MANILA — By the end of the year, a team of researchers are hoping to test in healthy volunteers a drug meant to treat a major cause of mortality among children under 2 years old.
The KDU731 is a candidate drug that has shown to inhibit the enzyme PI(4)K in cryptosporidium, the intestinal parasite causing cryptosporidiosis, a diarrheal disease affecting both humans and animals. The World Health Organization described it as a “potentially severe and life-threatening illness,” and in 2013, a groundbreaking discovery in the Global Enteric Multicenter Study revealed it is the second leading cause of moderate to severe diarrhea in children under 2, and the leading cause of death from diarrhea among the same age group.
Diarrheal disease is the second leading cause of death for children under 5 years old, according to WHO.
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The 2013 study raised concerns in the global health space, in particular those working to improve children’s health. While it provided important information on the leading diarrheal pathogen associated with the death of children under 2, the study also led to the revelation of how very few diagnostic tools and treatment options are available to address it. No vaccines currently exist to prevent cryptosporidiosis or “crypto” as it is more commonly referred to in the scientific community, and there is only one drug available — nitazoxanide — that is approved by the United States Food and Drug Authority for treatment. Nitazonaxide however has been shown to only be effective in healthy individuals who have contracted the disease, but not as much in malnourished and immunocompromised patients, such as those living with HIV.
This makes treating children in poor communities particularly challenging.
“We are told children in endemic countries, most of them would be malnourished and immunocompromised children. So these diseases are quite devastating,” Ujjini Manjunatha, cryptosporidiosis group leader at the Novartis Institute for Tropical Diseases which is leading the development of the KDU731 candidate drug, told Devex. “So that’s why [we have an] interest in getting a compound which works in malnourished and immunocompromised patients.”
Manjunatha said data shows endemic countries where there is a significant burden of diarrheal diseases are mostly in sub-Saharan Africa, such as Kenya, Mali, and Zambia, and Southeast Asian countries, which include Bangladesh, India, and Pakistan.
But while their candidate drug has shown some promise in blocking crypto infection in early in vitro and in vivo testing in mice with immunocompromised systems and neonatal calves, it needs to undergo proper safety studies and clinical trials in a large sample of human patients to ensure its effectiveness and safety, and that could take years or decades. At present, the drug is still in preclinical trials.
“The typical timeline for something at this stage is five to seven years to get to the point of a Food and Drug Administration decision whether to approve,” Thierry Diagana, head of NITD, told Devex. “We're hoping to go faster.”
NITD has recently announced its partnership with the Bill & Melinda Gates Foundation to further the drug’s development. Under the partnership, the foundation will provide $6.5 million in support of its development. This includes allowing NITD to tap a network of doctors “who have a deep understanding of the havoc wreaked by cryptosporidium,” Diagana said.
But this is not the only drug the foundation is supporting focused on crypto. Clofazimine is a drug currently undergoing phase 2 clinical trials, meaning it is being evaluated for its efficacy and any potential side effects in patient volunteers with HIV suffering from crypto as well as those in volunteers with HIV but without crypto or diarrhea. The drug has been used to treat leprosy for years, and recently it’s being tested as part of a WHO-recommended shorter regimen for the treatment of multidrug resistant tuberculosis.
But Clofazimine appears to be the only drug targeted to treat crypto that’s in clinical development at the moment. Other potential drugs have only been tested in vitro, or in animals. Some FDA-approved drugs, such as Auranofin for rheumatoid arthritis and Pyrvinium pamoate for pinworm infections, are being considered to treat crypto.
This is why PATH, in an editorial published in PLOS in 2016, proposed the development of an approach aimed at accelerating research and development for crypto. Titled ACcelerator for CryptOsporidium Research & Drug Development to Reduce Child Mortality, or ACCORD, inspired by the Gates Foundation’s TB Drug Accelerator, the approach is aimed at coordinating available resources and expertise of wide range of stakeholders — pharmaceutical companies, private foundations, governments, academic institutions and NGOs — to speed up development of new tools and drugs against crypto. As part of its vision, PATH started hosting a “Crypto Symposium” in 2017, gathering different organizations and experts on the topic to share knowledge and pursue collaborations for drug R&D.
“At the University of Vermont, we are collaborating with a team to develop new methods of testing crypto drug candidates,” Robert Choy, associate director, research, and preclinical development at PATH, told Devex. “These methods are shedding light on where in its life cycle the parasite is most vulnerable and also helping researchers generate a diverse panel of drug candidates to maximize the likelihood of success.”
Choy said they’ve also worked with the university to develop efficacy studies based on a calf model.
“Mice typically used for efficacy studies do not exhibit the symptom of severely dehydrating diarrhea as children infected with crypto,” he explained.
They’re also working with the University of Washington on refining computer simulations of drug action in the intestine to better understand the necessary properties for a drug against crypto, as well as on two other drug discovery projects for crypto.