Manjunatha, Ujjini, Lakshminarayana, Suresh, Jumani, Rajiv Satish, Chao, Alexander, Young, Joe, Gable, Jonathan, Knapp, Mark, Hanna, Imad, Galarneau, Jean-Rene, Cantwell, John, Kulkarni, Upendra, Turner, Michael, Chan, Katherine, Patra, Debjani, Mamo, Mulugeta, Luu, Catherine, Xiao, Linda, Chen, Ying-Bo, Shannon, Carney, Lakshman, Jay, Osborne, Colin, Zaror, Isabel, Jennifer, Zambriski, Gu, Feng, Sarko, Christopher and Diagana, Thierry (2022) Cryptosporidium PI(4)K inhibitor EDI048 is a gut-restricted parasiticidal agent to treat paediatric enteric cryptosporidiosis. Nature microbiology.. ISSN 2058-5276

Abstract

Diarrhoeal disease caused by Cryptosporidium is a major cause of
morbidity and mortality in young and malnourished children from low- and
middle-income countries, with no vaccine or efective treatment. Here
we describe the discovery of EDI048, a Cryptosporidium PI(4)K inhibitor,
designed to be active at the infection site in the gastrointestinal tract
and undergo rapid metabolism in the liver. By using mutational analysis
and crystal structure, we show that EDI048 binds to highly conserved
amino acid residues in the ATP-binding site. EDI048 is orally efcacious
in an immunocompromised mouse model despite negligible circulating
concentrations, thus demonstrating that gastrointestinal exposure is
necessary and sufcient for efcacy. In neonatal calves, a clinical model
of cryptosporidiosis, EDI048 treatment resulted in rapid resolution of
diarrhoea and signifcant reduction in faecal oocyst shedding. Safety and
pharmacological studies demonstrated predictable metabolism and low
systemic exposure of EDI048, providing a substantial safety margin required
for a paediatric indication. EDI048 is a promising clinical candidate for the
treatment of life-threatening paediatric cryptosporidiosis.

Item Type:	Article
Keywords:	Cryptosporidiosis, PI4K, EDI048,
Date Deposited:	22 Oct 2024 00:45
Last Modified:	22 Oct 2024 00:45
URI:	https://oak.novartis.com/id/eprint/52723