Salix Pharmaceuticals confirmed plans to set up a pre-NDA meeting with FDA early next year for the diarrhea treatment, crofelemer, on the back of positive data just reported from a Phase III study. The two-stage, adaptive Advent study evaluated crofelemer in the treatment of chronic diarrhea in HIV/AIDS patients receiving ARV therapy.
Data from the 374-patient study showed that in comparison with placebo, administration of 125 mg corfelemer twice daily resulted in significant improvements in the primary responder analysis, defined as patients having two or less watery stools during two of the four week placebo-controlled phase. The Advent trial was conducted under fast-track status, and is part of a special protocol assessment agreement with FDA. Salix is developing crofelemer under license from Napo Pharmaceuticals. The firm estimates the HIV-associated diarrhea market could be worth some $300 million per year in the U.S. alone.
“Crofelemer is a novel, first-in-class antidiarrheal agent that has a physiological and different mechanism of action from traditional antidiarrheal agents,” comments Pravin Chaturvedi, Ph.D., CSO at Napo. “We are very pleased with the efficient nature of the adaptive design of Advent that allowed us to conduct the dose assessment and dose confirmation in a single trial.”
Napo’s crofelemer is an antisecretory agent extracted from the bark latex of the South American tree Croton lecheri. The firm claims the drug is not absorbed systemically, but acts only at the local level on the gastrointestinal tract. Its activity impacts both the CFTR channel in the intestinal lumen to normalize flow of chloride ions and water into the GI tract, and also at the level of calcium-activated chloride ion channels. Napo says that these unique mechanisms of action mean crofelemert can treat watery/secretory diarrhea irrespective of etiology.
In addition to its development for treating diarrhea associated with HIV therapy, crofelemer is separately undergoing Phase II development for treating diarrhea associated with irritable bowel syndrome (IBS), and for the treatment of acute infectious diarrhea, including cholera. Phase I trials evaluating crofelemer against pediatric diarrhea are also under way. The drug has been granted fast track status by FDA for IBS- and HIV-related indications.
Salix has licensed development and commercial rights to crofelemer for all indications in North America, most of Europe and Japan. It has worldwide rights to the drug for certain other indications, including IBS. Napo has separately licensed crofelemer to Glenmark Pharmaceuticals for development in India and 140 emerging countries for indications related to HIV, acute adult infectious diarrhea, and pediatric diarrhea. Glemnark anticipates approval of the drug in India during 2012. Rights to crofelemer in China (including Hong Kong and Macau) have been licensed by Luye Pharmaceuticals for indications including HIV-associated diarrhea, infectious disease diarrhea, and pediatric diarrhea.
Napo hopes that crofelemer could help address the morbidity and mortality associated with diarrhea in developing countries, particularly in children. The firm suggests that some 2.5 million children under five years old die each year due to diarrhea and dehydration caused by a range of diseases, and primarily cholera. It says trials have already shown that adding crofelemer to rehydration and antibiotic therapy reduced stool volume output by 32% in the first six hours, and this reduction continued through the first 24 hours of observation, which is the time period during which cholera patients are most likely to succumb to severe dehydration.
Studies have previously confirmed that crofelemer is safe in children as young as three months, and Napo has created the Crofelemer Access Program (CAP) to provide the drug at cost to pediatric populations in disaster situations and resource-constrained geographies. Napo has received a cornerstone investment in this program from the principal of Palo Alto-based Asset Management.