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Curated Papers > Recent high-impact research on "Alzheimer's Disease" (IF≥30, last 5 years)

Lecanemab in Early Alzheimer's Disease. ​

Literature Information ​

DOI10.1056/NEJMoa2212948
PMID36449413
JournalThe New England journal of medicine
Impact Factor78.5
JCR QuartileQ1
Publication Year2023
Times Cited2132
KeywordsAlzheimer's Disease, Lecanemab, Amyloid, Cognitive Function, Clinical Trial
Literature TypeClinical Trial, Phase III, Journal Article, Multicenter Study, Randomized Controlled Trial, Research Support, Non-U.S. Gov't
ISSN0028-4793
Pages9-21
Issue388(1)
AuthorsChristopher H van Dyck, Chad J Swanson, Paul Aisen, Randall J Bateman, Christopher Chen, Michelle Gee, Michio Kanekiyo, David Li, Larisa Reyderman, Sharon Cohen, Lutz Froelich, Sadao Katayama, Marwan Sabbagh, Bruno Vellas, David Watson, Shobha Dhadda, Michael Irizarry, Lynn D Kramer, Takeshi Iwatsubo

TL;DR ​

This phase 3 trial investigated lecanemab, a monoclonal antibody targeting amyloid-beta, in 1795 participants with early Alzheimer's disease, revealing it significantly reduced amyloid burden and resulted in less cognitive decline compared to placebo at 18 months. While lecanemab showed promise in slowing disease progression, it was associated with adverse events, highlighting the need for further research to fully assess its long-term efficacy and safety.

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Alzheimer's Disease · Lecanemab · Amyloid · Cognitive Function · Clinical Trial

Abstract ​

BACKGROUND The accumulation of soluble and insoluble aggregated amyloid-beta (Aβ) may initiate or potentiate pathologic processes in Alzheimer's disease. Lecanemab, a humanized IgG1 monoclonal antibody that binds with high affinity to Aβ soluble protofibrils, is being tested in persons with early Alzheimer's disease.

METHODS We conducted an 18-month, multicenter, double-blind, phase 3 trial involving persons 50 to 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. 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. 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). 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 (ADCS-MCI-ADL; range, 0 to 53; lower scores indicate greater impairment).

RESULTS A total of 1795 participants were enrolled, with 898 assigned to receive lecanemab and 897 to receive 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). In a substudy involving 698 participants, there were greater reductions in brain amyloid burden with lecanemab than with placebo (difference, -59.1 centiloids; 95% CI, -62.6 to -55.6). Other mean differences between the two groups in the change from baseline favoring lecanemab were as follows: for the ADAS-cog14 score, -1.44 (95% CI, -2.27 to -0.61; P<0.001); for the ADCOMS, -0.050 (95% CI, -0.074 to -0.027; P<0.001); and for the ADCS-MCI-ADL score, 2.0 (95% CI, 1.2 to 2.8; P<0.001). Lecanemab resulted in infusion-related reactions in 26.4% of the participants and amyloid-related imaging abnormalities with edema or effusions in 12.6%.

CONCLUSIONS 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 but was associated with adverse events. Longer trials are warranted to determine the efficacy and safety of lecanemab in early Alzheimer's disease. (Funded by Eisai and Biogen; Clarity AD ClinicalTrials.gov number, NCT03887455.).

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Primary Questions Addressed ​

  1. What are the long-term effects of lecanemab on cognitive decline in early Alzheimer's patients beyond the 18-month trial period?
  2. How does lecanemab compare to other monoclonal antibodies currently in development for treating early Alzheimer's disease?
  3. What mechanisms underlie the infusion-related reactions and amyloid-related imaging abnormalities observed in patients treated with lecanemab?
  4. In what ways might the results of the lecanemab trial influence future guidelines for the treatment of early Alzheimer's disease?
  5. How do the changes in amyloid burden correlate with clinical outcomes in patients receiving lecanemab versus placebo?

Key Findings ​

Background and Objectives ​

Alzheimer's disease is characterized by the accumulation of amyloid-beta (Aβ) aggregates, which are thought to initiate or exacerbate pathological processes. This study evaluates the efficacy of lecanemab, a humanized IgG1 monoclonal antibody targeting soluble Aβ protofibrils, in individuals with early Alzheimer's disease.

Main Methods/Materials/Experimental Design ​

An 18-month, multicenter, double-blind, phase 3 trial was conducted involving participants aged 50 to 90 with early Alzheimer's disease (mild cognitive impairment or mild dementia) confirmed by amyloid presence via PET or cerebrospinal fluid analysis. Participants were randomly assigned (1:1) to receive either intravenous lecanemab (10 mg/kg biweekly) or a placebo.

Key Endpoints ​

  • Primary Endpoint: Change from baseline in the Clinical Dementia Rating-Sum of Boxes (CDR-SB) score at 18 months.
  • Secondary Endpoints: Changes in amyloid burden on PET, scores on the 14-item cognitive subscale of the Alzheimer's Disease Assessment Scale (ADAS-cog14), the Alzheimer's Disease Composite Score (ADCOMS), and the Alzheimer's Disease Cooperative Study-Activities of Daily Living Scale for Mild Cognitive Impairment (ADCS-MCI-ADL).

