Donanemab, which will be known as Kisunla, has been given full approval by the US Food and Drug Administration (FDA) for treatment of early, symptomatic Alzheimer’s disease.
Approval was initially expected last year, but the FDA first asked for more data from patients in early 2023 and then in March 2024 the regulator decided to convene an additional advisory panel to decide on whether donanemab should be approved.
In the TRAILBLAZER-ALZ 2 phase 3 study, which included 1736 participants with early symptoms of Alzheimer’s and both amyloid and tau accumulation in the brain, donanemab slowed cognitive decline by 35% compared with placebo in people with low-medium levels of tau. The treatment did help people with higher levels of tau, but to a lesser extent. Overall, when people with all levels of tau were included, cognitive decline was slowed by 22%. Participants given treatment versus placebo were also 39% less likely to progress to the next stage of the disease.
The study investigators also measured levels of amyloid plaques during the study to assess whether the treatment had a positive effect. The results showed that at 6 months amyloid plaques were reduced by 61%, by 80% at 12 months and by 84% at 18 months compared with the beginning of the study.
"Kisunla demonstrated very meaningful results for people with early symptomatic Alzheimer's disease, who urgently need effective treatment options. We know these medicines have the greatest potential benefit when people are treated earlier in their disease, and we are working hard in partnership with others to improve detection and diagnosis," said Anne White, executive vice president and president of Lilly Neuroscience, Eli Lilly and Company, in a press statement.
Caution needed for some patients
Amyloid-related imaging abnormalities (ARIA) are a known side effect of antibody therapies targeting amyloid. Many people do not experience symptoms of ARIA, but it can cause brain swelling or bleeding in some patients.
Certain people, such as those with two APOE4 mutations that increase the risk of Alzheimer’s, are at higher risk of ARIA on treatment with Leqembi (lecanemab) –Eisai and Biogen’s monoclonal antibody for treatment of early Alzheimer’s– and are excluded from treatment in some places. This will likely also be the case for Kisunla.
In the TRAILBLAZER-ALZ 2 trial, 205 participants given donanemab experienced ARIA, a quarter of which were symptomatic, compared with 18 in the placebo group. Infusion-related reactions were also seen in 8.7% of people treated with donanemab compared with 0.5% of the placebo group.
Leqembi has a box warning about this potential side effect and Lilly’s Kisunla will have a similar warning. ARIA was seen in more patients in late-stage trials of donanemab than lecanemab and its box warning will reflect this.
For example, four brain scans are required during treatment with Leqembi, at the beginning of treatment and then after infusion 5, 7 and 14, to check for ARIA, but an extra scan, after the first infusion with donanemab is also required to try and minimize the chance of serious, symptomatic ARIA.
Bringing new options for patients with Alzheimer’s
After many years of late-stage Alzheimer’s trial failures, the last few years saw the approval of two new therapies for treatment of the disease.
Leqembi was approved in July 2023. The Phase III trial that led to its full approval showed it was able to slow cognitive decline in early-stage Alzheimer’s patients by a significant 27% compared with placebo over 18-months.
In 2021, aducanumab (Aduhelm)—also developed by Biogen and Eisai—was granted accelerated (but not full) approval by the FDA. But controversy surrounded the decision because of a number of concerns about methodology, efficacy, and a high risk of side effects such as ARIA and ultimately the therapy was pulled from the market early last year.
The approval of Kisunla brings true competition to the market for Leqembi. Efficacy is similar for both therapies, although Kisunla arguably had better results in some groups.
Lilly’s therapy has some advantages over its predecessor in that it can be dosed once every four weeks as opposed to every two weeks for Leqembi. Kisunla can also be stopped if amyloid plaques are significantly reduced, which is not the case for Leqembi.
But Kisunla also has some disadvantages, such as additional side effects and higher therapy price of US $32,000 per year compared with US $26,500 per year for Leqembi.
