M, Lenz B, Specht S, Hoerauf A, Hübner MP, Scandale I. Frontiers in Tropical Diseases 2022; doi: 10.3389/fitd.2022.982421
Summary: Originally developed for the veterinary market, oxfendazole is a lead macrofilaricidal candidate for the treatment of onchocerciasis and lymphatic filariasis. The authors of this study compared the efficacy of oxfendazole isomers with the commercially available racemic mixture Dolthene in a mouse model of filariasis using Litomosoides sigmodontis. Overall, the results suggest that both oxfendazole isomers have similar anti-filarial activity and do not support the development of a single isomer for future use in human patients.
Efficacy and safety of moxidectin and albendazole compared with ivermectin and albendazole coadministration in adolescents infected with Trichuris trichiura in Tanzania: an open-label, non-inferiority, randomised, controlled, phase 2/3 trial
by Welsche S, Mrimi EC, Hattendorf J, Hürlimann E, Ali SM, Keiser J. The Lancet Infectious Diseases 2022. doi: 10.1016/S1473-3099(22)00589-8
Summary: Control efforts against soil-transmitted helminths focus on preventive chemotherapy with albendazole and mebendazole, however these drugs yield unsatisfactory results against Trichuris trichiura infections. We aimed to assess the efficacy and safety of moxidectin and albendazole compared with ivermectin and albendazole against T trichiura in adolescents living on Pemba Island, Tanzania. Our findings show inferiority of moxidectin and albendazole to ivermectin and albendazole against T trichiura. However, given the high efficacy, moxidectin coadministration might complement treatment progammes, particularly in areas in which ivermectin is not available
Discovery of substituted di(pyridin-2-yl)-1,2,4-thiadiazol-5-amines as novel macrofilaricidal compounds for the treatment of human filarial infections
by Hawryluk N, Robinson D, Shen Y, Kyne G, Bedore M, Menon S, Canan S, von Geldern T, Townson S, Gokool S, Ehrens A, Koschel M, Lhermitte-Vallarino N, Martin C, Hoerauf A, Hernandez G, Dalvie D, Specht S, Hübner MP, Scandale I. Journal of Medicinal Chemistry 2022, 65(16);11388-11403. doi: 10.1021/acs.jmedchem.2c00960
Summary: Efforts to control and eliminate onchocerciasis are impeded by a lack of effective treatments that target the adult filarial stage. The authors previously reported a platform using surrogate nematodes in phenotypic ex vivo assays to assess activity across various parasites, which led to a series of amino-thiazole molecules demonstrating ex vivo killing of adult O. gutturosa, B. malayi, B. pahangi, and L. sigmodontis. Following on from this, in this manuscript, the authors describe the discovery of a series of substituted di(pyridin-2-yl)- 1,2,4-thiadiazol-5-amines as novel macrofilaricides for the treatment of human filarial infections.
Filarial nematode phenotypic screening cascade to identify compounds with anti-parasitic activity for drug discovery optimization
by Hawryluk N, Zhiru L, Carlow C, Gokool S, Townson S, Kreiss T, Chojnowski A, Prorok M, Siekierka J, Ehrens A, Koschel M, Lhermitte-Vallarino N, Martin C, Hoerauf A, Hernandez G, Canan S, Khetani V, Zeldis J, Specht S, Hübner MP, Scandale I. International Journal for Parasitology: Drugs and Drug Resistance 2022. doi: 10.1016/j.ijpddr.2022.06.002
Summary: Filarial diseases, including lymphatic filariasis and onchocerciasis, are considered among the most devastating of all tropical diseases, affecting over 86 million people worldwide. To control and more rapidly eliminate onchocerciasis requires treatments that target the adult stage of the parasite. Drug discovery efforts are challenged by the lack of preclinical animal models using the human-pathogenic filariae, requiring the use of surrogate parasites for Onchocerca volvulus for both ex vivo and in vivo evaluation. Herein, we describe a platform utilizing phenotypic ex vivo assays consisting of the free-living nematode Caenorhabditis elegans, microfilariae and adult filariae of the bovine filariae Onchocerca lienalis and Onchocerca gutturosa, respectively, as well as microfilariae and adult filariae of the feline filariae Brugia pahangi, the rodent filariae Litomosoides sigmodontis and the human-pathogenic filariae Brugia malayi to assess activity across various surrogate parasites. Utilization of those surrogate nematodes for phenotypic ex vivo assays in order to assess activity across various parasites led to the successful establishment of a screening cascade and identification of multiple compounds with potential macrofilaricidal activity and desirable physicochemical, MW = 200–400 and low lipophilicity, logP <4, and pharmacokinetic properties, rat and human liver S9 stability of ≥70% remaining at 60 min, and AUC exposures above 3 μM h. This platform demonstrated the successful establishment of a screening cascade which resulted in the discovery of potential novel macrofilaricidal compounds for futher drug discovery lead optimization efforts. This screening cascade identified two distinct chemical series wherein one compound produced a significant 68% reduction of adult Litomosoides sigmodontis in the mouse model. Successful demonstration of efficacy prompted lead optimization medicinal chemistry efforts for this novel series.
