Periodic Reporting for period 2 - DRUGSBUGS (Improved therapies for soil-transmitted helminthiases: exploring pharmacomicrobiomics, novel drugs and microfluidic assay platforms)
Reporting period: 2023-07-01 to 2024-12-31
Soil-transmitted helminthiases are responsible for the infection of about 1.5 billion people worldwide, causing a considerable global health burden, yet treatment options are limited. My proposed research is of considerable public health relevance since it will ultimately result in improved treatments for soil-transmitted helminthiasis. DRUGSBUGS brings together different streams of advanced scientific inquiry, ranging from drug discovery to drug development. I aim to improve our understanding of major and upcoming anthelminthics, in particular the microbiome-driven modulation of anthelminthic treatment. The effects of gut communities on the efficacy of combination therapy for the treatment of T. trichiura will be investigated to provide new insight into improved, microbiome-specific treatment opportunities of trichuriasis. In addition, I speculate that emodepside might be a novel key player in the anthelminthic drug armamentarium, which will enhance efficacy and reduce the risk of selection of resistant helminth populations. In parallel, investing in innovative new technologies in the field of drug discovery will facilitate the discovery and development of the next generations of anthelminthics.
DRUGSBUGS addresses the following five objectives.
Objective 1: To assess association between albendazole-ivermectin and the gut microbiota and restoration of treatment efficacy.
Objective 2: To assess the activity and safety of emodepside against T. trichiura and hookworm infection in stage I dose-finding and stage II confirmatory trials.
Objective 3: To develop a microsampling tool to evaluate the pharmacokinetics of emodepside.
Objective 4: To evaluate interactions between the gut microbiome and emodepside pharmacokinetics and efficacy in in vitro and in vivo experimental models.
Objective 5: To establish a novel in vitro microfluidic screening assay for anthelminthic drug discovery using electrical-impedance spectroscopy.
DRUGSBUGS addresses the following five objectives.
Objective 1: To assess association between albendazole-ivermectin and the gut microbiota and restoration of treatment efficacy.
Objective 2: To assess the activity and safety of emodepside against T. trichiura and hookworm infection in stage I dose-finding and stage II confirmatory trials.
Objective 3: To develop a microsampling tool to evaluate the pharmacokinetics of emodepside.
Objective 4: To evaluate interactions between the gut microbiome and emodepside pharmacokinetics and efficacy in in vitro and in vivo experimental models.
Objective 5: To establish a novel in vitro microfluidic screening assay for anthelminthic drug discovery using electrical-impedance spectroscopy.
Our project yielded important findings in anthelminthic drug discovery and development. First, we have conducted two Phase 2a dose selection trials with emodepside against Trichuris trichiura (trial 1) and hookworm (trial 2) in adults and a subsequent Phase 2b study to show whether emodepside is superior to albendazole against hookworm and T. trichiura. Our studies showed that emodepside demonstrated superiority, with an observed cure rate against hookworm at 96.6%, and was significantly higher compared with albendazole (cure rate 81.2%). The predicted cure rate against T. trichiura in the 5-mg emodepside group (85%) was higher than the predicted cure rate in the placebo group (10%). Second, we analyzed the microbiome from stool samples obtained of T. trichiura and hookworm-infected patients and found a gut microbiome mechanism responsible for treatment failures of the currently best available treatment, albendazole-ivermectin. We identified three bacterial enterotypes and show that pre-treatment enterotype is associated with efficacy of the combination treatment for both T. trichiura and hookworm infections. We found, that antibacterial activity of two anthelminthics, ivermectin and moxidectin is comparable to a selection of tested antibiotics, as observed by potency and dose dependence. Bacterial anthelminthic challenging in vitro resulted in decreased anthelminthic sensitivity. Further, adaptation to anthelminthics is associated with decreased antibiotic sensitivity towards three macrolides, a lincosamide, a fluoroquinolone, a tetracycline and two carbapenems. Third our work resulted in the discovery of a novel Trichuris species, Trichuris hominis. We provide genomic evidence that supports the establishment of drug resistance in humans. These findings challenge the current understanding of species within the Trichuris genus and have profound implications for both parasitology and public health. Overall, our work is of considerable public health relevance since it will ultimately result in better understanding of helminth infections and improved treatments for soil-transmitted helminthiasis. Fourth, we developed an electric-impedance based microwell-platform to automatically assess motility of hookworm third stage larvae. Electric- and light-based excitation was evaluated on the potential to repeatedly and accurately stimulate inactive larvae. Fluorescence light triggered an immediate stimulation of larvae, without negatively impacting their viability. While electric-based excitation was also capable of repeatedly stimulating larvae, it required a longer excitation period and voltages close to the platforms capacity. 10-15 larvae were adequate to produce sufficient signal and remain viable over a 72 hour analysis period, reducing larval consumption up to 60-fold compared to standard visual evaluation
At this interim stage the project has achieved several groundbreaking results. First, the high activity of emodepside against Trichuris trichiura and hookworm is a breakthrough. We have started a collaboration with Bayer and the drug will be developed in collaboration for soil-transmitted helminth infections. Phase 3 studies will start in 2025. Emodepside will be the first drug developed against soil-transmitted helminth infections for several decades. As resistance is arising this will be of huge public health relevance. Moreover, our investigation mark a pioneering milestone in Trichuris research, unveiling the discovery of a previously unknown species - Trichuris hominis - naturally infecting humans in Côte d’Ivoire and demonstrating low responsiveness to conventional drug treatments. We present genomic data that imply -tubulin variations in resistance mechanisms, raising concerns about the efficacy of current mass deworming strategies. These findings challenge the current understanding of species within the Trichuris genus and have profound implications for both parasitology and public health. Efforts should support the development of species-level diagnostic tools, patient-centric treatment approaches in addition to mass-drug administration strategies, the definition of species-specific standard-of-care guidelines, and the incorporation of species diversity in vaccine development. Our work on the microbiome interactions with anthelminthics is the first to investigate gut microbial determinants of treatment failure for essential drugs used to treat human T. trichiura and hookworm infections. Our results represent a significant improvement in our understanding of gut microbiota-drug interaction in the context of anthelmintic treatment. Our observations indicate that the pre-treatment microbial composition of stool samples is strongly correlated with the treatment efficacy of both T. trichiura and hookworms when using ivermectin-based treatment. This finding is of huge public health relevance as the drug is given to millions of people. These findings will enable understanding of the cause of albendazole and ivermectin-based treatment failure in a large proportion of patients, while still being one of the most efficacious options in terms of success to treat helminth infections. This will hopefully lead to novel therapeutic opportunities based on the modulation of failure-associated features, and—perhaps more importantly—to optimized, evidence-based use of these powerful drugs.
In the next phase of the project we will elucidate the interaction of the gut microbiome with emodepside and the pharmacokinetic parameters of emodepside. We will study the efficacy of emodepside on Strongyloides stercoralis in Phase 2 clinical trials. We will continue our work on an electric-impedance based microwell-platform to automatically assess motility of hookworm third stage larvae.
In the next phase of the project we will elucidate the interaction of the gut microbiome with emodepside and the pharmacokinetic parameters of emodepside. We will study the efficacy of emodepside on Strongyloides stercoralis in Phase 2 clinical trials. We will continue our work on an electric-impedance based microwell-platform to automatically assess motility of hookworm third stage larvae.