Comparative Review of Lecanemab and Donanemab: Insights from Phase 3 Alzheimer’s Trials

Introduction

The intersection of an aging population and the rising prevalence of dementia presents a significant public health challenge. In the UK, approximately 850,000 people are currently living with dementia, a figure projected to surpass 1 million by 2025. Given the lengthy gaps between the approval of new treatments, the potential approval of Lecanemab and Donanemab marks a critical milestone in Alzheimer’s research, offering renewed hope for early-stage intervention. It is important to note, however, that both medications are still awaiting approval by the MHRA.This comparative review will delve into the key findings and implications of the trials involving these promising treatments. For a more personal and in-depth perspective on these developments, I recommend watching the BBC Panorama episode "Alzheimer’s: A Turning Point?" which follows patients participating in these groundbreaking studies.

Understanding Alzheimer’s

It is characterised by the accumulation of amyloid-beta plaques and tau tangles in the brain, leading to neurodegeneration and cognitive decline. Despite numerous efforts, effective treatments to slow or halt the progression of AD have been elusive. Please read more these of the symptoms of Alzheimer’s disease.

Figure 1: Pathophysiology of Alzheimer’s disease (Alzheimer's disease, 2024) 

Author of each paper

Lecanemab: Published in New England Journal of Medicine (2022) by researchers from Eisai Co., Ltd., Biogen, and academic institutions.

Donanemab: Published in JAMA (2023) by researchers from Eli Lilly and affiliated academic centres

Likely readership for both papers include researchers, neurologists, regulatory agencies and medical students interested in neurology.

Mechanism of action

Lecanemab is a humanised IgG1 monoclonal antibody that targets amyloid beta protofibrils, toxic precursors to amyloid plaques in the brain. By binding to these protofibrils, Lecanemab enables microglia (brain immune cells) to recognise and clear these complexes, reducing the overall amyloid load (Loeffler, 2023). This action is intended to slow cognitive decline in early Alzheimer’s disease.

Donanemabis also a humanised IgG1 monoclonal antibody, but it specifically targets and clears pGlu3, a particularly aggregation-prone form of amyloid-beta that forms the core of amyloid plaques. By binding to pGlu3, Donanemab facilitates its clearance by microglia, helping to remove amyloid plaques from the brain. This action aims to slow cognitive decline in early symptomatic Alzheimer’s, particularly in patients with more advanced amyloid plaque deposition.

Figure 2: Stages of Amyloid Pathology Targeted by Lecanemab and Donanemab (Taylor, 2024)

Both drugs are intended for early-stage Alzheimer’s disease, but Donanemab may be more effective in patients with advanced amyloid plaque deposition due to its specific targeting mechanism.

Hypothesis

Lecanemab: Hypothesises that reducing amyloid beta protofibrils will slow cognitive and functional decline in early Alzheimer’s.

Donanemab: Hypothesises that clearing specific amyloid plaques and reducing tau will slow cognitive and functional decline in early symptomatic Alzheimer’s

Study Design

Both studies were a randomised double-blind, placebo-controlled, Phase 3 trial assessing the efficacy and safety of their medications. Please click here to read more about the different phases of study.

Study Characteristic	Lecanemab	Donanemab
Study Name	CLARITY AD	TRAILBLAZER-ALZ 2
Population	Early Alzheimer’s, ages 50-90	Early symptomatic Alzheimer’s, ages 60-85
Intervention	Lecanemab, IV every two weeks for 18 months	Donanemab, IV every four weeks for 18 months
Primary Outcome	Change in Clinical Dementia Rating-Sum of Boxes (CDR-SB) score	Change in Integrated Alzheimer's Disease Rating Scale (iADRS) score
Secondary Outcomes	Amyloid plaque reduction, ARIA incidence	Plaque and tau reduction, ARIA incidence

Table 1: A comparison of Lecanemab and Donanemab in terms of population, intervention, primary outcome, and secondary outcomes

Differences with CD-R-SB and iADRS scores

CDR-SB focuses primarily on assessing the severity of dementia through six specific domains (O’Bryant, 2008), whereas iADRS provides a more integrated view of both cognitive and functional decline (Wessels et al., 2018). CDR-SB is used for detailed dementia severity assessment, whereas iADRS provides a broader evaluation of cognitive and functional impact.

Assessing the method

Both studies were methodologically rigorous, with strong designs, randomisation, blinding, and safety monitoring. Both employed intention-to-treat analysis, ensuring the reliability of results. The statistical methods used were appropriate and well-described, adding to the reliability of the results. This large sample size helps to ensure that the study is well-powered and that the findings are statistically reliable. Limitations include the relatively short 18-month duration, which is brief for a chronic condition like Alzheimer’s.