ILC2s Control Microfilaremia During Litomosoides sigmodontis Infection in Rag2 -/- Mice
by Reichwald JJ, Risch F, Neumann AL, Frohberger SJ, Scheunemann JF, Lenz B, Ehrens A, Strutz W, Schumak B, Hoerauf A, Hübner MP. Frontiers in Immunology 2022. doi: 10.3389/fimmu.2022.863663
Summary: Group 2 innate lymphoid cells (ILC2s) are inducers of type 2 immune responses, but their role during filarial infection remains unclear. In the present study, we used the Litomosoides sigmodontis rodent model of filariasis to analyze ILC2s during infection in susceptible BALB/c mice that develop a chronic infection with microfilaremia and semi-susceptible C57BL/6 mice that eliminate the filariae shortly after the molt into adult worms and thus do not develop microfilaremia. ILC2s (CD45+ Lineage– TCRβ– CD90.2+ Sca-1+ IL-33R+ GATA-3+) were analyzed in the pleural cavity, the site of L. sigmodontis infection, after the infective L3 larvae reached the pleural cavity (9 days post infection, dpi), after the molt into adult worms (30dpi) and during the peak of microfilaremia (70dpi). C57BL/6 mice had significantly increased ILC2 numbers compared to BALB/c mice at 30dpi, accompanied by substantially higher IL-5 and IL-13 levels, indicating a stronger type 2 immune response in C57BL/6 mice upon L. sigmodontis infection. At this time point the ILC2 numbers positively correlated with the worm burden in both mouse strains. ILC2s and GATA-3+ CD4+ T cells were the dominant source of IL-5 in L. sigmodontis-infected C57BL/6 mice with ILC2s showing a significantly higher IL-5 expression than CD4+ T cells. To investigate the importance of ILC2s during L. sigmodontis infection, ILC2s were depleted with anti-CD90.2 antibodies in T and B cell-deficient Rag2-/- C57BL/6 mice on 26-28dpi and the outcome of infection was compared to isotype controls. Rag2-/- mice were per se susceptible to L. sigmodontis infection with significantly higher worm burden than C57BL/6 mice and developed microfilaremia. Depletion of ILC2s did not result in an increased worm burden in Rag2-/- mice, but led to significantly higher microfilariae numbers compared to isotype controls. In conclusion, our data demonstrate that ILC2s are essentially involved in the control of microfilaremia in Rag2-/- C57BL/6 mice.
Current perspective of new anti-Wolbachial and direct-acting macrofilaricidal drugs as treatment strategies for human filariasis
by Ehrens A, Hoerauf A, Hübner MP. GMS Infectious Diseases 2022. doi: 10.3205/id000079
Summary: Filarial diseases like lymphatic filariasis and onchocerciasis belong to the Neglected Tropical Diseases and remain a public health problem in endemic countries. Lymphatic filariasis and onchocerciasis can lead to stigmatizing pathologies and present a socio-economic burden for affected people and their endemic countries. Current treatment recommendations by the WHO include mass drug administration with ivermectin for the treatment of onchocerciasis and a combination of ivermectin, albendazole and diethylcarbamazine (DEC) for the treatment of lymphatic filariasis in areas that are not co-endemic for onchocerciasis or loiasis. Limitations of these treatment strategies are due to potential severe adverse events in onchocerciasis and loiasis patients following DEC or ivermectin treatment, respectively, the lack of a macrofilaricidal efficacy of those drugs and the risk of drug resistance development. Thus, to achieve the elimination of transmission of onchocerciasis and the elimination of lymphatic filariasis as a public health problem by 2030, the WHO defined in its roadmap that new alternative treatment strategies with macrofilaricidal compounds are required. Within a collaboration of the non-profit organizations Drugs for Neglected Diseases initiative (DNDi), the Bill & Melinda Gates Foundation, and partners from academia and industry, several new promising macrofilaricidal drug candidates were identified, which will be discussed in this review.
Corallopyronin A: antimicrobial discovery to preclinical development
Krome AK, Becker T, Kehraus S, Schiefer A, Gütschow M, Chaverra-Muñoz L, Hüttel S, Jansen R, Stadler M, Ehrens A, Pogorevc D, Müller R, Hübner MP, Hesterkamp T, Pfarr K, Hoerauf A, Wagner KG, König GM. Natural Product Reports 2022. doi:
Summary: Worldwide, increasing morbidity and mortality due to antibiotic-resistant microbial infections has been observed. Therefore, better prevention and control of infectious diseases, as well as appropriate use of approved antibacterial drugs are crucial. There is also an urgent need for the continuous development and supply of novel antibiotics. Thus, identifying new antibiotics and their further development is once again a priority of natural product research. The antibiotic corallopyronin A was discovered in the 1980s in the culture broth of the Myxobacterium Corallococcus coralloides and serves, in the context of this review, as a show case for the development of a naturally occurring antibiotic compound. The review demonstrates how a hard to obtain, barely water soluble and unstable compound such as corallopyronin A can be developed making use of sophisticated production and formulation approaches. Corallopyronin A is a bacterial DNA-dependent RNA polymerase inhibitor with a new target site and one of the few representatives of this class currently in preclinical development. Efficacy against Gram-positive and Gram-negative pathogens, e.g., Chlamydia trachomatis, Orientia tsutsugamushi, Staphylococcus aureus, and Wolbachia has been demonstrated. Due to its highly effective in vivo depletion of Wolbachia, which are essential endobacteria of most filarial nematode species, and its robust macrofilaricidal efficacy, corallopyronin A was selected as a preclinical candidate for the treatment of human filarial infections. This review highlights the discovery and production optimization approaches for corallopyronin A, as well as, recent preclinical efficacy results demonstrating a robust macrofilaricidal effect of the anti-Wolbachia candidate, and the solid formulation strategy which enhances the stability as well as the bioavailability of corallopyronin A.
