2. Academic Validation
  3. Cryptosporidium PI(4)K inhibitor EDI048 is a gut-restricted parasiticidal agent to treat paediatric enteric cryptosporidiosis

Cryptosporidium PI(4)K inhibitor EDI048 is a gut-restricted parasiticidal agent to treat paediatric enteric cryptosporidiosis

  • Nat Microbiol. 2024 Nov;9(11):2817-2835. doi: 10.1038/s41564-024-01810-x.
Ujjini H Manjunatha # 1,  Suresh B Lakshminarayana # 2,  Rajiv S Jumani # 2,  Alexander T Chao 2,  Joseph M Young 3,  Jonathan E Gable 2,  Mark Knapp 3,  Imad Hanna 4,  Jean-Rene Galarneau 5,  John Cantwell 3,  Upendra Kulkarni 6,  Michael Turner 3,  Peichao Lu 3,  Kristen H Darrell 2 7,  Lucy C Watson 2,  Katherine Chan 2,  Debjani Patra 2,  Mulugeta Mamo 3,  Catherine Luu 3,  Carlos Cuellar 3,  Jacob Shaul 3 8,  Linda Xiao 2,  Ying-Bo Chen 2,  Shannon K Carney 9 10,  Jay Lakshman 11,  Colin S Osborne 2,  Jennifer A Zambriski 9 12,  Natasha Aziz 2 13,  Christopher Sarko 3,  Thierry T Diagana 14
Affiliations

Affiliations

  • 1 Global Health, Biomedical Research, Novartis, Emeryville, CA, USA. [email protected].
  • 2 Global Health, Biomedical Research, Novartis, Emeryville, CA, USA.
  • 3 Biomedical Research, Novartis, Emeryville, CA, USA.
  • 4 Biomedical Research, Novartis, East Hanover, NJ, USA.
  • 5 Biomedical Research, Novartis, Cambridge, MA, USA.
  • 6 Novartis Pharmaceutical Corporation, Cambridge, MA, USA.
  • 7 Metagenomi, Inc., Emeryville, CA, USA.
  • 8 Absci Corporation, Vancouver, WA, USA.
  • 9 Department of Population Health Sciences, College of Veterinary Medicine, Center for One Health Research, Blacksburg, VA, USA.
  • 10 Cornell University, College of Veterinary Medicine, Department of Population Medicine and Diagnostic Sciences, Ithaca, NY, USA.
  • 11 Novartis Pharmaceutical Corporation, East Hanover, NJ, USA.
  • 12 Veterinarians for Global Solutions, Washington, DC, USA.
  • 13 Genentech Research and Early Development, South San Francisco, CA, USA.
  • 14 Global Health, Biomedical Research, Novartis, Emeryville, CA, USA. [email protected].
  • # Contributed equally.
PMID: 39379634 DOI: 10.1038/s41564-024-01810-x
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 effective 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 efficacious in an immunocompromised mouse model despite negligible circulating concentrations, thus demonstrating that gastrointestinal exposure is necessary and sufficient for efficacy. In neonatal calves, a clinical model of cryptosporidiosis, EDI048 treatment resulted in rapid resolution of diarrhoea and significant 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.

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