Napo Pharmaceuticals ended its agreement with Salix Pharmaceuticals covering crofelemer on November 4, stating that Salix had breached terms of the collaboration. Napo asserts that despite obtaining positive Phase III results for the drug a year ago as a treatment for chronic diarrhea in HIV/AIDS patients, Salix has stalled on taking crofelemer to the FDA.
The termination paves the way for Napo to pursue an NDA, enter into new licensing agreements if it chooses, and press forward with commercialization plans for crofelemer. Salix had licensed crofelemer rights for all indications in North America, most of Europe, and Japan in December 2008.
Napo 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. 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.
FDA had given crofelemer fast-track status for chronic diarrhea in people living with HIV/AIDS (CRO-HIV) and diarrhea-predominant irritable bowel syndrome (CRO-IBS). On November 4, 2010, Salix confirmed plans to set up a pre-NDA meeting with FDA early in 2012 to discuss crofelemer as a diarrhea treatment on the back of positive late-stage data from the Advent trial. This study was conducted in HIV/AIDS patients receiving ARV therapy.
Napo reports, however, that Salix has not filed an NDA. “Napo believes Salix has materially breached the collaboration agreement by unnecessarily stalling the advancement of this compound,” says William A. Brewer III, partner at Bickel & Brewer and counsel for Napo. “Most notably, Salix has failed to file an NDA one year after a highly successful Phase III clinical trial or to prepare for commercial manufacture of the drug, critical tasks that were fundamental to its responsibilities.”
On September 16, 2011, Napo sent Salix a notice of default. But with Salix not rectifying the situation in a “timely manner,” Napo decided to suspend its arrangement with Salix.
“Crofelemer is a novel, first-in-class antidiarrheal agent that has a physiological and different mechanism of action from traditional antidiarrheal agents,” Pravin Chaturvedi, Ph.D., CSO at Napo commented when Phase III results were released last year. “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.”
Data from the 374-patient Advent 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.
Crofelemer is an antisecretory agent extracted from the bark latex of the South American tree Croton lechleri. Napo 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.