NodThera’s NLRP3 Inhibitor Reverses Neuroinflammation in Parkinson’s Disease Phase 1b/2a Trial

NodThera recently announced positive data from its Phase 1b/2a study in Parkinson’s disease patients, evaluating the effects of its oral, brain-penetrant NLRP3 inflammasome inhibitor NT-0796, on inflammatory and disease-specific biomarkers in the blood and cerebrospinal fluid (CSF).

NodThera’s study demonstrated mean reductions of key pro-inflammatory biomarkers in CSF (eg, IL-1β, IL-6, CCL2, CXCL1, and CXCL8) over 28 days compared to baseline to levels approximating those of healthy elderly controls, demonstrating reversal of NLRP3-mediated neuroinflammation. In addition, reductions in neurodegenerative markers were also observed following oral dosing of NT-0796, including NfL and soluble TREM (sTREM2). In subjects with elevated acute phase biomarkers CRP and fibrinogen, levels were reduced significantly, consistent with the peripheral anti-inflammatory effects of NT-0796 seen in elderly healthy volunteers studied in an earlier stage of the trial.

Alan Watt, Chief Executive Officer of NodThera, said “Our new findings in Parkinson’s disease, a condition with substantial unmet medical needs, are profound and highly encouraging. They bolster our confidence in the ongoing program, with Phase 2 studies now in advanced planning stages. The correlation between Parkinson’s disease and neuroinflammation is well-documented, with alpha-synuclein fibrils triggering microglial NLRP3 activation, leading to neuroinflammation and subsequent neurodegeneration. This is the inaugural demonstration of an NLRP3 inhibitor’s potential to not only address Parkinson’s disease but also offer a broader impact on neurodegenerative diseases. Given that existing Parkinson’s treatments primarily manage symptoms, our innovative, disease-modifying strategy presents a significant shift, aiming to stop the disease progression. NT-0796’s demonstrated efficacy in reducing neuroinflammation in patients heralds a substantial advancement towards halting this devastating disease.”

NT-0796 was safe and well tolerated; adverse events (AEs) were mainly mild and transient, and no serious adverse events (SAEs) were observed. Pharmacokinetics indicated the drug candidate’s potential for once-daily dosing and levels of the drug candidate in the brain, determined by measuring the concentration in CSF, were found to be maintained over 24 hours.

Taken together, the findings demonstrate that NT-0796 successfully delivered anti-neuroinflammatory and anti-inflammatory changes within 7 days and sustained for 28 days, indicating excellent potential for long-term, oral dosing in Parkinson’s disease patients.

Prof. Thomas Foltynie BSc, MBBS, MRCP, PhD, Professor of Neurology in the Department of Clinical and Movement Neurosciences, UCL Institute of Neurology and Consultant Neurologist at the National Hospital for Neurology and Neurosurgery, Queen Square, London, added “These results are particularly promising for the future of Parkinson’s disease treatment, providing a compelling approach to the modulation of inflammation in the brain, a key driver in the development of this disease. Such an approach has the potential to change the face of treatment – actually stopping the disease in its tracks, that would be of enormous value to those living with Parkinson’s disease.”

The findings from NodThera’s study will be presented on Friday March 8 at AD/PD 2024, the international conference on Alzheimer’s and Parkinson’s diseases and related neurological disorders, taking place in Lisbon, Portugal.

Additionally, following the recently published preclinical data demonstrating NodThera’s NLRP3 inflammasome inhibitors reversed diet-induced obesity (DIO) and inflammation in mice the Company’s pioneering Phase 1b/2a clinical study of NT-0796 in obese subjects with cardiovascular risk is in progress with results expected by end of 2Q24. This biomarker-rich study is measuring the change in baseline to Day 28 of CRP levels, a key peripheral inflammatory marker and known predictor of risk of developing atherosclerotic cardiovascular (CV) disease as well as the potential for modification of body weight over 28 days.

NodThera is a leading clinical-stage biotech developing brain-penetrant NLRP3 inflammasome inhibitors to treat chronic inflammatory diseases. Led by an experienced management team, NodThera is combining a deep understanding of NLRP3 inhibition, pharmaceutical neuroscience expertise and precision molecular chemistry. Its two lead clinical candidates are oral, small molecule NLRP3 inflammasome inhibitors, which have demonstrated differentiated, potentially best-in-class clinical profiles with significant anti-inflammatory effects and the ability to penetrate different areas of the brain, offering distinct opportunities to treat multiple indications. The company is backed by top-tier investors, including 5AM Ventures, Blue Owl Capital, Epidarex Capital, F-Prime Capital, Novo Holdings, Sanofi Ventures, and Sofinnova Partners. NodThera is headquartered in Boston, MA, with additional operations in Cambridge, UK, and Seattle, WA. For more information, visit www.nodthera.com.