The trial tested the effect of donanemab compared to a placebo in 1,182 patients with early symptomatic Alzheimer’s disease. The patients also had intermediate levels of a protein called tau in the brain – a sign of less advanced Alzheimer’s disease. According to the results, donanemab slowed clinical decline by 35% over 18 months, measured using a metric called the integrated Alzheimer's Disease Rating Scale (iADRS).
"We are extremely pleased that donanemab yielded positive clinical results with compelling statistical significance for people with Alzheimer's disease in this trial,” said Daniel Skovronsky, Lilly's chief scientific and medical officer. “This is the first phase 3 trial of any investigational medicine for Alzheimer's disease to deliver 35% slowing of clinical and functional decline."
Tau and amyloid in Alzheimer’s disease
Alzheimer’s disease is the most common cause of dementia, leading to the death of brain cells and a progressive deterioration in the cognition of older adults. The condition is linked to high levels of a peptide called beta-amyloid (Aβ), which can aggregate into plaques and trigger harmful inflammation in brain tissue. Donanemab targets a form of Aβ in plaques, and is designed to boost the clearance of the plaques from brain tissue.
Pathological forms of tau in the brain are another sign of advanced Alzheimer’s disease. Lilly additionally enrolled 552 patients in the trial that had high levels of tau in the brain and predicted that they would respond less strongly to donanemab than those with lower levels of tau. When pooling the patients together (1,736 patients), donanemab slowed iADRS-measured cognitive decline by 22%.
While around 24% of participants developed a common side effect in Alzheimer’s treatments known as amyloid-related imaging abnormalities (ARIA), the majority of the cases were mild to moderate and managed in the trial.
“This clinical trial is a real breakthrough, demonstrating a remarkable 35% slowing of cognitive decline in Alzheimer’s patients with high amyloid-beta but low tau burden. I believe this therapy has the potential to significantly improve patients’ and families’ lives today,” said Marc Busche, UK Dementia Research Institute Group Leader at University College London (UCL), who wasn’t involved in the development of donanemab.
“Notably, the beneficial effect was smaller in those with high tau levels, suggesting a potential interaction between these pathogenic proteins. Looking ahead, I anticipate that concurrently targeting amyloid-beta and tau could lead to even better patient outcomes, making this a crucial focus for future research and the next generation of clinical trials.”
Race to the market
Prior to these promising results, Lilly had hit setbacks in the treatment of Alzheimer’s disease. Over the last several years, its earlier antibody candidate called solanezumab hit multiple clinical disappointments. And in January 2023, the US Food and Drug Administration (FDA) declined to grant donanemab accelerated approval. With the latest positive results in hand, Lilly plans to apply for the traditional approval of donanemab by the U.S. FDA in the coming months.
After decades of failed clinical trials for many companies, donanemab is one of several successes in the field of Alzheimer’s antibody drugs, with others including Biogen’s Aduhelm and Leqembi, which was developed by Biogen and Eisai. Aduhelm was beset by controversy as it was approved without clear evidence for its clinical benefit, and Biogen scaled back commercial activity related to the drug last year. Leqembi, in contrast, is predicted by analysts to be a blockbuster.