Groundbreaking Drug Launches
Donanemab (Kisunla)
Mechanism of Action: Pyroglutamyl(3)-amyloid beta-protein (3-42) inhibitors Drug Class: Monoclonal antibodies Originator: Eli Lilly and Company Indication: Alzheimer's disease Trials: TRAILBLAZER-ALZ 2 trial
Alzheimer's disease
Alzheimer's disease (AD) is a progressive neurological condition that harms nerve cells in the brain. The neurons responsible for memory, language, and thinking are impacted by this disease, leading to memory loss and cognitive issues like language difficulties and trouble with navigation. The brain changes seen in Alzheimer's, such as the build-up of abnormal proteins named beta-amyloid and phosphorylated tau, along with neuronal degeneration, can affect basic functions like thinking, walking, mood, and behavior. Deposits of these proteins can also trigger inflammation in the brain and lead to tissue loss. In some rare cases, a genetic mutation can cause dominantly inherited Alzheimer's disease (DIAD). While symptoms of the disease may only appear later in life, the underlying brain changes may have started years earlier.
Why is Donanemab poised to make an impact in 2025?
Challenges in Alzheimer’s Drug Development:
However, many potential therapies have failed in late-stage trials, highlighting the critical need for accurate diagnostics and biomarkers. For example-
Gantenerumab
A phase III study of gantenerumab, which is believed to clear amyloid plaques, involved nearly 800 prodromal Alzheimer's disease (AD) patients treated over two years. The study was prematurely halted based on a futility analysis. The sponsors indicated that the chosen doses were too low, and dose-dependent effects were observed, suggesting that "higher dosing with gantenerumab may be necessary to achieve clinical efficacy.
Aducanumab
An interim analysis of two parallel phase III trials, which treated over 3,200 early AD patients for 1.5 years, recently reported futility for aducanumab, a drug that also targets amyloid plaques. However, after further analysis of the larger dataset across three different doses, effectiveness was observed in a subset of patients receiving the highest dose. While this is not an example of clinical failure, it highlights that optimal dosing was not firmly established before proceeding to phase III trials.
Promising treatments:
Aducanumab and Lecanemab address Alzheimer’s biology by targeting beta-amyloid, aiming to slow disease progression in early-stage patients. In 2023, Lecanemab became the first amyloid beta-directed antibody approved in both the USA and Japan, while Aducanumab received accelerated approval in 2021 for early Alzheimer's treatment.
Donanemab poised to make an impact in 2025:
Donanemab, an anti-amyloid immunotherapy targeting N3pG beta-amyloid, has demonstrated promising results in slowing cognitive decline in early symptomatic Alzheimer's patients. The Institute for Clinical and Economic Review, a prominent nonprofit organization, estimated in a draft report that donanemab would be more cost-effective than Leqembi on a per life-year gained basis if both drugs were priced similarly.
“BI analysts forecast that by 2030, Lilly will emerge as the dominant player in Alzheimer’s treatment. Donanemab is expected to generate $2.2 billion in annual sales by 2028.”
“By 2030, Donanemab and its self-injected counterpart, remternetug, could generate $6.5 billion in sales, more than double the $3.2 billion forecast for Leqembi.”
Regulatory milestones for Donanemab
Registrational Trial
TRAILBLAZER-ALZ 2
The regulatory applications to the US FDA, EMA, PMDA, NMPA, MHRA, etc. were based on the efficacy and safety data from the TRAILBLAZER-ALZ 2 phase 3 clinical study which is a double-blind, placebo-controlled, parallel-group study (NCT04437511) in patients with Alzheimer’s disease.
"TRAILBLAZER-ALZ 2 trial showed donanemab slowed cognitive decline in early Alzheimer's patients but was linked to amyloid-related imaging abnormalities (ARIA)"