For nearly three decades, the amyloid cascade hypothesis has dominated the field of Alzheimer’s disease. The main tenant of this hypothesis is that the accumulation of amyloid plaques physically blocks the connections between neurons resulting in loss of communication between neurons (synaptic dysfunction) and neuron cell death. INmune Bio believes the synaptic dysfunction and cell death observed in Alzheimer’s disease is caused by chronic neuroinflammation, the hallmark of dysregulated microglia. The company’s treatment strategy is to target the neuroinflammation that is the cause of nerve cell death and synaptic dysfunction.
No one argues that amyloid plaques are a pathologic hallmark of Alzheimer’s disease. The debate centers on whether treating those plaques is a therapeutic strategy. The failure of the many clinical trials targeting amyloid suggests that new approaches are needed. Targeting neuroinflammation as a cause of Alzheimer’s disease is one approach. This novel approach has gained support by the medical and academic community after repeated failures of anti-amyloid treatment strategies. Targeting neuroinflammation to treat Alzheimer’s disease is not as simple as just stopping chronic inflammation caused by microglial activation. The therapy must allow microglial cells to perform their critical supportive functions involved in the care and feeding of neurons and removal of the cellular debris that accumulates in the brain during normal function. A precise approach to targeting neuroinflammation has been hampered by the lack of the right drug. INmune Bio believes XPro1595 may be the perfect drug for this purpose.
INmune Bio is developing XPro1595, a novel biologic therapy that stops chronic inflammation without suppressing microglia functions that are important for brain activity. XPro1595 neutralizes soluble TNF (sTNF), the inflammatory cytokine that is the trigger for chronic inflammation in the brain. TNF biology in the brain is complicated because there are two TNF cytokines. Soluble TNF, the “BAD” TNF, facilitates the damaging inflammatory functions – nerve cell death and synaptic dysfunction. Trans-membrane TN (tmTNF)F, the “GOOD” TNF, promotes neuroprotective functions including those that drive learning and memory (plasticity and myelination). “By selectively neutralizing soluble TNF activity we eliminate unwanted neuroinflammation and cell death while sparring the critical functions of transmembrane TNF,” says Dr. Barnum, Director of Neuroscience at INmune Bio. In animal models of Alzheimer’s disease, XPro1595 improved cognition, facilitated the clearance of toxic cellular debris (amyloid), rescued neuronal communication, and normalized immune cell profiles.
The company recently received a $1M Part-the-Cloud Award from the Alzheimer’s Association to begin clinical testing of XPro1595 Alzheimer’s patients. INmuneBio is targeting Alzheimer’s disease patients that have biomarkers of chronic inflammation. They expect 35-40% of Alzheimer’s patients will be eligible to participate in the trial. “When you approach Alzheimer’s disease as an immunological disease, you have multiple biomarkers available. These biomarkers can help you identify patients that are most likely to respond to your treatment by aligning their pathology (inflammation) with the mechanism of your treatment (anti-inflammatory). As a result, you can do smaller studies, which have the potential to get to the clinic faster. Another important but less discussed benefit of using biomarkers is that you are not subjecting patients to a trial for which the likelihood of a clinical response is low. Biomarkers have not been used in this way in Alzheimer’s trials”, says Barnum.
Once enrolled in the study, INmune Bio will continue to use a novel set of inflammatory biomarkers to track the performance of XPro1595 over the course of 12 weeks. “Our approach to early phase studies is to take a small number of patients and study them intensively” says Barnum. INmune Bio will employ a suite of invasive (blood and cerebral spinal fluid) and non-invasive (neuroimaging — white matter free water measure by MRI and measurement of volatile organic compounds in expelled air — a “breath test”) measures to understand how XPro1595 treatment affects inflammation and Alzheimer’s pathology. While twelve weeks of treatment may not be long enough to see changes in cognition, it should be long enough to see changes in inflammatory biomarkers. The results of the study will help determine if a longer and larger Phase II clinical trial is warranted. According to Barnum “Ideally, the data we collect in the current study will help us design a biomarker directed, disease modification trial using a precision medicine approach that allows us to follow fewer patients for a shorter period of time.”
There are two other advantages of approaching Alzheimer’s disease as an immunologic disease. About 60% of patients with dementia have Alzheimer’s disease. By targeting patients with neuroinflammation as a cause of their cognitive decline, patients with other forms of dementia may benefit from XPro1595 therapy. Also, neuroinflammation is part of the pathology in other neurodegenerative diseases including Parkinson’s and Huntington’s Disease, MS, ALS and others. Success at targeting neuroinflammation in Alzheimer’s disease may provide clues of about treatment of these other diseases.
To learn more, visit inmunebio.com.