11th December 2022, Dr Chee L Khoo
You would have heard the exciting hype about lecanemab in the treatment of early Alzheimer’s disease. It’s all over the news and it is getting many patients excited. The Alzheimer’s disease community has become accustomed to false hope, disappointment, and controversy. Existing “treatments” of AD can hardly be called treatment as they can only slow down the progression of the disease (if it indeed work at all). Does lecanemab really work? Do we finally have treatment for Alzheimer’s dementia? Is the hype what is it really is? Just a hype. Is this another false dawn? What is lecanemab?
The accumulation of soluble and insoluble aggregated amyloid-beta (Aβ) may initiate or potentiate pathologic processes in Alzheimer’s disease. There have been efforts to develop an agent that can modify the course of AD, by using antibodies to first clear Aβ from the brain and later to clear tau proteins. We have seen numerous setbacks over the past 20 years. I have always thought that treatments targeting Aβ and/or tau proteins were barking up the wrong tree. Yes, we can reduce amyloid aggregates and/or tau neurofibrillary tangles with different monoclonal antibodies but do they really reduce the progression of AD? Are these aggregates and tangles just incidental bystanders?
Sure enough, almost a decade ago, the first of the anti-Aβ antibodies tested in phase 3 trials, bapineuzumab (2) and solanezumab (3) did not improve clinical outcomes in mild to moderate Alzheimer’s disease. The monoclonal antibodies reduce amyloid aggregates but there were no clinical improvement in patients. Hopes were dashed again in 2019 when 2 phase 3 trials of another anti-Aβ antibody, aducanumab were halted early for futility (4).
So, when the US FDA allow aducanumab to be marketed under its accelerated approval programme (which allows early approval of drugs in areas of unmet need based on a positive change on a surrogate endpoint—in this case amyloid reduction in the brain), the decision sparked furore among the research community (5).
Lecanemab is a humanised monoclonal antibody that binds with high affinity to soluble amyloid-beta (Aβ) protofibrils, which have been shown to be more toxic to neurons than monomers or insoluble fibrils. An earlier phase 2b, dose-finding trial involving smaller cohort of 854 participants with early Alzheimer’s disease did not show a significant difference between lecanemab and placebo in a Bayesian analysis of 12-month change in a composite score (primary end point) (1). However, analyses at 18 months showed dose- and time-dependent clearance of amyloid with lecanemab, and the drug was associated with less clinical decline on some measures than placebo.
The recent media hype was all about the CLARITY AD trial. The CLARITY AD trial is an 18-month, multi-centre, double-blind, phase 3 trial involving persons 50 -90 years of age with early Alzheimer’s disease (mild cognitive impairment or mild dementia due to Alzheimer’s disease) with evidence of amyloid on positron-emission tomography (PET) or by cerebrospinal fluid testing (6). Participants were randomly assigned in a 1:1 ratio to receive intravenous lecanemab (10 mg per kilogram of body weight every 2 weeks) or placebo.
Participants underwent serial blood testing for plasma biomarkers and could participate in three optional sub-studies that evaluated longitudinal changes in brain amyloid burden as measured by positron-emission tomography (PET), brain tau pathologic features as measured by PET, and cerebrospinal fluid (CSF) biomarkers of Alzheimer’s disease.
The primary end point was the change from baseline at 18 months in the score on the Clinical Dementia Rating–Sum of Boxes (CDR-SB; range, 0 to 18, with higher scores indicating greater impairment). The CDR-SB score is a validated outcome measure used in clinical trials of Alzheimer’s disease that is obtained by interviewing patients and their care partners and captures cognition and function. It assesses six domains that patients and caregivers identify as important (Memory, Orientation, Judgment and Problem Solving, Community Affairs, Home and Hobbies, and Personal Care).
Key secondary end points were the change in amyloid burden on PET, the score on the 14-item cognitive subscale of the Alzheimer’s Disease Assessment Scale (ADAS-cog14; range, 0 to 90; higher scores indicate greater impairment), the Alzheimer’s Disease Composite Score (ADCOMS; range, 0 to 1.97; higher scores indicate greater impairment), and the score on the Alzheimer’s Disease Cooperative Study–Activities of Daily Living Scale for Mild Cognitive Impairment (ADCSMCI-ADL; range, 0 to 53; lower scores indicate greater impairment).
