Scientific articles

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

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.

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.

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.

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.

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.

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.

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