A qPCR to quantify Wolbachia from few Onchocerca volvulus microfilariae as a surrogate for adult worm histology in clinical trials of antiwolbachial drugs
by Schlabe S, Korir P, Lämmer C, Landmann F, Dubben B, Koschel M, Albers A, Debrah LB, Debrah AY, Hübner MP, Pfarr K, Klarmann-Schulz U, Hoerauf A. Parasitology Research 2022. doi: 10.1007/s00436-021-07411-5
Summary: The filarial nematode Onchocerca volvulus causes onchocerciasis (river blindness), a neglected tropical disease affecting 21 million people, mostly in Sub-Saharan Africa. Targeting the endosymbiont Wolbachia with antibiotics leads to permanent sterilization and killing of adult worms. The gold standard to assess Wolbachia depletion is the histological examination of adult worms in nodules beginning at 6 months post-treatment. However, nodules can only be used once, limiting the time points to monitor Wolbachia depletion. A diagnostic to longitudinally monitor Wolbachia depletion from microfilariae (MF) at more frequent intervals < 6 months post-treatment would accelerate clinical trials of antiwolbachials. We developed a TaqMan qPCR amplifying the single-copy gene wOvftsZ to quantify Wolbachia from as few as one MF that had migrated from skin biopsies and compared quantification using circular and linearized plasmids or synthetic dsDNA (gBlock®). qPCR for MF from the rodent nematode Litomosoides sigmodontis was used to support the reproducibility and validate the principle. The qPCR using as few as 2 MF from O. volvulus and L. sigmodontis reproducibly quantified Wolbachia. Use of a linearized plasmid standard or synthesized dsDNA resulted in numbers of Wolbachia/MF congruent with biologically plausible estimates in O. volvulus and L. sigmodontis MF. The qPCR assay yielded a median of 48.8 (range 1.5–280.5) Wolbachia/O. volvulus MF. The qPCR is a sensitive tool for quantifying Wolbachia in a few MF from skin biopsies and allows for establishing the qPCR as a surrogate parameter for monitoring Wolbachia depletion in adult worms of new antiwolbachial candidates.
Efficacy and safety of co-administered ivermectin and albendazole in school-aged children and adults infected with Trichuris trichiura in Côte d’Ivoire, Laos, and Pemba Island, Tanzania: a double-blind, parallel-group, phase 3, randomised controlled trial
by Hürlimann E, Keller L, Patel C, Welsche S, Hattendorf J, Ali SM, Ame SM, Sayasone S, Coulibaly JT, Keiser J. The Lancet Infectious Diseases 2021. doi: 10.1016/S1473-3099(21)00421-7
Summary: Preventive chemotherapy with albendazole or mebendazole remains one of the cornerstones of soil-transmitted helminth control. However, these drugs are less effective against Trichuris trichiura. Combined ivermectin–albendazole is a promising treatment alternative, yet robust evidence is lacking. We aimed to demonstrate superiority of co-administered ivermectin–albendazole over albendazole monotherapy in three distinct epidemiological settings.
Diagnostics to support elimination of lymphatic filariasis—Development of two target product profiles
by Won KY, Gass K, Biamonte M, Dagne DA, Ducker C, Hanna C, Hoerauf A, Lammie PJ, Njenga SM, Noordin R, Ramaiah KD, Ramzy R, Scholte RGC, Solomon AW, Souza AA, Tappero J, Toubali E, Weil GJ, Williams SA, King JD. PLOS Neglected Tropical Diseases 2021; 15(11):e0009968. doi: 10.1371/journal.pntd.0009968.
Summary: High quality diagnostic tools are an essential component of lymphatic filariasis programs. Currently, diagnostic tools are used by national programs to establish baseline endemicity, monitor progress of program interventions, determine when interventions can be stopped, and surveillance. For years, lymphatic filariasis programs have relied on diagnostic tools that have been central to informing key program decisions but were not necessarily designed to undertake the roles for which they are used. Known limitations of existing diagnostic tools make it challenging to have confidence that program endpoints have been achieved. Target product profiles (TPP) provide product requirements to guide developers and manufacturers in their efforts to design tools fit for purpose. However, development of diagnostic tools used in public health programs requires consideration of aspects beyond those considered when developing diagnostic tools used for clinical diagnosis. The TPP process for two lymphatic filariasis use cases brought to the forefront the importance of linking use case, program platform and diagnostic performance characteristics when defining required criteria for diagnostic tools.
