Alzheimer’s Drug Discovery Foundation Comment on TRAILBLAZER-ALZ Results

Eli Lilly and Company presented detailed results of its phase 2 TRAILBLAZER-ALZ study today, showing that its investigational drug donanemab met its primary endpoint, slowing decline in a combined measure of cognition and daily function by 32% in patients with symptomatic early-stage Alzheimer’s disease. Donanemab also cleared amyloid plaques and slowed accumulation of tau tangles in the brains of treated patients. The results were presented at the 15th International Conference on Alzheimer’s & Parkinson’s Diseases (AD/PD 2021) and published simultaneously in the New England Journal of Medicine.

“The combination of changes in Alzheimer’s biomarkers and the slowing of clinical symptoms of the disease seen in this study is promising,” said Howard Fillit, M.D., ADDF Founding Executive Director and Chief Science Officer. “We are encouraged by today’s news, and if these results are confirmed in the larger study now in progress, donanemab could offer the potential for a disease-modifying therapy that can help patients maintain cognitive abilities and their independence longer. We eagerly await results from future trials.”

Secondary outcomes included four individual tests that measure patients’ memory and functional abilities. There were positive trends in each of these measures, with nominal statistical significance compared to placebo at different time points in the trial.

The TRAILBLAZER-ALZ study used biomarkers to enroll patients and monitor physiological changes in their brains. Amyvid™ PET scan, which was developed with early support from the ADDF, was used to measure amyloid plaques, and Tauvid™ PET scan was used to measure tau tangles.

The study proved that donanemab hit its intended target because amyloid plaques were cleared from patients’ brains. Six months after starting treatment, 40% of donanemab-treated patients achieved amyloid negativity and by 18 months this increased to 68%. Donanemab has a unique target—a modified form of beta amyloid called N3pG. Treatment also slowed but did not reverse levels of tau in specific regions of the brain. Researchers believe it is possible tau changes may lag compared with amyloid changes, meaning the 18-month follow up in this study was not long enough to detect a reduction in tau tangles.

“This is a well-designed trial that used biomarkers to enroll and follow patients most likely to benefit from therapy,” said Dr Fillit. “It is a “goldilocks strategy,” keying in on patients who are definitely in the early stages of Alzheimer’s disease, with certain levels of amyloid and tau in the brains that could be affected by treatment with donanemab.”

Positive results from the ongoing donanemab clinical trial would support the amyloid hypothesis, which has been a focus on Alzheimer’s research for many years. But even so, Alzheimer’s is a complicated disease and a combination of drugs addressing multiple targets will be needed to effectively treat it. Many of the new treatments being investigated are focused on targets associated with the biology of aging.

The goal is to develop drugs that work on many different pathways, including those beyond amyloid, that are implicated in Alzheimer’s disease. There are more than 120 drugs currently in clinical trials that address novel targets including misfolded proteins, inflammation, vascular problems, genetic mutations, and age-related changes associated with Alzheimer’s.

“These latest findings, along with several other recent trial reports, and more anticipated this year, are the results of years of progress in basic science, drug discovery and development,” added Dr. Fillit. “This is a defining time as progress is moving us closer to more effective drugs for the prevention and treatment of Alzheimer’s disease and related dementias, bringing renewed hope to many patients and their families.”