Viewing Alzheimer’s Disease as Immunological Offers New Approaches

 In December 2020, a $300 million increase for Alzheimer’s Disease (AD) and dementia research funding at the National Institutes of Health was signed into law, bringing the total of annual federal funding to $3.1 billion for researchers diligently working to understand the etiology of the disease and how it can be effectively treated.

Many research dollars, federal or otherwise, have been poured into developing therapeutics which target amyloid and tau “plaques and tangles”, accumulations of proteins which promote the cause of the neuronal death and atrophy seen in the more than six million Americans that live with AD.

“Biopharma has spent 30 years and billions of dollars repeating trials targeting amyloid and tau and keep failing – but they keep trying,” Raymond (RJ) Tesi, M.D., CEO of INmune Bio said in an interview with BioSpace. “INmune Bio views Alzheimer’s as an immunologic disease with neurologic symptoms. When AD is seen as an immune disease, it changes the drug discovery process and the design of clinical trials – and may provide new hope to patients and caregivers.”

According to the Alzheimer’s Association, aging is the greatest known risk factor for developing AD and other dementias, although aging itself is not a direct cause of the disease. Increasingly, researchers are providing evidence that inflammation could be a “mechanistic pillar” that age-related diseases share.

The term inflammaging refers to chronic, systemic, low-grade inflammation that develops as people age in the absence of overt infection. The direct cause of inflammaging is likely due to a combination of factors, with researchers suggesting a variety of hypotheses for the phenomenon. These include the accumulation of self-debris from cellular injury, persistent production of reactive molecules by immune cells that eventually damages cellular elements and harmful products produced by oral and gut microbiota. No matter the cause, inflammaging has been associated with a host of diseases including atherosclerosis, heart disease, cancer and AD. According to Tesi, elements of inflammaging can be first measured in the fourth decade of life and elements continue to increase every decade thereafter.

Although there are many mechanisms proposed that contribute to neuroinflammation and damage caused by inflammaging in the brain, INmune Bio has focused on tumor necrosis factor (TNF).

“One of the key measures of chronic inflammation of aging is increased soluble TNF levels in the blood. We suspect increasing levels of TNF correlate with destructive neuroinflammation,” Tesi said.

What makes TNF such a vicious proponent of pathophysiology in AD patients? First, it’s important to know that destructive neuroinflammation causes both nerve cell death and synaptic dysfunction, which are the two main contributors to cognitive decline in patients with AD. Therefore, treatments for the disease should focus on a target that causes both nerve cell death and synaptic dysfunction.

TNF fits the bill. Soluble TNF, a multifunctional cytokine that is secreted by inflammatory cells, is the only cytokine that kills neurons. Not only that, but soluble TNF promotes glial dysfunction which causes synaptic pruning, or synaptic dysfunction, and it paralyzes microglial cells and stops their phagocytic function, or their ingestion of cellular debris. Additionally, the cytokine is frequently reported to be elevated in AD patients.

INmune Bio is developing XPro1595 (XPro) to tackle TNF head-on. XPro1595 is a next-generation inhibitor of TNF, which can decrease destructive neuroinflammation in an attempt to slow or stop the progression of cognitive and psychiatric symptoms that develop in AD patients as the results of destroyed synapses and disconnection in nerve cell communication. The drug’s main mechanistic action is neutralizing soluble TNF.

In April, the company announced that it had dosed its first patient in a Phase II clinical trial evaluating XPro as a treatment for cognitive decline and other deficits in brain functioning in patients with AD, following a largely successful Phase I trial.

“Target engagement for XPro was successful as it decreased destructive neuroinflammation using three different measures. Downstream benefits of target engagement were real. There was increased nerve cell survival and improvement in synaptic function,” Tesi said. “XPro improved remyelination. Demyelination has not been considered an important part of AD, but it is a prominent part of CNS dysfunction in all neurodegenerative disease.” He added that several patients also had improved cognitive function after six weeks of receiving the therapy. 

In September 2021, INmune Bio shared results from the trial, which showed that patients dosed had a 46% reduction in a biomarker for AD, CSF pT217. Additionally, the drug was found to be safe and tolerated in AD patients. The recently launched Phase II trials will evaluate whether the decreases in neuroinflammation correlate with a restoration or improvement in cognitive functioning.

Drugs like XPro which target the underlying neuroinflammation that lead to neurodegenerative diseases are likely to become more important and needed as the effects of COVID-19 infection on the brain are further researched.

 “There are data that COVID-19 patients in the ICU have shown evidence of accelerated

cognitive decline after discharge,” Tesi said. “One paper suggests it is like fast forwarding by 20 years. In general, I believe there is a very real risk of increased AD in the next 40 years or so due to COVID-19 infections. I hope I am wrong, but time will tell.” He also noted that data involving patients who did not end up in the ICU from COVID-19 and cognitive decline will be telling as researchers investigate such patients.

Notably, XPro can be used to treat any CNS disease where destructive neuroinflammation is part of the pathophysiology. In fact, INmune Bio boasts over 60 publications involving dozens of CNS diseases, including Parkinson’s Disease, depression, spinal cord injury and multiple sclerosis. In addition to the AD program, the therapeutic is also being developed for depression and amyotrophic lateral sclerosis (ALS).

Tesi noted that XPro can be used to treat pathologies beyond CNS disease.

“We have announced a program in oncology and there are important roles of TNF in autoimmune, cardiovascular, pulmonary and metabolic disease. When given unlimited resources, a drug developer could spend two lifetimes developing XPro for all of the places it can make a difference,” he said.

Importantly, INmune Bio is not only trying to treat AD but also prevent it. Three key innovations are at the core of this goal. The company uses “enrichment criteria” to enroll patients with destructive neuroinflammation, allowing clinical trials to be smaller and move more quickly with less risk of failure. INmune Bio also uses a different clinically relevant endpoint which is more sensitive to cognitive changes in patients with mild AD, rather than the traditional endpoint developed for patients with moderate or severe AD. And finally, the company’s focus on neuroinflammation paves the way for a new approach to preventing AD.

“These three innovations give XPro a fighting chance for success,” Tesi said. “Time will tell if we are right. Time will tell if our confidence is misplaced. For the benefit of humanity, I hope we are right.”    

https://www.biospace.com/article/viewing-alzheimer-s-disease-as-immunological-offers-new-approaches/