“Exciting” New Alzheimer’s Drug Slows Disease Progression, But Side Effects Dampen Celebrations

A paper outlining the efficacy of a new drug for Alzheimer’s disease has been published. The hotly awaited findings confirm that the compound, donanemab, can delay the rate of decline in individuals with early-stage Alzheimer’s by 22.3%. Over the study’s 18-month timeline, that equates to a 4-month delay in disease progression. Those four months come at a cost, however, as over 6% of patients receiving donanemab infusions showed symptoms related to brain swelling and bleeding that included headache, confusion and even seizures. The publication of the trial’s full results in the Journal of the American Medical Association follows a press release from manufacturer Eli Lilly in May.

The results are “fantastic news” for the overall progression of the field, said Professor Tara Spires-Jones, group leader at the UK Dementia Research Institute at the University of Edinburgh and president of the British Neuroscience Association in an interview with Technology Networks. Spires-Jones pointed to the recent approval of another compound, Leqembi, which was given the go-ahead by the U.S. Food and Drug Administration (FDA) earlier this month to suggest that the field is moving in the right direction. “It shows that we can do something that will help people even if it is a moderate slowing,” said Spires-Jones.

The overall clinical significance of dodanemab’s performance will remain under debate in a field that has desperately sought treatments of any efficacy after two decades of failure. The compound seems tipped for approval, given that its performance roughly matches Leqembi’s.

Donanemab is an anti-amyloid monoclonal antibody, a type of treatment that aims to reduce the amount of a protein called amyloid-beta drastically in the brain. One of the first and most defining clinical signs of the disease is amyloid-beta buildup. The protein is deposited in lumps and plaques across the Alzheimer’s-affected brain. The protein’s significance to the current direction of Alzheimer’s research cannot be overstated. The amyloid hypothesis, a theory that puts the protein at the heart of the disease’s effects, has driven much of the thinking around drug design in the area for multiple decades.

Tau-informed trial design

Donanemab was assessed in a Phase 3 trial called TRAILBLAZER-ALZ 2. This trial’s setup was slightly different from comparable efforts, changes that acknowledge the growing influence of another protein, tau, on the Alzheimer’s field. Increases in tau are also seen in the Alzheimer’s brain. Although this rise happens sequentially after amyloid-beta, research has recognized that tau levels are a greater indicator of disease progression in Alzheimer’s. Reflecting this, TRAILBLAZER-ALZ 2 stratified its cohort into different groups, depending on the level of tau detected in their brains using positron emission tomography imaging.

The study enrolled 1,736 participants, all of whom had early symptoms of dementia. The cohort was divided in two and, every four weeks, patients were intravenously infused with either donanemab or a placebo. This continued for 18 months.

The treatment’s effect was measured using several different dementia rating scales. In total, 24 different outcomes were measured to assess how well donanemab addressed dementia-related decline.

These included the integrated Alzheimer disease rating scale (iADRS) and the sum of boxes of the clinical dementia rating scale (CDR-SB) score. In iARDS ratings, lower scores indicate greater impairment. After 18 months, scores in patients given donanemab fell by 2.92 points less than those given a placebo, a statistically significant difference. Scores in the CDR-SB, which uses a different scale where higher values indicate greater impairment, were 0.7 points lower in the drug-treated cohort, a finding that was also statistically significant. Eli Lilly was keen to promote more impressive differences noted among those who had been segmented into lower-tau groups. As more tau indicates a more advanced disease progression, this suggests that people with early-stage disease stand to benefit most from donanemab. Individuals in high tau groups saw no benefit from the drug as measured by the iARDS rating system and most other secondary measures.

The Eli Lilly researchers behind the paper were keen to put these figures in terms of slowing of disease progression. The iARDS scores suggested a 22.3% slowing of disease while the CDR-SB showed a 28.9% slowing of disease. These figures are “hopeful”, said Spires-Jones, who acknowledged that a 30% slowing of disease progression would only be the first step towards treatments that could stop or reverse Alzheimer’s.

Safety data raises red flags and black boxes

There are some reasons not to take this promising result as an indication we are on the way to an Alzheimer’s-free future.

Some critics suggest that the reliance on “slowing of disease” in data around monoclonal antibodies is meant to mask unconvincing raw data – it is unclear whether a 2.92-point difference in iARDS rating at the 18-month mark will produce a clinically meaningful difference. The iARDS scale itself is an Eli Lilly creation and the only assessment of clinically significant differences on the scale was authored by Eli Lilly researchers.

The most significant hurdle facing donanemab, by far, is its safety data. Monoclonal anti-amyloid antibodies have been noted to cause changes in the brain that can be picked up on imaging machines. These are collectively called amyloid-related imaging abnormalities (ARIA). There are two types of ARIA, ARIA-E and ARIA-H. ARIA-E reflects swelling in the brain, while ARIA-H is indicative of microbleeds.

These kinds of effects already happen in the brains of people with Alzheimer’s disease, but are more common in people treated with donanemab. In this group, 36.8% of those dosed showed at least one type of ARIA, compared to 14.9% of the placebo group. Many of these cases will not produce any symptoms and will have only emerged after careful analysis of brain images. But in 52 cases, ARIA-E swelling was severe enough to produce symptoms that the authors listed as including confusion, headache and seizures. The rate of brain bleeds was far higher in the donanemab group as well. In 1.6% of the cohort, the side effects were so dramatic that patients were hospitalized. Three patients died as a result of ARIA effects brought on by the drug.

These side effects, although present, are thought to be less severe in Eisai’s Leqembi, which may ultimately reduce the adoption of donanemab. The fact that the drug is most useful to those with less severe disease, who would stand to lose the most from a severe reaction to the drug, does not tip the scales in Eli Lilly’s favor.  

Reference: Sims JR, Zimmer JA, Evans CD, et al. Donanemab in Early Symptomatic Alzheimer Disease: The TRAILBLAZER-ALZ 2 Randomized Clinical Trial. JAMA. Published online July 17, 2023. doi:10.1001/jama.2023.13239