Flowchart of Study Design ​

Mermaid diagram

Key Results and Findings ​

  • A total of 1795 participants were enrolled: 898 received lecanemab and 897 received placebo.
  • Baseline mean CDR-SB score was approximately 3.2 for both groups.
  • At 18 months, the adjusted mean change in CDR-SB score was:
    • Lecanemab: 1.21
    • Placebo: 1.66
    • Difference: -0.45 (95% CI: -0.67 to -0.23; P<0.001)
  • Substudy results showed:
    • Greater reduction in brain amyloid burden with lecanemab (-59.1 centiloids; 95% CI: -62.6 to -55.6).
    • Other significant mean differences favoring lecanemab included:
      • ADAS-cog14: -1.44 (95% CI: -2.27 to -0.61; P<0.001)
      • ADCOMS: -0.050 (95% CI: -0.074 to -0.027; P<0.001)
      • ADCS-MCI-ADL: 2.0 (95% CI: 1.2 to 2.8; P<0.001)
  • Adverse events included infusion-related reactions (26.4%) and amyloid-related imaging abnormalities (12.6%).

Main Conclusions/Significance/Innovation ​

Lecanemab demonstrated a significant reduction in amyloid levels and resulted in moderately less cognitive and functional decline compared to placebo over 18 months. Despite these positive outcomes, the treatment was associated with adverse events, indicating a need for careful monitoring. The findings suggest that lecanemab could be a promising therapeutic option for early Alzheimer's disease, warranting further long-term studies to assess its safety and efficacy.

Research Limitations and Future Directions ​

  • Limitations: The trial duration of 18 months may not be sufficient to fully understand the long-term effects and safety of lecanemab. The occurrence of adverse events raises concerns about the risk-benefit profile.
  • Future Directions: Longer-term studies are necessary to confirm the efficacy and safety of lecanemab in a broader population, as well as to explore the mechanisms underlying the observed adverse effects. Further research could also investigate the optimal patient population and treatment regimen for maximizing benefits while minimizing risks.

Literatures Citing This Work ​

  1. The science events to watch for in 2023. - Miryam Naddaf - Nature (2023)
  2. TREM2 dependent and independent functions of microglia in Alzheimer's disease. - Jinchao Hou;Yun Chen;Gary Grajales-Reyes;Marco Colonna - Molecular neurodegeneration (2022)
  3. Aβ42 oligomer-specific antibody ALZ-201 reduces the neurotoxicity of Alzheimer's disease brain extracts. - Anders Sandberg;Ernesto Berenjeno-Correa;Rosa Crespo Rodriguez;Michael Axenhus;Sophia Schedin Weiss;Kevin Batenburg;Jeroen J M Hoozemans;Lars O Tjernberg;Wiep Scheper - Alzheimer's research & therapy (2022)
  4. Multiple Cerebral Hemorrhages in a Patient Receiving Lecanemab and Treated with t-PA for Stroke. - Nicholas J Reish;Pouya Jamshidi;Brian Stamm;Margaret E Flanagan;Elizabeth Sugg;Mengxuan Tang;Kelly L Donohue;Matthew McCord;Chase Krumpelman;Marek-Marsel Mesulam;Rudolph Castellani;Sherry H-Y Chou - The New England journal of medicine (2023)
  5. Moving the Needle on Alzheimer's Disease with an Anti-Oligomer Antibody. - Sam Gandy;Michelle E Ehrlich - The New England journal of medicine (2023)
  6. Lecanemab trial in AD brings hope but requires greater clarity. - Madhav Thambisetty;Robert Howard - Nature reviews. Neurology (2023)
  7. FDA approves Alzheimer's drug lecanemab amid safety concerns. - Sara Reardon - Nature (2023)
  8. Application of 89Zr-DFO*-immuno-PET to assess improved target engagement of a bispecific anti-amyloid-ß monoclonal antibody. - N Stergiou;T E Wuensche;M Schreurs;I Mes;M Verlaan;E J M Kooijman;A D Windhorst;L Helboe;S Vergo;S Christensen;A A Asuni;A Jensen;G A M S Van Dongen;B Bang-Andersen;D J Vugts;W Beaino - European journal of nuclear medicine and molecular imaging (2023)
  9. Editorial: Accelerating Innovations for Enhanced Brain Health. Can Artificial Intelligence Advance New Pathways for Drug Discovery for Alzheimer's and other Neurodegenerative Disorders? - A S Khachaturian;A Dengel;V Dočkal;P Hroboň;M Tolar - The journal of prevention of Alzheimer's disease (2023)
  10. Initial non-amnestic symptoms relate to faster rate of functional and cognitive decline compared to amnestic symptoms in neuropathologically confirmed dementias. - Jagan A Pillai;James Bena;Emily F Maly;James B Leverenz - Alzheimer's & dementia : the journal of the Alzheimer's Association (2023)

... (2122 more literatures)

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