NLRP3 inflammasome

The research record

This is the project's file for this landmark, as written and checked. Sources are listed at the end; anything not yet confirmed is marked "Not yet verified".

Who

Richard Gordon, Trent Woodruff (last author) and Matthew Cooper (University of Queensland), with Kate Schroder, Luke O'Neill (Trinity College Dublin), Anumantha Kanthasamy (Iowa State) and colleagues. Science Translational Medicine 10(465):eaah4066, 31 Oct 2018. Funders listed in Europe PMC include Australia's NHMRC and Research Council, the Queensland Government, the NIH and the Michael J. Fox Foundation. The paper discloses a conflict: Cooper and O'Neill co-founded Inflazome, which licensed NLRP3-inhibitor patents from four of the authors, and are its chief executive and chief scientist.

What happened

The NLRP3 inflammasome is a protein complex inside immune cells that, when triggered, releases the inflammatory messenger IL-1β. Cleaved caspase-1 and the adaptor ASC, both markers of an active inflammasome, were raised in the substantia nigra of people with Parkinson's and in several preclinical models. In mouse microglia, fibrillar synuclein triggered a delayed NLRP3 response with release of IL-1β and ASC. A small-molecule NLRP3 blocker, MCC950, abolished this at nanomolar doses in cells. Given by mouth in several rodent models, it blocked inflammasome activation and reduced motor deficits, loss of nigrostriatal dopamine neurons and synuclein aggregates (abstract, read via Europe PMC).

Why it moved us toward a cure

It linked the central protein (synuclein, landmark 5) directly to an innate immune pathway (landmark 52) and gave a drug-able target: an oral small molecule worked in mice.

An earlier inflammation drug, tested in people. AZD3241 (later called verdiperstat) blocks myeloperoxidase, an enzyme that microglia use to make damaging oxidants. A Phase 2a placebo-controlled brain-scan study (Jucaite et al., Brain 2015) gave 24 people with Parkinson's AZD3241 600 mg twice a day (18) or placebo (6) for 8 weeks. A PET tracer for microglia (11C-PBR28) fell 13-16% across the nigrostriatal regions at 8 weeks on the drug and did not change on placebo. The drug was safe and well tolerated. It was a proof-of-mechanism study with no efficacy measure, so it shows the target can be hit, not that the disease slows. AstraZeneca's own Phase 2 safety study of AZD3241 in 51 people (NCT01603069, 2012–13) has no results posted. Under the name verdiperstat, the drug failed its Phase 3 trial in multiple system atrophy: Biohaven announced on 27 Sep 2021 no separation from placebo on the primary or key secondary measures (release, read through a search summary only).

Outcome

Open. MCC950 itself was not developed for people. Roche bought the NLRP3 company Inflazome in September 2020 for a reported €380 million upfront (release). Roche's NLRP3 blocker selnoflast (RO7486967) was tested in a 28-day Phase 1b trial in early Parkinson's (NCT05924243; September 2022 to July 2024). Roche's plain-language summary counts 57 participants; the registry and Alzforum say 60 enrolled against 72 planned. Per Roche, it was well tolerated with no serious unwanted effects, and a brain-scan marker of inflammation differed from placebo, which Roche took as evidence the drug reaches its target. Alzforum reports a 30% fall in spinal-fluid IL-18 and small, non-significant clinical differences. The trial was not designed to show benefit. Alzforum also quotes company information that selnoflast "does not enter the brain", which sits uneasily with these results; that is unresolved in the sources read. The registry shows no Parkinson's efficacy trial of selnoflast; a Phase 2 in atherosclerosis (NCT07448038) started in June 2026. A second company, Ventus Therapeutics, started a Phase 1b of its NLRP3 blocker VENT-02 in mild to moderate Parkinson's (NCT06822517, March 2025; 29 enrolled); the registry shows it ended on 9 October 2025, "sponsor decision", with no results posted.

RRx-001 (nibrozetone), a cancer drug reported to block NLRP3, was funded by Shake It Up Australia and the Michael J. Fox Foundation in 2022 for Parkinson's models; only a 2024 conference abstract in a rat model is public, with no trial.

Sources

• Shake It Up Australia project page (funding and status facts only)
• Inflazome acquisition by Roche, 21 Sep 2020 (release copy)
• Gordon et al., "Inflammasome inhibition prevents α-synuclein pathology and dopaminergic neurodegeneration in mice," Sci Transl Med 2018;10(465):eaah4066, DOI 10.1126/scitranslmed.aah4066, PMID 30381407 (abstract and competing interests read via Europe PMC and PubMed) · Alzforum record
• Roche plain-language summary of the selnoflast Phase 1b (BP43176), Sept 2025 (sponsor document; not peer reviewed)
• Alzforum trial entry for selnoflast (planned 72; 60 enrolled) · ClinicalTrials.gov NCT05924243 (60 enrolled, completed 18 Jul 2024; no results posted) · VENT-02, NCT06822517 · Selnoflast atherosclerosis, NCT07448038
• AZD3241 Phase 2, NCT01603069
• Jucaite et al., "Effect of the myeloperoxidase inhibitor AZD3241 on microglia: a PET study in Parkinson's disease," Brain 2015;138:2687-2700, DOI 10.1093/brain/awv184, PMID 26137956 (abstract read via Europe PMC)
• Not yet verified: the species and models used in each experiment beyond the abstract; peer-reviewed publication of the selnoflast results (none found); whether selnoflast enters the brain; the reason VENT-02 stopped; the Biohaven MSA trial's full results (press release only). No correction or retraction found for Gordon et al. or Jucaite et al.