INmune Bio Inc. (NASDAQ: INMB) has announced the publication of a significant study in Cell Reports, demonstrating that its drug candidate, XPro™, promotes remyelination in animal models of demyelinating diseases. The research, led by Dr. Leslie Probert at the Hellenic Pasteur Institute, reveals that XPro1595 converts microglia from damaging cells to reparative cells by selectively neutralizing soluble TNF (sTNF). This mechanism has potential therapeutic implications for various central nervous system (CNS) diseases, including Alzheimer's Disease (AD), where myelin loss significantly impairs neuronal function.
The study, titled Microglia Regulate Cortical Remyelination via ΤNFR1-Dependent Phenotypic Polarization, highlights the critical role of microglia in both demyelination and remyelination processes. Dr. Probert, the senior author of the publication, stated, "Our data identify solTNF as a critical cytokine checkpoint that converts microglia from a reparative, remyelinating cell to a damaging, demyelinating cell. These data suggest that blocking soluble TNF is a promising strategy for treating demyelinating diseases."
Demyelination in Alzheimer's Disease
Demyelination, the loss of the myelin sheath that insulates nerve fibers, is increasingly recognized as a significant factor in the pathogenesis of Alzheimer's disease. Research indicates that demyelination occurs in brain regions crucial for cognitive function in AD patients and is often associated with amyloid-beta (Aβ) plaques. Changes in myelin structure can be detected even before the onset of typical AD symptoms, suggesting that it may serve as an early biomarker for the disease. Advanced imaging techniques have revealed alterations in myelin density and integrity in individuals at risk for AD.
The mechanisms underlying myelin damage in AD involve oligodendrocyte dysfunction, which can lead to the breakdown of myelin sheaths. This breakdown not only affects neuronal health but may also contribute to the accumulation of Aβ, creating a feedback loop that exacerbates both myelin loss and neurodegeneration. Studies utilizing techniques like myelin water fraction imaging have shown significant reductions in myelin integrity among individuals with mild cognitive impairment and dementia, reinforcing the notion that demyelination is prevalent in AD.
XPro1595: A Potential Therapeutic Approach
XPro1595, INmune Bio's lead drug candidate, is designed to selectively neutralize soluble TNF (sTNF), a key driver of inflammation and immune dysfunction in various diseases. By blocking sTNF, XPro1595 aims to modulate the activity of microglia, shifting them from a pro-inflammatory, demyelinating phenotype to a reparative, remyelinating phenotype. This approach could potentially address a critical unmet need in Alzheimer's disease by promoting myelin repair and restoring neuronal function.
RJ Tesi MD, CEO of INmune Bio, commented on the new data, stating, "Demyelination is a core mechanism of neurodegeneration that has been overlooked in Alzheimer's disease, despite the evidence that it’s a critical element of the disease's pathology. These new data further support the potential for XPro1595 in neurodegenerative diseases by restoring glia function to improve key components of neurodegeneration at multiple levels, including restoration of synaptic function, remyelination, and ceasing cell loss."
Clinical Development and Future Outlook
INmune Bio anticipates reporting top-line cognitive results from its ongoing blinded randomized Phase II trial in early AD patients in the first half of 2025. This trial is evaluating the safety and efficacy of XPro1595 in improving cognitive function and reducing neuroinflammation in patients with mild Alzheimer's disease. The results of this trial will provide further insights into the therapeutic potential of XPro1595 in addressing the underlying pathology of Alzheimer's disease.