Towards the sustainable discovery and development of new antibiotics
by Miethke M, Pieroni M, Weber T, Brönstrup M, Hammann P, Halby L, Arimondo PB, Glaser P, Aigle B, Bode HB, Moreira R, Li Y, Luzhetskyy A, Medema MH, Pernodet JL, Stadler M, Tormo JR, Genilloud O, Truman AW, Weissman KJ, Takano E, Sabatini S, Stegmann E, Brötz-Oesterhelt H, Wohlleben W, Seemann M, Empting M, Hirsch AKH, Loretz B, Lehr CM, Titz A, Herrmann J, Jaeger T, Alt S, Hesterkamp T, Winterhalter M, Schiefer A, Pfarr K, Hoerauf A, Graz H, Graz M, Lindvall M, Ramurthy S, Karlén A, van Dongen M, Petkovic H, Keller A, Peyrane F, Donadio S, Fraisse L, Piddock LJV, Gilbert IH, Moser HE, Müller R. Nature Reviews Chemistry 2021: 1-24. doi: 10.1038/s41570-021-00313-1.
Summary: An ever-increasing demand for novel antimicrobials to treat life-threatening infections caused by the global spread of multidrug-resistant bacterial pathogens stands in stark contrast to the current level of investment in their development, particularly in the fields of natural-product-derived and synthetic small molecules. New agents displaying innovative chemistry and modes of action are desperately needed worldwide to tackle the public health menace posed by antimicrobial resistance. Here, our consortium presents a strategic blueprint to substantially improve our ability to discover and develop new antibiotics. We propose both short-term and long-term solutions to overcome the most urgent limitations in the various sectors of research and funding, aiming to bridge the gap between academic, industrial and political stakeholders, and to unite interdisciplinary expertise in order to efficiently fuel the translational pipeline for the benefit of future generations.
The burden of skin disease and eye disease due to onchocerciasis in countries formerly under the African Programme for Onchocerciasis Control mandate for 1990, 2020, and 2030
by Vinkeles Melchers NVS, Stolk WA, van Loon W, Pedrique B, Bakker R, et al. PLOS Neglected Tropical Diseases 2021; 15(7): e0009604. doi: 10.1371/journal.pntd.0009604
Summary: Mass drug administration (MDA) with ivermectin and vector control have been used in Central and East Africa to control onchocerciasis as a public health problem under the mandate of the African Programme for Onchocerciasis Control (APOC). The authors assess the impact of MDA on onchocercal morbidity and calculate the burden of disease in terms of disability-adjusted life years (DALYs) in 1990 (pre-control), 2020, and 2030. From 1990 to 2030, the total population at risk is predicted to increase (from 79.8 to 236.1 million) while the number of people with skin or eye morbidity is predicted to decrease (from 17.5 million, with 2.5 million DALYs lost, to 4.2 million, with 0.7 million DALYs lost).
Development of emodepside as a possible adulticidal treatment for human onchocerciasis—The fruit of a successful industrial–academic collaboration
by Krücken J, Holden-Dye L, Keiser J, Prichard RK, Townson S, Makepeace BL, Hübner MP, Hahnel SR, Scandale I, Harder A, Kulke D. PLOS Pathogens 2021;17(7): e1009682. doi: 10.1371/journal.ppat.1009682
Summary: Current programmes to eliminate river blindness use ivermectin, which kills juvenile worms. Since no drug is available to kill adult worms, elimination programmes must be sustained over several decades. Emodepside, a veterinary dewormer that kills juvenile and adult worms, is considered an excellent candidate for the treatment of onchocerciasis and in 2014 Bayer and DNDi started a collaboration to develop it for use in humans. This collaboration has led to a deep understanding of the drug’s mode of action, Phase I clinical trials have demonstrated its safety and activity against adult forms of a closely related cattle parasite, and Phase II clinical trials are planned to confirm safety and efficacy in humans.
Safety, tolerability, and pharmacokinetics of emodepside, a potential novel treatment for onchocerciasis (river blindness), in healthy male subjects
by Gillon J-Y, Dennison J, van den Berg F, Delhomme S, Dequatre Cheeseman K, Peña Rossi C, Strub Wourgaft N, Specht S, Pedrique B, Monnot F, Skrabs S, Rodriguez M-L, Stass H. British Journal of Clinical Pharmacology 2021. doi: 10.1111/bcp.14816
Summary: Emodepside is an anthelmintic agent, currently registered for veterinary use in combination with other drug substances. Emodepside may have the potential to treat parasitic infections in humans, including onchocerciasis. The authors investigated the safety and pharmacokinetics of a liquid service formulation (LSF) and an immediate release tablet of emodepside in two placebo‐controlled, Phase I studies. No major safety concerns were identified, and tissue distribution was relatively rapid, which, along with a long terminal half‐life, is expected to be beneficial for the treatment of onchocerciasis. The rate and extent of absorption was significantly lower with the tablets compared to the LSF. Further clinical trials are on-going to develop a tablet formulation to overcome the limitations observed in this study.
Efficacy and safety of ascending doses of moxidectin against Strongyloides stercoralis infections in adults: a randomised, parallel-group, single-blinded, placebo-controlled, dose-ranging, phase 2a trial
by Hofmann D, Sayasone S, Sengngam K, Chongvilay B, Hattendorf J, Keiser J. The Lancet Infectious Diseases 2021. doi: 10.1016/S1473-3099(20)30691-5
Summary: Strongyloidiasis, a parasitic worm infection caused by soil-transmitted helminths, remains a neglected public health problem with limited treatment options. Swiss TPH researchers conducted the first dose-finding study with moxidectin against strongyloidiasis. The drug could become a treatment alternative to the only treatment available so far and help fill the empty anthelminthic drug pipeline.
