After decades of frustration at the lack of an effective treatment for Alzheimer's disease, today a second new drug — donanemab (Eli Lilly) — was reported to have positive effects. The trial results come hot on the heels of a similar drug, lecanemab (Eisai), which was last year shown to slow a decline in memory and thinking skills in early Alzheimer's disease by 27%.
Lecanemab was approved by the US Food and Drug Administration (FDA) earlier this month, and British authorities were urged to speed the approval process in the UK, despite warnings that the NHS may lack capacity for the necessary testing and monitoring.
Both drugs are based on monoclonal antibody technology and claim to clear amyloid build-up in the brain. Professor Giles Hardingham, interim director of the UK Dementia Research Institute (DRI) at University College London, explained to the Science Media Centre (SMC) that these first-generation drugs are "by no means perfect", but are still "an important breakthrough that will pave the way for many future therapies".
NHS Lacks Necessary Infrastructure
The latest results from the aptly named TRAILBLAZER-ALZ 2 trial were published online in JAMA to coincide with a presentation at the Alzheimer's Association International Conference in Amsterdam. However, despite the fanfare greeting the announcements, experts are cautioning that side-effects may not be insignificant, cost-effectiveness has yet to be established and, in the UK, the NHS lacks some of the clinical infrastructure needed to facilitate treatment.
The TRAILBLAZER-ALZ 2 study involved 1736 participants with early symptomatic Alzheimer's disease recruited from 277 centres across 8 countries. Results from the 18-month phase 3 trial showed that for 23 of 24 outcomes, donanemab gave a statistically significant result compared with placebo, including for improvements in the primary outcome, the integrated Alzheimer Disease Rating Scale.
This represented a slowing of clinical progression by 38.6%, though at a cost of various amyloid-related imaging abnormalities — oedema or effusion — in 205 (24%) participants in the donanemab group, of whom 52 were symptomatic, compared with 18 (2.1%, none symptomatic) in the placebo group. Infusion-related reactions occurred in 74 (8.7%) versus four (0.5%) participants, respectively. Three deaths in the donanemab group and one in the placebo group were considered treatment-related.
A "critical observation" is that patients with a lower burden of tau tangles — which are more strongly correlated with cognitive function than amyloid plaques — demonstrated a better response to donanemab, Dr Marc Aurel Busche, group leader at the DRI, told the SMC. "This emphasises the crucial importance of initiating treatment early." Combination treatment involving both anti-amyloid and anti-tau therapies could be even more effective, he suggested.
Beginning of the End for Alzheimer's Disease?
"This could be the beginning of the end of Alzheimer's disease," Dr Richard Oakley, associate director of research at the Alzheimer's Society, said when TRAILBLAZER's preliminary results were announced in May. "After 20 years with no new Alzheimer's drugs, we now have two potential new drugs in just 12 months — and for the first time, drugs that seem to slow the progression of disease." The latest results are "truly a turning point", and Alzheimer's disease could in future be considered a long-term condition like diabetes or asthma, he told the SMC today.
However, Dr Oakley cautioned that approval was not enough if people couldn't access the drugs at an early stage, when they work best, and the NHS must provide earlier, more accurate dementia diagnoses.
Donanemab must be given by monthly infusion after a PET scan or lumbar puncture to confirm that a patient is amyloid positive. This means that "the NHS itself will need to undergo significant changes" in order to deliver the drug, including setting up infusion clinics, greater capacity for diagnostic tests, and MRI scans to monitor for side effects, according to an explainer from Alzheimer's Research UK released in May.
Best available data suggested that the proportion of patients who might currently receive donanemab as routine could be as low as 2%. "That needs to change," the charity said. It also warned that given the number of people who could be eligible for the drug, "this is likely to be very expensive".
Both charities pointed out that even with positive decisions on approval by the Medical and Healthcare products Regulatory Agency (MHRA) and the National Institute of Health and Care Excellence (NICE), "the very earliest donanemab might be available on the NHS is 2025".
Alzheimer's Association International Conference (AAIC) 2023: Presented July 17, 2023.
JAMA. Published online 17 July 2023. Full text