Drugs for Alzheimer’s disease in clinical trials reduce molecular markers of the disease

The Alzheimer’s disease drug in clinical trial is a phase 2/3 clinical trial led by researchers at the University of Washington School of Medicine in St. Louis through the Alzheimer’s network, which presents molecular markers for the disease without showing evidence of cognitive benefit. Reduced and suppressed neurodegeneration in the brain-Clinical Trial Unit (DIAN-TU). These results led the study leader to provide participants with a drug known as gantenumab as part of an exploratory, open-label extension. Researchers continue to monitor changes in Alzheimer’s disease readings in participants taking the drug.

The DIAN-TU study (ClinicalTrials.gov identifier: NCT01760005), presented at Nature Medicine on June 21, includes Gantenerumab manufactured by Roche and its US affiliate Genentech and Solanezumab manufactured by Eli Lilly and Company. We evaluated the effects of the two investigational drugs. .. – People with rare hereditary early-onset Alzheimer’s disease, known as dominantly inherited Alzheimer’s disease or autosomal dominant Alzheimer’s disease. Such people are born with mutations that cause Alzheimer’s disease and experience memory and thinking loss from their 30s or 40s.

Gantenerumab had a significant impact on the biomarkers of Alzheimer’s disease. The ability of the drug to successfully shift multiple Alzheimer’s disease biomarkers indicates that it has a positive impact on the disease process. The effect was strong enough that we started an open-blind extension of the study, so participants have the opportunity to stay on the drug while we continue to study it. “

Randall J. Bateman, MD, Principal Investigator, DIAN-TU Director, Charles F. and Joan Knight, Professor of Neurology, University of Washington

Over the past few decades, scientists have stitched together the changes that accompany the development of Alzheimer’s disease. This process takes over 20 years. First, the protein amyloid beta begins to form amyloid plaques in the brain. The tau and neurofilament light chain levels then rise in the cerebrospinal fluid that surrounds the brain and spinal cord, causing the brain to begin to contract. Next, tau protein tangles are formed in the brain. Only then will people with this illness begin to show signs of amnesia and confusion.

In this study, 52 patients were randomized to gantenerumab, reducing the amount of amyloid plaque in the brain, lowering soluble and phosphotau, and slowing the rise in neurofilament light chain levels in cerebrospinal fluid. It was. The neurofilament light chain is a marker that reflects neurodegeneration. Overall, the safety profile of gantenumab in this study was consistent with the profile of other clinical trials of the investigational drug, and no new safety issues were identified.

The primary endpoint of the DIAN-TU study was the prevention or delay of cognitive decline in people who are almost certain to develop Alzheimer’s disease due to genetic mutations. Neither drug met the primary endpoint, but with little or no decline in cognitive function, it was not possible to determine the thought and memory effects of participants in the study without symptoms. The study also failed to assess the efficacy of high-dose drugs escalated to desirable levels later in the study after protocol modifications. Participants who received gantenerumab, prompted by observations from other studies of gantenumab, started at low doses and began to increase to a five-fold higher target dose in about half of the trial.

However, as a secondary endpoint, the study also evaluated the effect of the drug on the molecular and cellular signs of Alzheimer’s disease. Gantenerumab has shown potential benefits in these measures.

“The results of these biomarkers suggest that gantenerumab had a positive effect on the targets and downstream markers of dominant hereditary Alzheimer’s disease,” said Rachel, Global Head of Neurodegeneration at Roche and Genentech. Dr. Doudi said. “We endorse Gantenerumab’s ongoing scientific research in an exploratory open-label extension trial at the University of Washington, based on learning from DIAN-TU-001, and continue this among industry, academia, and patients. Thank you for your participation in close cooperation. Addressing the complex challenges of Alzheimer’s disease. We are encouraged to see progress and look forward to the continued progress of the people with Alzheimer’s disease. . “

The study followed 144 participants for up to 7 years. The average follow-up was about 5 years. All participants have a genetic mutation that causes a type of Alzheimer’s disease at an early age. The researchers recruited participants who were expected to develop symptoms within 15 years, or who had already exhibited very mild amnesia and cognitive decline at the start of the study. In most cases, their brains were already showing early signs of illness. Participants were randomly assigned to receive solanezumab, gantenumab, or placebo.

“While this trial focuses on people with rare mutations, successful drugs in this population are promising candidates for preventing or treating the more common forms of Alzheimer’s disease in the elderly. The destructive molecular and cellular processes of the brain are both types of disease. “