Alzheimer’s disease research appears to be hitting its stride, thanks to recent therapeutic advances in drug development and the emergence of biomarkers to detect the condition. “All the pieces of the puzzle of precision medicine, which is already quite common in oncology, are now in place,” said Hartmuth Kolb, vice president, neuroscience biomarkers and R&D global imaging at Johnson & Johnson Innovative Medicine.

There’s urgency to stem the tide of the disease, which not only can be heart-wrenching for patients and caregivers, but also its financial burden. The cost of caring for individuals living with Alzheimer’s or other dementias in the U.S. could hit $345 billion in 2023, according to the Alzheimer’s Association, marking a $24 billion increase over the prior year​.

Aiming to stop the cascade

FDA has approved two amyloid-targeting antibodies, lecanemab and aducanumab, which slow the progression of the disease. Yet, the battle is far from won. “We think it will take more than just anti-amyloid treatment to stop the disease,” Kolb said.

The goal of the precision medicine approach in Alzheimer’s disease is to match patients to a treatment based on what’s happening in their brain potentially years before symptoms develop. Because amyloid and tau proteins begin accumulating years before symptoms occur, an ideal approach would be to spot the aggregation at the earliest possible stages and halt its aggregation. Future therapies could minimize neuronal damage and delay or even prevent the onset of cognitive impairments associated with Alzheimer’s disease.

For now, researchers’ improved understanding of the disease can assist with clinical studies. “In neuroscience, it’s very hard to probe the brain. But now, in the case of Alzheimer’s disease, we know a lot about the disease pathology, how it develops, and how the pathology is related to the cognitive and functional impairment. We can now reliably identify patients, stage them, assign them to clinical trials, and also monitor their progression, objectively using imaging tools,” Kolb said.

J&J’s Alzheimer’s approach

Johnson & Johnson has long approached Alzheimer’s from a variety of angles, Kolb said. “We’ve worked on anti-amyloid and we have now focused more on tau, which is more closely linked to the actual symptoms of cognitive decline,” he noted.

J&J’s pipeline currently includes seltorexant, now in phase 2 trials, which targets probable Alzheimer’s with clinically significant agitation/aggression. Another phase 2 candidate, anti-phospho-tau mAb (JNJ-63733657), is a humanized IgG1 monoclonal antibody that zeroes in on the tau pathology associated with Alzheimer’s.

The company is also developing VAC20121 (also known as ACI 35), in partnership with AC Immune, which is now in phase 1b/2a trials. The therapy, designed to stimulate antibodies against extracellular phosphorylated tau, aims to thwart the spread of tau pathology. “We inject it and it binds to the pathological tau,” Kolb said. The accumulation of tau in the brain is a bit like a seeding process, where the presence of the protein appears to attract more tau over time. “The theory is, if we capture that seed with the antibody, then we prevent the spreading and hopefully the disease progression,” he said.

VAC20121, an active immunotherapy, is vaccine-like, where the aim is to spur the immune system to target the pathological tau. “The goal is the same — to halt the spread of the disease,” Kolb said. “We are able to track that with imaging. And that is why I am so excited.”

Toward a global screening paradigm

Kolb stresses the need for a global screening paradigm “similar to what we get when we do an annual workup with a physician.” Given the aging population of the U.S. and throughout much of the world, early detection could emerge as a strategy in defraying the tremendous treatment costs linked to the disease. With early specialized treatment, the hope is to avoid or at least slow down the entire cascade of events that follows an early diagnosis.

Recent advances in neuroimaging, biomarker assays and diagnostic tests based on amyloid-beta and tau protein concentrations could lead to new treatment paradigms for Alzheimer’s. Kolb, for one, was instrumental in the development of the Tau PET tracer, now FDA-approved for imaging aggregated tau neurofibrillary tangles in Alzheimer’s patients. He also helped pioneer the p217Tau blood plasma assay, a peripheral biomarker for the disease.

Ultimately, mainstream diagnostics could encompass tests such as the p-tau217 blood test. “The hope is that in a few years, this test could be globally available, facilitating population-based screening,” Kolb said. “If you test positive, then there’ll be a treatment waiting for you. That’s the future we’re aiming for.”

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Filed Under: Brain Breakthroughs, Drug Discovery, Drug Discovery and Development, Neurological Disease
Tagged With: Alzheimer's research, amyloid-targeting, biomarkers, clinical trials, drug development, precision medicine, tau pathology
 

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