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

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.

A Repurposed Drug Interferes with Nucleic Acid to Inhibit the Dual Activities of Coronavirus Nsp13

“…IOWH-032 was originally developed as a cystic fibrosis transmembrane conductance regulator (CFTR) inhibitor. The compound reached phase 2 clinical trials for the treatment of infectious diarrhea resulting from continuous activation of CFTR caused by Vibrio cholerae infection. , As several structural analogs of IOWH-032 have been synthesized, we performed a focused structure–activity relationship (SAR) study with compounds containing functional group variations in different positions around the parent scaffold (Figure A). The tested analogs were also selected based on favorable molecular docking scores with Nsp13.…”

“…IOWH-032 was first reported as an inhibitor of the human CFTR chloride and bicarbonate transporter for the treatment of infections related to acute watery diarrhea (AWD). 35 Sustained activation of CFTR by bacterial toxins contributes to AWD since regulated transporter function is important for maintaining fluid homeostasis in intestinal epithelial cells. In another well-known disease state, cystic fibrosis (CF), patients contain loss of function mutations in CFTR.…”

“…Hence, IOWH-032 is not a pan microbial DNA or RNA helicase inhibitor among examined proteins, and likely would not disrupt human helicases. 53 IOWH-032 has already been examined as a therapeutic in humans; 34,35 hence, we last aimed to evaluate the compound in a viral infection model. We first evaluated toxicity against three commonly used cell lines, two of which were derived from monkey kidney cells and one from human lung cancer cells, with and without overexpression of the human SARS-CoV-2 receptor ACE2 and associated TMPRSS2 protease (Figure S13).…”

Ca2+ fortified oral rehydration solution is effective in reducing diarrhea morbidity in cholera toxin-pretreated mice

“…This will inevitably reduce the residence and contact time of the substances with the intestine unless they are delivered frequently and or in high doses. Otherwise, their anticipated drug effect on diarrhea may be compromised or not produced as evidenced in a recent study with an oral CFTR inhibitor [ 43 ] . Continuously or frequently administering Ca 2+ via ORS in a drinking bottle that was adopted in the present study could avoid or minimize this risk.…”

Nontoxigenic Vibrio cholerae Challenge Strains for Evaluating Vaccine Efficacy and Inferring Mechanisms of Protection

“…Currently, the V. cholerae strain used in most CHIMs is N16961, a 1971 7PET wave 1 Inaba isolate ( 24 – 27 ). Although N16961 has been widely used for CHIM studies, there are several compelling reasons why a new challenge strain would be valuable for cholera CHIM studies.…”