FDA advisers endorse Eli Lilly’s early-stage Alzheimer’s drug donanemab
What specific effects does donanemab have on amyloid plaques in the brain, and how does this relate to its proposed benefits for Alzheimer's disease?
Donanemab is a monoclonal antibody designed to help the body remove amyloid plaque buildups in the brain that are a hallmark of Alzheimer's disease. These plaques are harmful deposits that can form in the brain as people age. Removing the plaque seems to slow down the brain changes that seem to happen with Alzheimer's. As the drug enters the brain, it binds to the amyloid plaques, and its presence catches the attention of the immune system, which facilitates the plaque removal.
In a phase 2 clinical trial, donanemab showed a substantial reduction in Alzheimer's disease-associated cerebral amyloid-plaque load, measured by amyloid positron emission tomography (PET), in the intervention group compared with the placebo group2. The drug's proposed benefits for Alzheimer's disease are based on the premise that reducing amyloid plaques in the brain may slow the progression of the disease in its early stages. In late-stage clinical research, donanemab demonstrated a 37% lower risk of progression of the disease over a year and a half compared to patients who received the placebo.
What additional safety measures did Lilly implement during the trials to address the issue of ARIA in patients?
During the trials, Lilly implemented additional safety measures to address the issue of ARIA (amyloid-related imaging abnormalities) in patients. Since most donanemab patients who experienced problems with ARIA did so in the first six weeks of the trial, Lilly added another MRI to the trial to look for the problem before giving the patient a second infusion. The aim was to detect patients with asymptomatic ARIA. If it was detected, providers would pause treatment so it could resolve and not become more serious or symptomatic.
How did the clinical trial results for donanemab compare to those of Leqembi, another Alzheimer's drug on the market?
The clinical trial results for donanemab and Leqembi, another Alzheimer's drug on the market, showed similarities in their ability to slow the progression of the disease in its early stages. Both drugs are monoclonal antibodies that target amyloid plaque in the brain, which is considered a hallmark of Alzheimer's.
In Lilly's large clinical trial, donanemab, given by infusion once a month, slowed progression of memory and thinking problems by 29% overall, roughly comparable to the 27% slowing seen with Leqembi2. Both medications showed a modest slowing of cognitive problems in patients with early-stage Alzheimer's.
However, there were differences in the trial designs for the two treatments. Lilly measured levels of a second Alzheimer's-related protein called tau, associated with brain cell death, to select patients most likely to show a benefit within the study's 76-week trial period. As a result, Lilly excluded patients with very low or no levels of tau from the pivotal trial.
In terms of side effects, both drugs have shown risks of brain swelling and bleeding. Around 24% of trial participants who took donanemab experienced brain swelling, while 31% experienced brain bleeding. For Leqembi, 12.6% of participants experienced brain swelling and 17.3% experienced brain bleeding.
Overall, the clinical trial results for donanemab and Leqembi show that both drugs can slow cognitive decline in early-stage Alzheimer's patients, with donanemab showing a slightly higher percentage of slowing in the Lilly trial2. However, both drugs come with risks that will need to be monitored and managed in patients.