Results
898 participants received lecanemab and 897 received placebo. The mean CDR-SB score at baseline was approximately 3.2 in both groups. The adjusted least-squares mean change from baseline at 18 months was 1.21 with lecanemab and 1.66 with placebo (difference, −0.45; 95% confidence interval [CI], −0.67 to −0.23; P<0.001).
For secondary end points, lecanemab was associated with a -1.44 reduction in ADAS-cog14 score (p<0.001), -0.050 in the ADCOMS (p<0.001) and + 2.0 for the ADCS-MCIADL score (p<0.001).
There were greater reductions in brain amyloid burden with lecanemab than with placebo.
Safety
Deaths occurred in 0.7% of the participants in the lecanemab group and 0.8% of those in the placebo group. The most commonly reported serious adverse events were infusion‑related reactions (in 1.2% of the participants in the lecanemab group and 0 participants in the placebo group), amyloid related imaging abnormalities (ARIA) with oedema (ARIA-E) (in 0.8% and 0, respectively), atrial fibrillation (in 0.7% and 0.3%), syncope (in 0.7% and 0.1%), and angina pectoris (in 0.7% and 0). The overall incidence of adverse events was similar in the two groups.
ARIA with cerebral microhaemorrhages, cerebral macro-haemorrhages, or superficial siderosis (ARIA-H; 17.3% with lecanemab and 9.0% with placebo); ARIA-E (12.6% with lecanemab and 1.7% with placebo); headache (11.1% with lecanemab and 8.1% with placebo); and falls (10.4% with lecanemab and 9.6% with placebo).
In summary
The authors concluded that lecanemab reduced markers of amyloid in early Alzheimer’s disease and resulted in moderately less decline on measures of cognition and function than placebo at 18 months. Does it really make a difference in practice?
The CDR-SB scores is an 18 point scale. A 0.45 point reduction, although statistically significant, may not be clinically significant. A definition of clinically meaningful effects in the primary end point of the CDR-SB score has not been established.
We’ll just have to wait and see whether lecanemab is the saviour or another false dawn.
Reference:
- Swanson CJ, Zhang Y, Dhadda S, et al. A randomized, double-blind, phase 2b proof-of-concept clinical trial in early Alzheimer’s disease with lecanemab, an anti-Aβ protofibril antibody. Alzheimers Res Ther 2021;13:80-80.
- Salloway S, Marshall GA, Lu M, Brashear HR. Long-Term Safety and Efficacy of Bapineuzumab in Patients with Mild-to-Moderate Alzheimer’s Disease: A Phase 2, Open-Label Extension Study. Curr Alzheimer Res. 2018;15(13):1231-1243. doi: 10.2174/1567205015666180821114813. PMID: 30129411.
- Farlow, M., Bateman, R., Aschenbrenner, A., Benzinger, T., Clifford, D., Coalier, K., et al. (2020). Solanezumab in-depth outcomes: results of the DIAN-TU prevention trial of solanezumab and gantenerumab in dominantly inherited AD. Alzheimers Dement. 16:e038028. doi: 10.1002/alz.038028
- Beshir SA, Aadithsoorya AM, Parveen A, Goh SSL, Hussain N, Menon VB. Aducanumab Therapy to Treat Alzheimer’s Disease: A Narrative Review. Int J Alzheimers Dis. 2022 Mar 9;2022:9343514. doi: 10.1155/2022/9343514. PMID: 35308835; PMCID: PMC8926483.
- Tampi, R. R., Forester, B. P., and Agronin, M. (2021). Aducanumab: evidence from clinical trial data and controversies. Drugs Context 10, 2021–2027. doi: 10.7573/dic.2021-7-3
- van Dyck CH, Swanson CJ, Aisen P, Bateman RJ, Chen C, Gee M, Kanekiyo M, Li D, Reyderman L, Cohen S, Froelich L, Katayama S, Sabbagh M, Vellas B, Watson D, Dhadda S, Irizarry M, Kramer LD, Iwatsubo T. Lecanemab in Early Alzheimer’s Disease. N Engl J Med. 2022 Nov 29. doi: 10.1056/NEJMoa2212948. Epub ahead of print. PMID: 36449413.