A long-term human trial has found that a discontinued drug halved the presentation of early-onset Alzheimer's disease in people with a genetic predisposition to the devastating condition. Right now, symptoms are almost 100% likely to develop in patients between the ages of 30 and 65.
In a groundbreaking study led by the Washington University School of Medicine (WashU Medicine), 73 individuals with the telltale inherited gene variants, who had already been enrolled in experimental treatment research, were given either ganternerumab, another drug or a placebo. Gantenerumab, a drug developed by Roche, was the company's big hope a few years back but failed to meet its benchmarks in its pivotal Phase III trial. The drug, which targets amyloid plaque buildup, fell short of expectations and added fuel to the theory that these plaques may be overstated in how responsible they are for the onset of Alzheimer's.
The inherited genetic mutations cause the buildup of plaque in the brain and all but guarantees that it's not if, but when, Alzheimer's symptoms begin. It commonly develops in people in their 40s and 50s, but can present in individuals as young as 30. While, let's face it, none of us are going to live forever, this genetic combination is ultimately an early death sentence.
In the study, a subset of 22 individuals with no cognitive issues and who received ganternerumab for an average of eight years, the experimental treatment slashed their risk of early-onset Alzheimer's from almost 100% to 50%. For some, 50/50 odds may not sound like a success – but one in two people having their cognitive decline put on hold is a massive deal.
“Everyone in this study was destined to develop Alzheimer’s disease and some of them haven’t yet,” said senior author Randall J. Bateman, MD, Professor of Neurology at WashU Medicine. “We don’t yet know how long they will remain symptom-free – maybe a few years or maybe decades. In order to give them the best opportunity to stay cognitively normal, we have continued treatment with another anti-amyloid antibody in hopes they will never develop symptoms at all. What we do know is that it’s possible at least to delay the onset of the symptoms of Alzheimer’s disease and give people more years of healthy life.”
The ongoing Knight Family DIAN-TU-001 study began in 2012 to assess anti-amyloid therapeutics as Alzheimer's prevention. In the trial, some participants had mild cognitive issues, while others had none. The full extent of the benefits of the maligned Roche drug are still to be known; many participants who had been given a placebo also had not yet shown signs of cognitive decline. As such, everyone was able to extend the trial – and this time all participants received ganternerumab, with a related external study (which ultimately saw the drug discontinued before the research reached its anticipated three-year period) serving as the control group.
Ultimately, the cohort who had taken the drug in both the initial trial and the extension showed the strongest results, suggesting that long-term treatment well before symptoms are most likely to develop could be key to ganternerumab's success. It was among this group, who has taken the drug continuously for at least eight years, that had the 50% success rate.
Ganternerumab, however, does come with the risk of a side effect known as amyloid-related imaging abnormalities (ARIA), which in most cases will be unnoticeable to the patient and resolve itself. However, for some it's more serious and, although rare, has been deadly. In this study, higher doses of ganternerumab over the longer period resulted in higher rates of ARIA (30%). While there were no deaths, two participants had to discontinue treatment.
As the trial continues, participants in the extended study are now receiving lecanemab, due to the discontinuation of ganternerumab in late-2022. It's another anti-amyloid treatment, which was approved by the Food and Drug Administration in 2023 to slow the advancement of the disease in those who had already begun to show signs of cognitive decline. And this stage of the trial is not restricted to early-onset Alzheimer's disease but all forms.
However, for the trial to continue and conclude, WashU Medicine is waiting on news of a grant application from the National Institutes of Health (NIH).
“If late-onset Alzheimer’s prevention trials have similar results to the DIAN-TU trials, there soon could be Alzheimer’s preventions available for the general population,” Bateman said. “I am highly optimistic now, as this could be the first clinical evidence of what will become preventions for people at risk for Alzheimer’s disease. One day soon, we may be delaying the onset of Alzheimer’s disease for millions.”
While gantenerumab is no more, adjacent anti-amyloid drugs may still prove their worth as preventative drugs.
“These exciting preliminary findings hint very clearly at the potential role of lowering beta amyloid in prevention of Alzheimer’s disease,” said Maria C. Carrillo, Alzheimer’s Association chief science officer and medical affairs lead. “The Alzheimer’s Association looks forward with great anticipation to replication, extension and expansion of this genuinely unprecedented and groundbreaking research, and we have made a significant investment in ensuring these important scientific questions can be investigated. Discoveries like this convincingly illustrate why it is so important for research into Alzheimer’s and all diseases that cause dementia to continue, expand and accelerate.”
The study was published in the journal The Lancet Neurology.
Source: WashU Medicine