Evaluation of the in vitro susceptibility of various filarial nematodes to emodepside
by Hübner MP, Townson S, Gokool S, Tagboto S, Maclean MJ, Verocai GG, Wolstenholme AJ, Frohberger SJ, Hoerauf A, Specht S, Scandale I, Harder A, Glenschek-Sieberth M, Hahnel SR, Kulke D. International Journal for Parasitology: Drugs and Drug Resistance 2021; 17:27-35. doi: 10.1016/j.ijpddr.2021.07.005
Summary: Efforts to eliminate human filariasis have been hampered by the lack of a drug with sufficient macrofilaricidal and/or long-term sterilizing effects suitable for use in mass drug administration programs. Emodepside, a semi-synthetic cyclooctadepsipeptide, has broad-spectrum efficacy against gastrointestinal nematodes in a variety of mammalian hosts, and has been approved as an active ingredient in veterinary dewormers. The authors evaluate, compare (where appropriate) and summarize the in vitro effects of emodepside against a range of filarial nematodes at various developmental stages. Although both stage- and species-specific differences were observed, emodepside inhibited the motility of all tested stages of filariae in a concentration-dependent manner, making emodepside a promising candidate for the treatment of human filariases, including onchocerciasis and lymphatic filariasis.
A systematic review and an individual patient data meta-analysis of ivermectin use in children weighing less than fifteen kilograms: Is it time to reconsider the current contraindication?
by Jittamala P, Monteiro W, Smit MR, Pedrique B, Specht S, Chaccour CJ, Dard C, Giudice PD, Khieu V, Maruani A, Failoc-Rojas VE, Sáez-de-Ocariz M, Soriano-Arandes A , Piquero-Casals J, Faisant A, Brenier-Pinchart M-P, Wimmersberger D, Coulibaly JT, Keiser J, Boralevi F, Sokana O , Marks M, Engelman D, Romani L, Steer AC, von Seidlein L, White NJ, Harriss E, Stepniewska K, Humphreys GS, Kennon K, Guerin PJ, Kobylinski KC. PLOS Neglected Tropical Diseases 2021;15(3): e0009144. 10.1371/journal.pntd.0009144
Summary: Oral ivermectin is a safe and efficacious drug for the treatment of neglected tropical diseases. It is not currently indicated in children weighing less than 15 kg due to insufficient safety data. The authors conducted a PRISMA-level systematic review and identified 97 potential sources. All lead investigators were contacted and individual-level patient data from 15 studies were provided, representing a database of 1,088 children weighing less than 15 kg treated with oral ivermectin. Mild and self-limiting adverse events were reported in 1.4% of children and there were no serious adverse events. This suggests that ivermectin is safe for use in children weighing less than 15 kg. Further data are needed to assess its safety at escalating doses in this population.
Establishment of an in vitro culture system to study the developmental biology of Onchocerca volvulus with implications for anti-Onchocerca drug discovery and screening
by Gandjui NVT, Njouendou AJ, Gemeg EN, Fombad FF, Ritter M, Kien CA, Chunda VC, Fru J, Esum ME, Hübner MP, Enyong PA, Hoerauf A, Wanji S. PLOS Neglected Tropical Diseases 2021; 15(2):e0008513. doi: 10.1371/journal.pntd.0008513.
Summary: The present study describes an in vitro system in which O. volvulus L3 larvae can be maintained in culture leading to the development of adult stages. Thus, this in vitro system may provide a platform to investigate mating behaviour and early stage of nodulogenesis of O. volvulus adult worms that can be used as additional targets for macrofilaricidal drug screening.
Human filariasis-contributions of the Litomosoides sigmodontis and Acanthocheilonema viteae animal model
by Risch F, Ritter M, Hoerauf A, Hübner MP. Parasitology Research 2021; 120(12):4125-4143. doi: 10.1007/s00436-020-07026-2.
Summary: Filariae are vector-borne parasitic nematodes that are endemic worldwide, in tropical and subtropical regions. Important human filariae spp. include Onchocerca volvulus, Wuchereria bancrofti and Brugia spp., and Loa loa and Mansonella spp. causing onchocerciasis (river blindness), lymphatic filariasis (lymphedema and hydrocele), loiasis (eye worm), and mansonelliasis, respectively. It is estimated that over 1 billion individuals live in endemic regions where filarial diseases are a public health concern contributing to significant disability adjusted life years (DALYs). Thus, efforts to control and eliminate filarial diseases were already launched by the WHO in the 1970s, especially against lymphatic filariasis and onchocerciasis, and are mainly based on mass drug administration (MDA) of microfilaricidal drugs (ivermectin, diethylcarbamazine, albendazole) to filarial endemic areas accompanied with vector control strategies with the goal to reduce the transmission. With the United Nations Sustainable Development Goals (SDGs), it was decided to eliminate transmission of onchocerciasis and stop lymphatic filariasis as a public health problem by 2030. It was also requested that novel drugs and treatment strategies be developed. Mouse models provide an important platform for anti-filarial drug research in a preclinical setting. This review presents an overview about the Litomosoides sigmodontis and Acanthocheilonema viteae filarial mouse models and their role in immunological research as well as preclinical studies about novel anti-filarial drugs and treatment strategies.
