Objective: We recently confirmed that nibrozetone (RRx-001), a Phase 3 small molecule chemoprotective agent, is a direct NLRP3 inhibitor that is CNS permeable. Nibrozetone displays nanomolar potency against inflammasome activation, which is a neuropathological hallmark of PD. In this study, we evaluated if RRx-001 could be developed as a novel disease-modifying therapeutic for PD.

Background: There are currently no effective disease-modifying treatments for Parkinson’s disease (PD) which is currently one of the fastest growing neurological diseases globally. Given the complex multifactorial etiology of PD, emerging evidence suggests that targeting multiple pathological mechanisms and hubs in addition to protection against the neurotoxicity of protein aggregates could be necessary to achieve disease modification and slow progression. Chronic immune and inflammasome activation, mitochondrial dysfunction and impaired autophagy are well-established mechanisms whose complex interactions drive progressive dopaminergic degeneration and synuclein pathology.

Method: To develop nibrozetone for PD, we evaluated its therapeutic efficacy using a combination of mechanistically distinct pre-clinical animal models of PD including the 6-OHDA neurotoxicant model and the PFF-synuclein model of PD. We also evaluated the distribution of nibrozetone and its metabolites in the CNS and conducted mechanistic studies using isolated immune and neuronal cells. 

Results: We confirmed that once daily dosing with RRx-001 (10 mg/kg) reduced NLRP3 inflammasome activation markers such as caspase-1 p20 and ASC in both neurotoxicant and synuclein-based animal models of PD. In RRx-001 treated mice, we also confirmed central and systemic activation of the neuroprotective NRF2 pathway, which is a marker of target engagement. Nibrozetone therapy improved motor deficits and dopaminergic degeneration in the 6-OHDA model of PD. Our findings confirm RRx-001 is centrally active, and targets multiple pathological mechanisms including the attenuation of neuro-inflammatory responses linked to PD progression.

Conclusion: Given the excellent clinical safety record of RRx-001 in human studies to date, our results suggest that RRx-001 could be an attractive neuroprotective strategy for disease modification of PD, with the potential for rapid clinical translation.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/validating-the-clinical-stage-nlrp3-inflammasome-inhibitor-nibrozetone-as-a-disease-modifying-therapeutic-for-parkinsons-disease/