Results and discussion

Lecanemab

Efficacy: Lecanemab slowed cognitive decline by 27% over 18 months (0.45-point improvement on CDR-SB). The effect, while statistically significant and supports the amyloid hypothesis, the modest clinical impact may be difficult for patients and caregivers to perceive in everyday life

Safety: Approximately 21% of Lecanemab-treated patients experienced Amyloid-Related Imaging Abnormalities (ARIA), including oedema (ARIA-E) and haemorrhage (ARIA-H), necessitating careful patient monitoring. These safety concerns could restrict its use in certain populations.

Limitations: The study encountered challenges related to the COVID-19 pandemic, such as missing data and delays, which might have influenced the outcomes. Nevertheless, the trial was well-designed, with robust evidence of amyloid plaque reduction, reinforcing the drug's proposed mechanism.

Donanemab

Efficacy: Donanemab demonstrated a 35% reduction in cognitive and functional decline, along with significant reductions in amyloid plaques and tau pathology. These results bolster the theory that targeting amyloid-beta offers clinical benefits.

Safety: Donanemab was associated with higher rates of ARIA, with 26% experiencing ARIA-E and 24% ARIA-H. This necessitates vigilant monitoring and may limit the drug's suitability for some patients. The study's focus on efficacy may have underplayed the clinical implications of these ARIA rates

Limitations: The authors' financial ties to Eli Lilly could introduce bias, though the study itself was rigorous, with significant reductions in amyloid and tau, affirming its potential as a disease-modifying therapy

Conclusion

Lecanemab and Donanemab represent significant strides in the treatment of Alzheimer’s disease, demonstrating statistically significant reductions in cognitive decline. However, their real-world impact on patients' daily lives may be more modest than the data suggests. While these treatments show promise, it is crucial to question whether the observed improvements in cognitive scores translate into meaningful enhancements in the quality of life for patients. Moreover, the potential for ARIA-related unblinding introduces the risk of bias, and the relatively short 18-month study duration leaves important questions unanswered. These uncertainties highlight the need for more extended follow-up periods to assess the long-term efficacy and safety of these therapies. The complexities of Alzheimer’s disease suggest that future research should explore combination therapies targeting multiple pathways to offer a more comprehensive treatment approach. Ongoing open-label extensions and future studies will be essential in determining the full potential and limitations of Lecanemab and Donanemab in altering the course of Alzheimer’s disease.

For those interested in learning more about current research trials, reputable clinics such as UCL and Recognition Health offer opportunities to contribute to this important field of study

Additional reading

"Emerging Therapies for Alzheimer's Disease: A Review" by Nature Reviews Drug Discovery: This review covers the latest advancements in Alzheimer’s treatments, including Lecanemab and Donanemab, and explores the potential of combination therapies.

"Comparative Efficacy and Safety of Anti-Amyloid Monoclonal Antibodies in Alzheimer's Disease" by The Lancet Neurology: This article provides a comparison of different anti-amyloid therapies, including Lecanemab and Donanemab, highlighting their strengths and limitations.

References

Alzheimer’s disease (2024) Mayo Clinic. Available at: https://www.mayoclinic.org/diseases-conditions/alzheimers-disease/symptoms-causes/syc-20350447

Health matters: Midlife approaches to reduce dementia risk (no date) GOV.UK. Available at: https://www.gov.uk/government/publications/health-matters-midlife-approaches-to-reduce-dementia-risk/health-matters-midlife-approaches-to-reduce-dementia-risk#:~:text=There%20are%2047.5%20million%20people,figure%20will%20exceed%202%20million.

Loeffler, D.A. (2023) ‘Antibody-mediated clearance of brain amyloid-β: Mechanisms of action, effects of natural and monoclonal Anti-Aβ antibodies, and downstream effects’, Journal of Alzheimer’s Disease Reports, 7(1), pp. 873–899. doi:10.3233/adr-230025. 

O’Bryant, S.E. (2008) ‘Staging dementia using clinical dementia rating scale sum of boxes scores’, Archives of Neurology, 65(8), p. 1091. doi:10.1001/archneur.65.8.1091. 

Sims, J.R. et al. (2023) ‘Donanemab in early symptomatic alzheimer disease’, JAMA, 330(6), p. 512. doi:10.1001/jama.2023.13239. 

Taylor, E. (2024) New alzheimer’s drug, donanemab – what is it and how does it work?, Alzheimer’s Research UK. Available at: https://www.alzheimersresearchuk.org/news/new-alzheimers-drug-donanemab-what-is-it-and-how-does-it-work/

van Dyck, C.H. et al. (2023) ‘Lecanemab in early alzheimer’s disease’, New England Journal of Medicine, 388(1), pp. 9–21. doi:10.1056/nejmoa2212948. 

Wessels, A.M. et al. (2018) ‘The integrated alzheimer’s disease rating scale (IADRS) findings from the expedition3 trial’, The Journal Of Prevention of Alzheimer’s Disease, pp. 1–3. doi:10.14283/jpad.2018.10. 

‘Alzheimer’s: A Turning Point?’ (2024) Panorama. BBC.