Evaluation of commercially available anthelminthics in laboratory models of human intestinal nematode infections
by Keiser J, Häberli C. ACS Infectious Diseases 2021. doi: 10.1021/acsinfecdis.0c00719
Summary: Drug repurposing from veterinary to human medicine has been the main strategy to develop the four recommended human anthelminthics for the treatment of soil-transmitted helminthiasis. A systematic, head-to-head comparison of the anthelminthic activity profile of derivatives of these drugs and other anthelminthics developed in succession has not been conducted to date. We studied eight benzimidazoles, five macrocyclic lactones, tribendimidine, levamisole, and pyrantel pamoate in laboratory models of human intestinal nematode infections. Laboratory models for soil-transmitted helminthiasis can assist characterizing potential drug candidates. Drugs should be evaluated against different species, and both the adult and larval stages as activities could differ considerably.
Corallopyronin A for short-course anti-wolbachial, macrofilaricidal treatment of filarial infections
by Schiefer A, Hübner MP, Krome A, Lämmer C, Ehrens A, Aden T, Koschel M, Neufeld H, Chaverra-Muñoz L, Jansen R, Kehraus S, König GM, Pogorevc D, Müller R, Stadler M, Hüttel S, Hesterkamp T, Wagner K, Pfarr K, Hoerauf A. PLOS Neglected Tropical Diseases 2020; 14(12):e0008930. doi: 10.1371/journal.pntd.0008930.
Summary: Infections with filarial roundworms can cause the disfiguring human neglected tropical diseases onchocerciasis and lymphatic filariasis. Treatment of these diseases is limited, as there is no well-tolerated treatment available that kills the adult worms after a short-term regimen. Thus, mass drug administrations (MDA) are performed with drugs that temporarily clear the microfilariae, the filarial offspring, to inhibit the transmission of the disease. As these MDA treatments have to be given 1–2 times per year for many years, the goal to eliminate onchocerciasis and lymphatic filariasis is hampered. In the present study we investigated a novel preclinical candidate for the treatment of filariasis. Corallopyronin A (CorA) is a natural compound that clears the essential Wolbachia endobacteria of filariae. Using the Litomosoides sigmodontis rodent model of filariasis we demonstrated that 2 weeks of CorA treatment clears Wolbachia endosymbionts in vivo, leading to a maintained clearance of microfilariae by inhibition of filarial embryogenesis. Combination therapy of CorA with the MDA drug albendazole allowed lower CorA doses and shortened treatment to 7 days. More importantly, it also led to the death of the adult filariae. Portfolios (Target Product Profiles) of new drugs against filariae should show adult killing efficacy like CorA.
Oxfendazole mediates macrofilaricidal efficacy against the filarial nematode Litomosoides sigmodontis in vivo and inhibits Onchocerca spec. motility in vitro
by Hübner MP, Martin C, Specht S, Koschel M, Dubben B, Frohberger SJ, Ehrens A, Fendler M, Struever D, Mitre E, Vallarino-Lhermitte N, Gokool S, Lustigman S, Schneider M, Townson S, Hoerauf A, Scandale I. PLOS Neglected Tropical Diseases 2020;14(7): e0008427. doi: 10.1371/journal.pntd.0008427
Summary: Current efforts to eliminate onchocerciasis and lymphatic filariasis are hampered by the lack of short-course drugs that kill adult worms or regimens that are proven to be safe for both diseases. The authors investigated the efficacy of anthelmintic drug oxfendazole, used in veterinary medicine, in an animal model of filariasis. Oxfendazole caused complete clearance of adult worms but was not directly active against juvenile worms, suggesting that drug-induced serious adverse events due to microfilariae clearance are unlikely. Based on these results, the predicted human dose is within a range already been shown to be safe in phase 1 clinical trials. Oxfendazole is a promising drug candidate for the treatment of human filarial diseases.
Short-course quinazoline drug treatments are effective in the Litomosoides sigmodontis and Brugia pahangi jird models
by Hübner MP, Gunderson E, Vogel I, Bulman CA, Lim KC, Koschel M, Ehrens A, Frohberger SJ, Fendler M, Tricoche N, Voronin D, Steven A, Chi V, Bakowski MA, Woods AK, Petrassi HM, McNamara CW, Beerntsen B, Chappell L, Sullivan W, Taylor MJ, Turner JD, Hoerauf A, Lustigman S, Sakanari JA. International Journal for Parasitology: Drugs and Drug Resistance 2020: 18-27. doi: 10.1016/j.ijpddr.2019.12.001.
