Cryptosporidiosis is one of the leading causes of diarrhea in children under the age of 2 in developing countries, and there is no available treatment approved for use in the pediatric population.1 Childhood diarrheal diseases are not only the second leading cause of death in children under 5, causing 525,000 deaths annually, they are also a leading cause of malnutrition, which is associated with growth stunting and poor cognitive development.2 In immunocompromised individuals, cryptosporidiosis can be life-threatening, since there is no fully effective drug treatment. Calibr has now identified and repurposed an FDA-approved drug, clofazimine, used for decades to treat leprosy, as a potential new treatment for cryptosporidiosis.
Clofazimine was identified as part of a concerted effort at Calibr to repurpose known drugs, in the hopes of accelerating the time it takes for innovative research to impact patients. Based on a similar theme, Calibr created a set of chemical compounds called “ReFRAME” to better mine known drugs. ReFRAME was built with the support of a grant from the Bill & Melinda Gates Foundation. ReFRAME consists of ~13,000 high-value compounds and is truly unique among repurposing collections in both scale and comprehensiveness. Because the compounds in this collection are either known drugs or molecules that are advanced in the drug discovery process, a clinical drug candidate can be rapidly generated and accelerated through the development process.
Identification of clofazimine as a potential novel treatment for cryptosporidiosis is the first example of how ReFRAME can help accelerate the development of drugs for new medical needs. In a study published in PLOS on February 3, 2017, a Calibr team led by Principal Investigator Case McNamara showed that clofazimine inhibited proliferation of the Cryptosporidium parasite in a mouse model, resulting in significantly reduced fecal shedding of Cryptosporidium oocysts. Their findings suggest that clofazimine could prove to be an effective treatment for cryptosporidiosis relative to the approved drug, Nitazoxanide, which has little to no efficacy in HIV positive patients and low efficacy in malnourished children. Calibr is collaborating with the University of Washington, who is sponsoring the Phase 2A clinical trial in Malawi, and the Bill and Melinda Gates Foundation to study the safety, tolerability, pharmacokinetics and efficacy of clofazimine in the treatment of cryptosporidiosis in HIV positive patients (clinical trial no. NCT03341767).
“We’re excited for the results of this trial and we hope to make an important impact against a neglected infectious disease,” says Case McNamara. With support from the Bill & Melinda Gates Foundation, work is ongoing at Calibr to develop a special formulation of clofazimine ideally suited to treat children.
Cryptosporidiosis is caused by a parasite, Cryptosporidium, that lives in the intestine of infected humans and animals. It is difficult to eradicate, since the oocysts excreted in feces can remain infectious in certain environments for up to six months, resisting disinfection attempts that include chlorination. Prevalent around the world, the parasite has been implicated in a number of outbreaks across the United States, including one statewide outbreak in 2007 that sickened more than 5,500 individuals and contaminated approximately 450 recreational water venues. Because Cryptosporidium spreads so easily in settings without adequate sanitation and hygiene, the parasite is a serious threat in developing countries.
Calibr’s research was performed with support of a grant from the Bill & Melinda Gates Foundation.