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This Phase 1b clinical trial will explore the safety and efficacy of a drug- XPRO1595 as a strategy to combat brain inflammation in individuals with Alzheimer’s.
Raymond Tesi
INmuneBio Inc.
La Jolla, CA - United States
Background
The immune system consists of many different cell types whose interactions and functions govern the immune response in the body. Tumor Necrosis Factor (TNF) is an important immune signaling molecule that helps recruit immune cells to the sites of damage or infection and help turn on immune cells that are not active. However, excessive TNF can cause immune cells to be too active, cause abnormal inflammation and lead to damaged cells. People with Alzheimer’s have elevated levels of TNF in their brains, which could contribute to death of nerve cells in the brain and cause existing cells to not communicate. This may contribute to cognitive impairment. Previous studies in animal models have shown that TNF’s involvement in activation of immune cells in the brain can result in nerve cell death and too much activity of another process that eliminates excess nerve cells and connections - activities commonly seen increased in Alzheimer’s. However, not all TNF is bad; some TNF molecules, called trans-membrane TNF may protect the nerve cells and release signals that may remove toxic debris and help to keep the brain healthy.
Despite the evidence, currently approved drugs that block TNF activity are not ideal candidates for Alzheimer’s. The physical size of the drugs keeps them from effectively crossing from the bloodstream into the brain, and many drugs do not selectively block the TNF molecules, which disturb the delicate balance of TNF activity in the brain. Animal studies using XPRO1595- a compound that is designed to selectively block abnormal TNF activity in the brain while preserving the healthy TNF response- demonstrated improved cognition, enabled removal of toxic debris in brain cells, and stabilized the immune system thereby preventing inflammation.
Research Plan
Dr. Tesi and team plan to use a compound called XPRO1595 to target the bad TNF -blocking its abnormal activity in a specific way. Dr. Tesi will enroll people with moderate Alzheimer’s that have confirmed elevated levels of beta-amyloid as well as high levels of biomarker C-reactive protein (CRP) in their blood.
Elevated CRP levels in the blood suggest that there is also increased brain inflammation; Tesi and colleagues suggest that people with elevated levels of CRP in their blood may be more likely to respond better to drugs targeting TNF and specifically to XPRO1595. By identifying volunteers with increased CRP levels, Dr. Tesi and his team hope to see an increase in the benefit of XPRO1595 over 12 weeks.
Impact
This study is the first step towards a larger Phase 2 clinical trial, which could establish the effectiveness of the drug, XPRO1595 in Alzheimer’s. This Phase1b study will provide key data to support the use of CRP as a biological marker in blood, for measuring brain inflammation as well as how CRP relates to Alzheimer’s cognitive symptoms, and markers like amyloid and tau.
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