Drug Development

The development of novel drugs to treat infectious diarrhea should help reduce the global burden of diarrheal disease. There are very few drug treatments for specific diarrheal pathogens. In low-resource settings, diarrhea is often inappropriately treated with antibiotics, but they are ineffective against many pathogens, and indiscriminate antibiotic use can lead to bacterial resistance. 

Drugs for diarrhea will be important additions to an integrated approach that includes greater access to safe water, new and improved vaccines, oral rehydration therapy, zinc supplementation, and nutrition.

iOWH032, investigational new drug for secretory diarrhea

PATH has led the discovery and development of iOWH032, a new chemical entity with the potential to be the first synthetic drug of its kind designed to reduce fluid loss from secretory diarrhea, which is most commonly caused by rotavirus, Vibrio cholerae, and enterotoxigenic Escherichia coli bacteria transmitted through poor sanitation and contaminated water in developing countries.1,2,3 Secretory diarrhea can last from hours to days and is associated with copious fluid loss and rapid, life-threatening dehydration. By targeting the cystic fibrosis transmembrane conductance regulator (CFTR) chloride channels in the cells that line the intestines, iOWH032 directly inhibits diarrheal secretion and aims to shorten the duration and severity of dehydration.

To date, an investigational new drug application was filed and sanctioned in 2011; two phase 1 clinical trials in US healthy volunteers and a two-part bridging study to assess pharmacokinetics, safety, and tolerability in Bangladeshi adult volunteers and male cholera patients were completed in 2013. If approved, iOWH032 would be recommended for use with oral rehydration and other proven therapies and could encourage wider adoption of and compliance with those lifesaving treatments.

Chemical structure of iOWH

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References

1 Lundgren O, Peregrin AT, Persson K, Kordasti S, Uhnoo I, Svensson L. Role of the enteric nervous system in the fluid and electrolyte secretion of rotavirus diarrhea. Science 287(5452), 491495 (2000).

2 Nelson EJ, Harris JB, Morris JG Jr, Calderwood SB, Camilli A. Cholera transmission: the host, pathogen and bacteriophage dynamic. Nat. Rev. Microbiol. 7(10), 693–702 (2009).

3 Qadri F, Svennerholm AM, Faruque AS, Sack RB. Enterotoxigenic Escherichia coli in developing countries: epidemiology, microbiology, clinical features, treatment, and prevention. Clin. Microbiol. Rev. 18(3), 465–483 (2005).

Photo: Jonathan Torgonovik