A Phase 2a randomized, single-center, double-blind, placebo-controlled study to evaluate the safety and preliminary efficacy of oral iOWH032 against cholera diarrhea in a controlled human infection model

Rahsan Erdem,Sharon M Tennant,Christopher Gast,Robert K M Choy,Gwen Ambler,Mohamed Al-Ibrahim,Wilbur H Chen,Michael Raine,Eugenio L De Hostos,Katarzyna Fraczek,Laina D Mercer,Steven D Dong,James Michael Fleckenstein

doi:10.1371/journal.pntd.0009969

Abstract

Cholera remains a major cause of infectious diarrhea globally. Despite the increased availability of cholera vaccines, there is still an urgent need for other effective interventions to reduce morbidity and mortality. Furthermore, increased prevalence of antibiotic-resistant Vibrio cholerae threatens the use of many drugs commonly used to treat cholera. We developed iOWH032, a synthetic small molecule inhibitor of the cystic fibrosis transmembrane conductance regulator chloride channel, as an antisecretory, host-directed therapeutic for cholera. In the study reported here, we tested iOWH032 in a Phase 2a cholera controlled human infection model. Forty-seven subjects were experimentally infected with V. cholerae El Tor Inaba strain N16961 in an inpatient setting and randomized to receive 500 mg iOWH032 or placebo by mouth every 8 hours for 3 days to determine the safety and efficacy of the compound as a potential treatment for cholera. We found that iOWH032 was generally safe and achieved a mean (± standard deviation) plasma level of 4,270 ng/mL (±2,170) after 3 days of oral dosing. However, the median (95% confidence interval) diarrheal stool output rate for the iOWH032 group was 25.4 mL/hour (8.9, 58.3), compared to 32.6 mL/hour (15.8, 48.2) for the placebo group, a reduction of 23%, which was not statistically significant. There was also no significant decrease in diarrhea severity and number or frequency of stools associated with iOWH032 treatment. We conclude that iOWH032 does not merit future development for treatment of cholera and offer lessons learned for others developing antisecretory therapeutic candidates that seek to demonstrate proof of principle in a cholera controlled human infection model study.Trial registration: This study is registered with ClinicalTrials.gov as NCT04150250.

Highlights

Acute secretory diarrhea caused by infection with the bacterium Vibrio cholerae is a major cause of diarrheal disease morbidity and mortality
A disease caused by infection with the bacterium Vibrio cholerae, remains a major cause of diarrheal illness and death, in settings with poor sanitation and hygiene
Study volunteers were intentionally infected with V. cholerae in an inpatient clinic setting to better study the effects of iOWH032 on infected individuals

Summary

Introduction

Acute secretory diarrhea caused by infection with the bacterium Vibrio cholerae is a major cause of diarrheal disease morbidity and mortality. Cholera diarrhea is triggered by the action of cholera toxin, an AB5-family toxin secreted by V. cholerae that is taken up by intestinal epithelial cells, which activates cyclic adenosine monophosphate signaling and thereby stimulates activity of the cystic fibrosis transmembrane conductance regulator (CFTR) chloride channel [9]. Activation of CFTR results in hypersecretion of chloride and water into the intestinal tract, leading to rapid, severely dehydrating diarrhea, and up to 50% mortality if untreated [10]. Appropriate treatment of cholera, including oral rehydration therapy, is highly effective and can reduce mortality to

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