Research into Alzheimer’s disease is shifting from amyloid plaque and tau protein to neuroinflammation, white matter changes and insulin resistance.
INmune Bio President and CEO Dr. R.J. Tesi, M.D./Courtesy INmune Bio
Research into Alzheimer’s disease is shifting from amyloid plaque and tau protein to neuroinflammation, white matter changes and insulin resistance. The reasons include failures in amyloid and tau therapeutics and new findings that are helping to uncover the breadth of pathology in the onset and progression of this neurodegenerative condition.
For example, the University of Pittsburgh School of Medicine showed in August 2021 that inflammation in the brain drives the progression of Alzheimer’s disease from its onset. The data is finding its way into an increasing number of company-sponsored research programs, “driven by some well-heeled companies and venture capitalists,” Dr. R.J. Tesi, M.D., CEO, president, and acting CMO for INmune Bio, told BioSpace.
Alzheimer’s disease has long been associated with the brain’s gray matter. Now, multiple research reports indicate that white matter abnormalities – and therefore, axonal integrity and neuronal signaling – also are important components of the disease. “White matter tracts are superhighways of axonal fibers that connect the parts of the brain that must work as a unit,” Tesi said. “It turns out that white matter gets sick first. Imeka, a Canadian neuroimaging company combining diffusion imaging and AI to map white matter integrity, can quantify it and follow disease progression or therapeutic changes non-invasively with what it calls a virtual biopsy.”
Research into the correlation between insulin resistance and Alzheimer’s disease is coming to the fore, too. “Think about it. The brain’s primary fuel source is glucose, so insulin resistance could compromise the brain’s ability to work. Targeting insulin resistance may be a viable strategy for improving cognition.” In fact, Alzheimer’s disease and type 2 diabetes mellitus each feature neuronal degradation, oxidative stress and inflammation. Tesi suggested that inhibitors like GLP-1, which Novo Nordisk is investigating to treat obesity, may be useful therapies.
Additionally, “a number of companies are interested in the role of lysosomal and mitochondrial dysfunctions,” as well as lipid abnormalities in the onset and progression of Alzheimer’s disease. “There’s a lot of new, innovative research going on now,” Tesi said.
Anti-amyloid therapies were a first step in addressing Alzheimer’s disease, but will not be the ultimate solution. “Anti-amyloid therapies aren’t that powerful,” Tesi said. “They slow the rate of decline by 20 to 30%. So, patients taking these therapies are still declining, but not as fast. Merely slowing the decline is an abysmal goal.” Industry’s goal should be to halt progression.
The discovery of biomarkers for brain health is a tremendous catalyst for innovation. Until relatively recently, they weren’t available. “Alzheimer’s disease,” Tesi stressed, “is absolutely not the same for every person.”
The availability of biomarkers means trials that may have failed under an “all-comers” approach now have an opportunity to match participants to a therapy, and thus improve the chances of favorable outcomes. At INmune, which uses biomarkers, “we expect – at best – that only half of the patients will be eligible for our therapy. The goal is to help the people you can help, then expand that circle to include the patients you have not yet included in your trials.
“The biomarkers we use should not yet be a surrogate for efficacy,” he cautioned. “To get XPro approved, we still use ‘effect on cognition’ as the primary endpoint. We use biomarkers to enrich specific patient populations. This approach is novel today, but in three years, everyone will be doing this in CNS drug development.”
Drug developers seem to be getting some assistance thanks to changes at the U.S. Food and Drug Administration. As the science behind Alzheimer’s disease is better understood, the FDA is beginning to support more innovation and accept biomarker-related data as valid data points. It’s also accepting more risk for intractable diseases. Its controversial approval of Biogen’s aducanumab – the first drug approved for Alzheimer’s in 18 years – is a prime example. This is similar to the approach the oncology division has used for years, Tesi pointed out.
In developing XPRO1595™, which addresses chronic inflammation by targeting soluble tumor necrosis factor, INmune “made a conscious decision to create an oncology-like drug development strategy,” Tesi said. That meant adopting a biomarker-directed, step-by-step process that advances at a steady pace.” The drug is in Phase I clinical trials.
Using a baseball analogy, “we’re not trying to hit home runs. We’re trying to hit a series of singles. We have hit the first single – Xpro decreases neuroinflammation. Now we must hit the second single and prove that if you control neuroinflammation, you make a difference in cognition. We must prove this in a blinded, randomized trial. We hope to show we are stabilizing the disease and not just slowing the rate of cognitive decline.”
A Phase II trial begins enrolling participants this quarter. Plans call for enrolling 200 patients, of which two-thirds will receive XPro. The endpoint will be cognitive improvement measured by the Early AD/MCI Alzheimer’s Cognitive Composite (EMACC) assessment.
