Donanemab is an investigational antibody therapy developed for the treatment of early-stage Alzheimer’s disease. The results of its significant Phase 3 clinical trial have generated considerable interest, providing new information on the drug’s potential role in managing the condition.
How Donanemab Works
The development of donanemab is based on the amyloid cascade hypothesis. This theory suggests that the accumulation of a protein called beta-amyloid in the brain is a primary driver of Alzheimer’s disease. These proteins form deposits known as amyloid plaques, which disrupt communication between brain cells and lead to cognitive and functional decline.
Donanemab targets a modified form of beta-amyloid called N3pG, a component of established amyloid plaques. The antibody binds to these plaques, marking them for removal by the body’s immune system. This process is designed to clear the harmful protein deposits from the brain and slow the progression of the underlying disease.
The TRAILBLAZER-ALZ 2 Trial Design
The study evaluating donanemab was the TRAILBLAZER-ALZ 2 trial. This was a large-scale, Phase 3, randomized, double-blind, placebo-controlled study. The double-blind protocol meant that neither the participants nor the investigators knew who was receiving donanemab and who was receiving a placebo.
The study enrolled 1,736 participants between the ages of 60 and 85 who were in the early stages of symptomatic Alzheimer’s disease. A requirement for inclusion was the confirmed presence of both amyloid and tau protein pathology in their brains, as measured by positron emission tomography (PET) imaging. Participants were divided into groups based on having either low/medium or high levels of tau, a protein that forms tangles within brain cells.
The primary measure for success was the change from baseline on the integrated Alzheimer’s Disease Rating Scale (iADRS) over 76 weeks. This tool assesses both cognitive abilities and a person’s capacity to perform activities of daily living. A feature of the trial was that participants on donanemab could be switched to a placebo if their brain scans showed significant amyloid plaque clearance at the 24 or 52-week marks.
Efficacy and Primary Outcomes
The TRAILBLAZER-ALZ 2 trial showed donanemab slowed cognitive and functional decline in participants with early Alzheimer’s. In the group with low-to-medium tau pathology, treatment slowed decline by 35% on the iADRS compared to placebo over 76 weeks. The change in the iADRS score was -6.02 for the donanemab group versus -9.27 for the placebo group.
The positive effects were also evident in secondary measures. On the Clinical Dementia Rating-Sum of Boxes (CDR-SB), a scale that also assesses cognitive and functional abilities, donanemab slowed decline by 36% in the same population group. Nearly half of the participants treated with donanemab, 47%, showed no clinical progression of their disease at one year, compared to 29% of those who received the placebo.
Donanemab led to significant reductions in amyloid plaque levels as seen on PET scans. Among participants with low-to-medium tau levels, 34% achieved amyloid clearance at six months, and this figure rose to 71% by the 12-month mark. The results also indicated the treatment effect was most pronounced in patients who had lower levels of tau protein when the trial began.
Safety Profile and Adverse Events
The primary safety concern observed in the trial was the development of Amyloid-Related Imaging Abnormalities, or ARIA. This is a known side effect associated with this class of amyloid-targeting antibody therapies. ARIA can manifest in two forms: ARIA-E, which refers to cerebral edema or swelling in the brain, and ARIA-H, which involves microhemorrhages on the brain’s surface.
In the donanemab treatment group, ARIA-E occurred in 24.0% of participants, with 6.1% of those cases being symptomatic. The incidence of ARIA-H was 31.4% among those receiving the drug. Most of these imaging abnormalities were mild to moderate and resolved on their own. However, serious adverse events were reported in 17.4% of participants on donanemab compared to 15.8% on placebo.
The trial reported that three deaths were related to serious cases of ARIA among participants receiving donanemab. Another common side effect was infusion-related reactions, which occurred in 8.7% of individuals in the donanemab group. The safety profile necessitates careful monitoring, including regular MRI scans, for patients undergoing this form of therapy.
Regulatory Path and Comparison
Following the results from the TRAILBLAZER-ALZ 2 trial, the manufacturer, Eli Lilly and Company, has submitted the data to the U.S. Food and Drug Administration (FDA) to seek full regulatory approval for donanemab.
Donanemab’s mechanism of targeting amyloid plaques is similar to another approved therapy, lecanemab. The availability of multiple treatments could provide more options for clinicians and patients in managing this complex disease.