Summary: The quinazolines CBR417 and CBR490 were previously shown to be potent anti-wolbachials that deplete Wolbachia endosymbionts of filarial nematodes and present promising pre-clinical candidates for human filarial diseases such as onchocerciasis. In the present study we tested both candidates in two models of chronic filarial infection, namely the Litomosoides sigmodontis and Brugia pahangi jird model and assessed their long-term effect on Wolbachia depletion, microfilariae counts and filarial embryogenesis 16−18 weeks after treatment initiation (wpt). Once per day (QD) oral treatment with CBR417 (50 mg/kg) for 4 days or twice per day (BID) with CBR490 (25 mg/kg) for 7 days during patent L. sigmodontis infection reduced the Wolbachia load by >99% and completely cleared peripheral microfilaremia from 10–14 wpt. Similarly, 7 days of QD treatments (40 mg/kg) with CBR417 or CBR490 cleared >99% of Wolbachia from B. pahangi and reduced peritoneal microfilariae counts by 93% in the case of CBR417 treatment. Transmission electron microscopy analysis indicated intensive damage to the B. pahangi ovaries following CBR417 treatment and in accordance filarial embryogenesis was inhibited in both models after CBR417 or CBR490 treatment. Suboptimal treatment regimens of CBR417 or CBR490 did not lead to a maintained reduction of the microfilariae and Wolbachia load. In conclusion, CBR417 or CBR490 are pre-clinical candidates for filarial diseases, which achieve long-term clearance of Wolbachia endosymbionts of filarial nematodes, inhibit filarial embryogenesis and clear microfilaremia with treatments as short as 7 days.
Designing antifilarial drug trials using clinical trial simulators
by Walker M, Hamley JID, Milton P, Monnot F, Pédrique B, Basanez M-G. Nature Communications 2020, 11: 2685. doi: 10.1038/s41467-020-16442-y
Summary: The treatments used in mass drug administration for Lymphatic filariasis and onchocerciasis are predominantly active against the microfilarial progeny of adult worms. New treatments are needed, and several therapies and regimens are currently in (pre-)clinical testing. Clinical trial simulators have not been widely applied to neglected tropical diseases, where their resource-saving payoffs could be highly beneficial. The authors use an individual-based onchocerciasis transmission model that projects trial outcomes of a hypothetical drug that kills adult worms. They identify key design decisions that influence the power of clinical trials and discuss how clinical trial simulators help to inform target product profiles.
Onchocerciasis elimination: What’s left to do?
by Specht S, Monnot F. Bulletin of the Netherlands Society for Tropical Medicine and International Health 2020: 13-14.
Summary: This review explains that years of experience show that current mass drug administration with ivermectin has severe shortcomings in onchocerciasis control. New approaches are needed, such as development of macrofilarial drugs, to supplement current mass drug administration in order to meet the sustainable development goals.
Solubility and stability enhanced oral formulations for the anti-infective corallopyronin A.
by Krome AK, Becker T, Kehraus S, Schiefer A, Steinebach C, Aden T, Frohberger SJ, López Mármol Á, Kapote D, Jansen R, Chaverra-Muñoz L, Hübner MP, Pfarr K, Hesterkamp T, Stadler M, Gütschow M, König GM, Hoerauf A, Wagner KG. Pharmaceutics 2020; 12(11):1105.
Summary: Novel-antibiotics are urgently needed to combat an increase in morbidity and mortality due to resistant bacteria. The preclinical candidate corallopyronin A (CorA) is a potent antibiotic against Gram-positive and some Gram-negative pathogens for which a solid oral formulation was needed for further preclinical testing of the active pharmaceutical ingredient (API). The neat API CorA is poorly water-soluble and instable at room temperature, both crucial characteristics to be addressed and overcome for use as an oral antibiotic. Therefore, amorphous solid dispersion (ASD) was chosen as formulation principle. The results demonstrated that the ASD formulation principle is a suitable stability- and solubility-enhancing oral formulation strategy for the API CorA to be used in preclinical and clinical trials and as a potential market product.
Whipworm and roundworm infections
by Else KJ, Keiser J, Holland CV, Grencis RK, Sattelle DB, Fujiwara RT, Bueno LL, Asaolu SO, Sowemimo OA, Cooper PJ. Nature Reviews Diseases Primers 2020, 6:44. doi: 10.1038/s41572-020-0171-3
Summary: Trichuriasis and ascariasis are neglected tropical diseases caused by the gastrointestinal dwelling nematodes Trichuris trichiura (a whipworm) and Ascaris lumbricoides (a roundworm), respectively. Both parasites are staggeringly prevalent, particularly in tropical and subtropical areas, and are associated with substantial morbidity. Infection is initiated by ingestion of infective eggs, which hatch in the intestine. Thereafter, T. trichiura larvae moult within intestinal epithelial cells, with adult worms embedded in a partially intracellular niche in the large intestine, whereas A. lumbricoides larvae penetrate the gut mucosa and migrate through the liver and lungs before returning to the lumen of the small intestine, where adult worms dwell. Both species elicit type 2 anti-parasite immunity. Diagnosis is typically based on clinical presentation (gastrointestinal symptoms and inflammation) and the detection of eggs or parasite DNA in the faeces. Prevention and treatment strategies rely on periodic mass drug administration (generally with albendazole or mebendazole) to at-risk populations and improvements in water, sanitation and hygiene. The effectiveness of drug treatment is very high for A. lumbricoides infections, whereas cure rates for T. trichiura infections are low. Novel anthelminthic drugs are needed, together with vaccine development and tools for diagnosis and assessment of parasite control in the field.
