Crofelemer is an orally administered, non-absorbed, oligomeric proanthocyanidin, which acts through luminal blockade of the cystic fibrosis transmembrane conductance regulator (CFTR). Crofelemer has in vitro activity against cholera toxin (CT)-stimulated Cl- efflux across CFTR channels, has been shown to normalize fluid accumulation in CT treated mice, significantly improves secretory diarrhea in humans due to ETEC, and has been studied in almost 1000 patients with a very promising safety profile. While crofelemer is being evaluated for several gastrointestinal indications, it is uniquely suited for the treatment of secretory diarrhea induced by V. cholerae, a category B biodefense pathogen. Development for cholera is not on our critical path, as there is no commercial market in the US or the rest of the developed world. We do, however, have the financial resources to conduct a controlled trial in Bangladesh to definitively determine the efficacy of ? crofelemer in patients infected with V. cholerae. The only component which is lacking is an adequate oral dosage form to treat these patients. We need to develop and manufacture a new oral dosage form that has a better dissolution profile than the tablet currently used for clinical trials for other indications. Without this improved dosage form, the cholera trial cannot proceed. ? ? We believe that treatment with crofelemer will have a dramatic impact on the duration and severity of V. cholerae-induced secretory diarrhea. Improving our treatment armamentaria for cholera is of great importance as natural or man-made catastrophes like the massive flooding in New Orleans or the tsunamilike situation in Asia, where the infrastructure of a region is destroyed, can lead to conditions which are ideal for outbreaks of severe secretory diarrhea from insufficiently purified water. This grant will fund the final stages of development for an important treatment of a category B biodefense pathogen, which would not otherwise be developed for this indication, and the results from this trial will be available years before the closest competitor could even begin such a study. Since the NIH has provided funding for the preclinical development of that compound, the advanced stage of development and overwhelming data available for crofelemer should make completion of our proposed cholera study an even higher priority. ? ? ?
