Oral Presentation Lorne Infection and Immunity 2023

ADS032, the first dual NLRP1 and NLRP3 inflammasome inhibitor for the treatment of infectious and inflammatory diseases (#4)

Ashley Mansell 1 2 3 , Callum Docherty 1 , Anu Fernando 4 , Sarah Rosli 1 , Maggie Lam 1 , Michelle Tate 1 , Christopher Murphy 3 , Adriano Rossi 4
  1. Centre for Innate Immunity and Infectious Diseases, Hudson Institute of Medical Research, Melbourne, VIC, Australia
  2. Adiso Therapeutics, Concord, MA, USA
  3. Adiso Therapeutics, Concord, MA, USA
  4. University of Edinburgh Centre for Inflammation, , Queen's Medical Research Institute, Edinburgh, United Kingdom

Inflammasomes induce maturation of the inflammatory cytokines IL-1β and IL-18, whose activity is associated in the pathophysiology of a wide range of infectious and inflammatory diseases including influenza A virus (IAV), SARS CoV2, pulmonary, neurodegenerative, metabolic and cardiovascular diseases, monogenic autoinflammatory syndromes and cancer. As validated therapeutic targets for the treatment of acute and chronic inflammatory diseases, there has been intense interest in developing small molecule inhibitors to target inflammasome activity.

We here describe ADS032 as the world’s first dual NLRP1 and NLRP3 inhibitor. ADS032 is a rapid, reversible and stable small molecule inflammasome inhibitor that directly binds both NLRP1 and NLRP3, reducing secretion and maturation of IL-1β in mouse macrophages, human blood-derived macrophages, stimulated with both NLRP1 and NLRP3 agonists. ADS032 suppressed IL-1β secretion from human primary bronchial epithelial cells in response to the NLPR1 agonists anisomycin and poly I:C, and NLRP3 agonists nigericin and silica.

Demonstrating its therapeutic potential, in vivo administered ADS032 reduced IL-1β and TNF levels in the serum of mice both systemically and intranasally challenged with LPS and reduced pulmonary inflammation in an acute model of lung silicosis. Importantly, while we previously found that ablating NLRP3 functionality with potent inhibitors such as MCC950 had both positive and detrimental disease outcomes during IAV infection; we found that mice treated with ADS032 protected mice from lethal IAV challenge when administered at any time post-infection, displaying increased survival and reduced pulmonary inflammation.

Ex vivo treatment of human alveolar macrophages and intra-pulmonary imaging demonstrate rapid and effective target engagement with a fluorescently tagged ADS032, and efficacy in inhibiting NLRP3, highlighting impending clinical translation.

ADS032 is therefore a potential drug to treat NLRP1- and NLRP3-associated inflammatory diseases in first in human trials and a novel tool to allow examination of the role of NLRP1 in human disease.