The design and development of a multicentric protocol to investigate the impact of adjunctive doxycycline on the management of peripheral lymphoedema caused by lymphatic filariasis and podoconiosis
by Horton J, Klarmann-Schulz U, Stephens M, Budge PJ, Coulibaly Y, Debrah A, Debrah LB, Krishnasastry S, Mwingira U, Ngenya A, Wanji S, Weerasooriya M, Yahathugoda C, Kroidl I, Deathe D, Majewski A, Sullivan S, Mackenzie C, Nutman TB, Shott JP, Weil G, Ottesen E, Hoerauf A. Parasites & Vectors 2020; 13(1):155. doi: 10.1186/s13071-020-04024-2.
Summary: This paper provides details of what challenges were faced during its development and discusses the issues and how they were resolved. In particular, the reasons for inclusion of new technology and the problems encountered with the supply of drugs for the studies are described in detail. By making these details available, it is hoped that the study protocol will help others interested in improving treatment for filarial lymphoedema in the design of future studies.
Implications of asymptomatic infection for the natural history of selected parasitic tropical diseases
by Alvar J, Alves F, Bucheton B, Burrows L, Büscher P, Carrillo E, Felger I, Hübner M, Moreno J, Pinazo M-J, Ribeiro I, Sosa-Estani S, Specht S, Tarral A, Strub-Wourgaft N, Bilbe G. Seminars in Immunopathology 2020, doi: 10.1007/s00281-020-00796-y
Summary: Progress has been made in the control or elimination of tropical diseases, but there is a risk of re-emergence if the factors fuelling transmission are not dealt with. While it is essential to understand the underlying factors for each disease, asymptomatic carriers (people infected with the parasite, but without symptoms) are a common element that may promote resurgence. The authors review the current evidence on whether to treat asymptomatic carriers given the differing context of each disease. Safer drugs with good risk/benefit profiles are needed in order to allow treatment of both symptomatic and non-symptomatic infected persons.
Macrofilaricidal benzimidazole-benzoxaborole hybrids as an approach to the treatment of river blindness: Part 1. Amide linked analogs
Akama T, Freund YR, Berry PW, Carter DS, Easom EE, Jarnagin K, Lunde CS, Plattner JJ, Rock F, Stefanakis R, Fischer C, Bulman CA, Lim KC, Suzuki BM, Tricoche N, Mansour A, DiCosty U, McCall S, Carson B, McCall JW, McKerrow J, Hübner MP, Specht S, Hoerauf A, Lustigman S, Sakanari JA, Jacobs RT. ACS Infectious Diseases 2020 Feb 14;6(2):173-179. doi: 10.1021/acsinfecdis.9b00396.
Summary: Flubendazole has been shown to kill adult filarial worms, providing promise that this molecule could be useful in the treatment of onchocerciasis and lymphatic filariasis, however, it suffers from several limitations. The authors prepared a series of benzimidazole–benzoxaborole analogues in an attempt to overcome these. These exhibited good in vitro activity against Onchocerca volvulus, the nematode responsible for onchocerciasis. In vivo results suggested that these benzimidazole drugs require a long (>28 day) exposure to the drug to be effective. Although the authors were encouraged by the proof of concept, it was clear that the lead molecule from the series would not meet the target candidate profile. An additional series of hybrid molecules is being explored
In vivo efficacy of the boron-pleuromutilin AN11251 against Wolbachia of the rodent filarial nematode Litomosoides sigmodontis
by Ehrens A, Lunde CS, Jacobs RT, Struever D, Koschel M, Frohberger SJ, Lenz F, Fendler M, Turner JD, Ward SA, Taylor MJ, Freund YR, Stefanakis R, Easom E, Li X, Plattner JJ, Hoerauf A, Hübner MP. PLOS Neglected Tropical Diseases 2020; 14(1):e0007957. doi: 10.1371/journal.pntd.0007957.
Summary: Onchocerciasis and lymphatic filariasis are human filarial tropical diseases, which can cause blindness and severe dermatitis (onchocerciasis) or lymphedema and hydrocele (lymphatic filariasis). Current strategies to eliminate these diseases include the mass drug administration (MDA) of drugs that target the progeny of the filariae, the microfilariae, and temporarily inhibit filarial embryogenesis and, therefore, the transmission of the disease. However, MDA has several limitations that delay the goal of elimination including the lack of a drug with a short term regimen and a potent macrofilaricidal effect. As an alternative approach, the antibiotic doxycycline has been proven to be effective in depleting Wolbachia endosymbionts from adult filariae, which then leads to permanent sterilization and death of the adult worms. Due to contraindications for doxycycline and prolonged treatment regimen of at least 4 weeks, there is an urgent need for new anti-filarial drugs with an improved safety profile and shorter regimens. The current study demonstrates that the boron-pleuromutilin derivative AN11251 provides an excellent in vivo anti-Wolbachia depletion in the Litomosoides sigmodontis filarial mouse model that is superior to doxycycline and comparable to rifampicin, allowing for regimens as short as 10–14 days. Combination with doxycycline for 7 days had no significant beneficial effect on efficacy, achieving Wolbachia reductions of more than 97%. Therefore, AN11251 shows potent anti-Wolbachia activity in the L. sigmodontis mouse model and may also present an alternative pre-clinical candidate for filariasis treatment.