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On June 24th, NodThera, an entrepreneurial team from the University of Cambridge in the United Kingdom, received $40 million in financing to advance the development of small-molecule NLRP3 inhibitors. This was NodThera’s second round of financing. This round of financing was led by Sofinnova Partners and 5 AM Ventures, followed by Epidarex Capital and F-Prime Capital Partners.

Nodthera is a small 5-person research team with members primarily based in Boston and Seattle. Team CEO Alan Watt worked at GlaxoSmithKline.

NLRP3 is one of the nucleotide-binding oligomerization domain (NOD)-like proteins whose main function is to regulate the formation of immunoinflammatory bodies. Inflammatory humor is a multi-protein complex in the body, which is usually composed of sensor receptors, adaptors, and effectors.

Sensor receptors can sense the presence of PAMPs (pathogen-associated model molecules) and DAMPs (damage-associated model molecules) in the environment, which in turn activates effectors via transducer signaling to drive downstream caspase-1 (Caspas-1) cascade pathway produces a series of immune-related effects, and can induce the formation of IL-1β, IL-18 and other cytokines and cell death (new definition of the cause of programmed cell death). Diseases associated with abnormal NLRP3 function include a variety of cardiovascular diseases, autoimmune diseases, and various psychiatric diseases.

NLRP3 Known Function Diagram

NLRP3 mode of action diagram

The study of NLRP3 inhibitors was first reported in 2015. The authors are Luke A. J. O’Neill of Ireland and Matthew A. Cooper of Australia. The compound name reported in this study was MCC950 (CP-456773) and was licensed to Pfizer for development. Preclinical studies have shown that MCC950 has a significant inhibitory effect on IL-1β, with specific target inhibition and reduced experimental autoimmune encephalomyelitis. In a mouse model of an autoimmune disease associated with Cryopyrin protein-associated cyclic syndrome, MCC950 can rescue its neonatal death. In in vitro experiments, samples derived from patients with Welch’s syndrome were active, but the compound was not marketed.

MCC950 (CP-456773)

Nodthera is confident in the development of NLRP3 inhibitors and said that Pfizer’s unfinished business will continue. Alan Watt said in an interview with the media: “I believe NLRP3 inhibitors will give birth to great drugs.”

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