Emodepside

Strongyloidiasis is a pernicious, sometimes fatal, infectious disease caused by the parasitic nematode Strongyloides stercoralis and infects millions of people worldwide. Ivermectin is the only recommended single-dose treatment option available, but concerns of drug resistance are rightly founded, therefore driving the demand for efficacious alternatives. Emodepside, an anthelmintic recently repurposed from the veterinary field, is currently under clinical development for the treatment of onchocerciasis and soil-transmitted helminthiasis. We aimed to identify the most efficacious and safe dose of emodepside against S stercoralis infections.

We conducted a phase 2a, dose-ranging, randomised, parallel-group, placebo-controlled, single-blind clinical trial. Recruitment took place in 17 endemic villages in the Champhone district of Laos. Adults aged 18-60 years who provided three stool samples with a mean number of S stercoralis larvae per g of at least 0·75, as assessed by sextuplicate Baermann assays, were invited to participate. Clinically eligible participants were randomly assigned (1:1:1:1:1:1:1:1) to receive a single oral dose of placebo, ivermectin (200 μg/kg), or emodepside at doses 5 mg, 10 mg, 15 mg, 20 mg, 25 mg, or 30 mg. The participants, laboratory technicians, study nurses, and physicians were masked to the treatment assignments; study investigators were not masked. Participants providing at least one sample during follow-up were included in the primary outcome analysis, whereby efficacy was estimated by cure rate (defined as the proportion of participants who became S stercoralis negative 14-21 days after treatment). Treated patients were assessed for adverse events at 3-h, 24-h, 72-h, and 14 days post-treatment. This trial is registered at ClinicalTrials.gov (NCT06373835) and is completed.

Between May 20, 2024, and Aug 14, 2024, 820 individuals were screened for S stercoralis infection and, of these, 202 individuals (108 male and 94 female) were randomly allocated to treatment groups and treated. 25 participants were treated with ivermectin, 25 with placebo, 25 participants with emodepside at 5 mg, 15 mg, 25 mg, or 30 mg dose, and 26 participants with emodepside at 10 mg or 20 mg dose. 5 mg emodepside had a predicted cure rate of 78·3% (95% CI 59·4-89·9), which was higher than the observed cure rate in the placebo treatment group (0%; 0·0-13·7; 0 of 25 participants). The dose-response curve plateaued at 15 mg, with a predicted cure rate of 89·1% (81·6-93·7). The observed cure rate in the ivermectin treatment group was 88·0% (68·8-97·5; 22 of 25 participants). The most common adverse event in all treatment groups was somnolence at 3-h post-treatment (ranging from nine [36%] of 25 participants in the emodepside 15 mg group to 17 [68%] of 25 in the 30 mg group). Other common adverse events included vision blur (two [8%] of 25 participants in the ivermectin group to 11 [44%] of 25 in the emodepside 30 mg group at 3-h post-treatment), vision impairment (three [4%] of 26 in the 10 mg group to eight [32%] of 25 in the emodepside 30 mg group), and dizziness (two [8%] of 25 participants in the emodepside 5 mg group to seven [28%] of 25 in the emodepside 30 mg group) at 3-h post-treatment. Adverse events were predominantly mild in nature and no serious adverse events occurred.

At all doses tested, emodepside was efficacious and well tolerated in individuals infected with S stercoralis. The broad-spectrum weight-independent dose and robust safety profile positions emodepside as a promising new candidate for strongyloidiasis treatment.

European Research Council and the Uniscientia Foundation.