XPro1595 Lowers Neuroinflammation in Mild to Moderate Alzheimer’s, Interim Results Show

XPro1595, an investigational therapy by INmune Bio, can lower brain inflammation in people with mild to moderate Alzheimer’s disease, according to interim results of a clinical trial.

Specifically, the Phase 1b clinical trial (NCT03943264) shows evidence that XPro1595 decreases white matter free water, a biomarker of neuroinflammation measured by magnetic resonance imaging (MRI).

XPro1595 was designed to lower inflammation by selectively neutralizing soluble tumor necrosis factor (sTNF), an inflammatory cell signaling molecule, or cytokine, implicated in Alzheimer’s progression, without affecting TNF or TNF receptors present on cells’ membranes.

TNF levels increase among Alzheimer’s patients and mark an earlier step in progression than the characteristic clumps of misfolded proteins known as amyloid plaques, which form later in patients’ brains. Neuroinflammation has been shown to play a role in the loss of nerve signaling, nerve cell death, cognitive impairment, and plaque formation.

The Phase 1b trial is enrolling adults with mild to moderate Alzheimer’s disease who show signs of inflammation (assessed via blood test) at six locations in Australia. More information on enrollment can be found here.

Patients receive either a low (0.3 mg/kg) or high (1.0 mg/kg) dose of XPro1595 injected subcutaneously (under the skin) once a week for 12 weeks.

The study intends to identify Alzheimer’s patients who are most likely to benefit from XPro1595 treatment while evaluating its safety.

The trial will also look at changes in the levels of C-reactive protein, which is produced by the liver in response to systemic inflammatory molecules like sTNF; measure changes in the levels of other inflammatory cytokines as well as amyloid beta and tau in both the blood and cerebrospinal fluid (the fluid that surrounds the brain and spinal cord); and assess XPro1595’s effects on cognitive and neuropsychiatric symptoms.

Researchers have now compared results from six patients treated with XPro1595 to those from 25 Alzheimer’s patients from the Alzheimer’s Disease Neuroimaging Initiative (ADNI). The ADNI is a long-running study with a large collection of clinical, imaging, genetic, and biochemical biomarker information.

Over a 12-week period, whole brain inflammation increased by 5.1% in the ADNI patients, compared to 1.7% in patients treated with the high dose of XPro1595 and to a 2.3% decrease in those treated with the lower dose.

The difference between patient groups grew more pronounced when only the white brain matter was compared. Here, patients receiving XPro1595 showed a 40.6% reduction in neuroinflammation in a major white matter bundle called the arcuate fasciculus. In contrast, neuroinflammation increased by 4.6% in this structure among the ADNI patients.

The arcuate fasciculus connects the Broca’s and Wernicke’s brain areas, two key language processing centers, and is important for short-term memory.

“We are extremely encouraged by these findings at such an early stage in our clinical trial,” CJ Barnum, PhD, director of neuroscience at INmune, said in a press release. “Not only do we see a clear reduction in neuroinflammation, but we also know where in the brain this is occurring, which may inform us on the domains of cognition that might be affected.”

With this clinical trial, INmune also hopes to identify the dose of XPro1595 to be used in a larger Phase 2 study.

“The preliminary results from INmune Bio’s Phase Ib study add to the growing enthusiasm for tackling neuroinflammation in the treatment of Alzheimer’s disease,” said Sharon Cohen, MD, neurologist and medical director of Toronto Memory Program, who was not involved with the clinical trial.

“Furthermore, MRI assessment of free water content in the brain holds promise as an exciting surrogate marker for tracking the impact of such treatment,” she said.