The development of Crofelemer: Connecting ethnobotany, conservation, biocultural diversity, global public health and indigenous knowledge

Crofelemer is a novel first in class compound extracted, isolated and purified from the stem bark latex of the widespread pioneer tree species Croton lechleri, (Sangre de Drago). The natural distribution of this species includes the Northwest Amazon regions of Colombia, Ecuador, Peru, Bolivia and adjacent regions of the Brazil. The latex of this species has been utilized by numerous indigenous peoples of the western Amazon basin orally for the treatment of diarrhea, topically for wound healing and many other therapeutic applications. Crofelemer is an acid-labile oligomeric proanthocyanidin. The primary monomers include (+)-gallocatechin; (-)-epigallocatechin; (+)-catechin and (-)-epicatechin. The oligomer predominantly contains 7–11 linked monomers in varying ratios and an average molecular weight ranges from 1800 to 2200 Da. A new drug application (NDA) for crofelemer for the treatment of HIV/AIDS related chronic diarrhea was submitted on December 5, 2011 to the US FDA and was granted a 6 month priority review designation. Crofelemer's antidiarrheal activity is mediated primarily through its action on two chloride channels. Specifically the compound reduces fluid loss and Cl- secretion through inhibition of both the cystic fibrosis transmembrane conductance regulator (CFTR) and calcium activated Cl- channels (CaCC) in the intestinal epithelium. The drug has minimal systemic absorption and has demonstrated an excellent safety profile in global clinical trials with >2,000 patients dosed across multiple trials conducted in numerous countries. Most recently crofelemer demonstrated excellent efficacy and safety in a pivotal Phase 3 trial in HIV patients (ADVENT) in reducing secretory diarrhea with a p-value of 0.0096. Clinical trials have also been conducted at the International Center for Diarrheal Disease Research (ICDDR) in Dhaka, Bangladesh, demonstrating significant reduction in fluid loss in patients with cholera-induced diarrhea, a life-threatening condition that most recently killed 7,000 people Haiti. One goal of Napo is to make certain that crofelemer can be made available to help save lives in cholera outbreaks wherever they may occur in the world.

Crofelemer cannot be produced synthetically for commercialization due to its complex chiral chemistry. The compound is extracted and isolated from latex of the Croton lechleri. We have created long-term sustainable management and harvest programs of latex in collaboration with local business partners and communities. This includes reforestation and management programs in multiple sites. Cultivation and wild harvest of this species has and will continue to provide income to local communities who are seeking to utilize tropical forest biodiversity in a sustainable long-term manner. These programs will be discussed along with our focus on the conservation of biocultural diversity and long-term benefit sharing through the Healing Forest Conservancy (HFC).

Diarrhea continues to kill more then 2 million children per year and is one of the major causes of childhood illness and death. Napo is focusing on accelerating the development of a pediatric form of crofelemer that can be distributed to pediatric patients, to be used in combination with ORS and zinc, to prevent the severe dehydration and resulting death caused by acute infectious diarrhea in children.