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

Donanemab in Early Alzheimer's Disease. ​

Literature Information ​

DOI10.1056/NEJMoa2100708
PMID33720637
JournalThe New England journal of medicine
Impact Factor78.5
JCR QuartileQ1
Publication Year2021
Times Cited717
KeywordsDonanemab, Early Alzheimer's Disease, Amyloid-beta, Cognitive Function, Clinical Trial
Literature TypeClinical Trial, Phase II, Journal Article, Multicenter Study, Randomized Controlled Trial, Research Support, Non-U.S. Gov't
ISSN0028-4793
Pages1691-1704
Issue384(18)
AuthorsMark A Mintun, Albert C Lo, Cynthia Duggan Evans, Alette M Wessels, Paul A Ardayfio, Scott W Andersen, Sergey Shcherbinin, JonDavid Sparks, John R Sims, Miroslaw Brys, Liana G Apostolova, Stephen P Salloway, Daniel M Skovronsky

TL;DR ​

This phase 2 trial evaluated donanemab, an antibody targeting amyloid-β, in patients with early symptomatic Alzheimer's disease, finding that it improved cognitive and daily living abilities compared to placebo at 76 weeks, as indicated by a higher iADRS score. While reductions in amyloid and tau burden were noted, secondary outcomes showed mixed results, highlighting the need for further research to assess donanemab's long-term efficacy and safety.

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Donanemab · Early Alzheimer's Disease · Amyloid-beta · Cognitive Function · Clinical Trial

Abstract ​

BACKGROUND A hallmark of Alzheimer's disease is the accumulation of amyloid-β (Aβ) peptide. Donanemab, an antibody that targets a modified form of deposited Aβ, is being investigated for the treatment of early Alzheimer's disease.

METHODS We conducted a phase 2 trial of donanemab in patients with early symptomatic Alzheimer's disease who had tau and amyloid deposition on positron-emission tomography (PET). Patients were randomly assigned in a 1:1 ratio to receive donanemab (700 mg for the first three doses and 1400 mg thereafter) or placebo intravenously every 4 weeks for up to 72 weeks. The primary outcome was the change from baseline in the score on the Integrated Alzheimer's Disease Rating Scale (iADRS; range, 0 to 144, with lower scores indicating greater cognitive and functional impairment) at 76 weeks. Secondary outcomes included the change in scores on the Clinical Dementia Rating Scale-Sum of Boxes (CDR-SB), the 13-item cognitive subscale of the Alzheimer's Disease Assessment Scale (ADAS-Cog13), the Alzheimer's Disease Cooperative Study-Instrumental Activities of Daily Living Inventory (ADCS-iADL), and the Mini-Mental State Examination (MMSE), as well as the change in the amyloid and tau burden on PET.

RESULTS A total of 257 patients were enrolled; 131 were assigned to receive donanemab and 126 to receive placebo. The baseline iADRS score was 106 in both groups. The change from baseline in the iADRS score at 76 weeks was -6.86 with donanemab and -10.06 with placebo (difference, 3.20; 95% confidence interval, 0.12 to 6.27; P = 0.04). The results for most secondary outcomes showed no substantial difference. At 76 weeks, the reductions in the amyloid plaque level and the global tau load were 85.06 centiloids and 0.01 greater, respectively, with donanemab than with placebo. Amyloid-related cerebral edema or effusions (mostly asymptomatic) occurred with donanemab.

CONCLUSIONS In patients with early Alzheimer's disease, donanemab resulted in a better composite score for cognition and for the ability to perform activities of daily living than placebo at 76 weeks, although results for secondary outcomes were mixed. Longer and larger trials are necessary to study the efficacy and safety of donanemab in Alzheimer's disease. (Funded by Eli Lilly; TRAILBLAZER-ALZ ClinicalTrials.gov number, NCT03367403.).

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Primary Questions Addressed ​

  1. What are the long-term effects of donanemab on cognitive decline in early Alzheimer's patients compared to other treatments?
  2. How does donanemab's mechanism of action differ from other amyloid-targeting therapies currently in development?
  3. What specific patient populations might benefit the most from donanemab treatment based on the trial results?
  4. How does the presence of tau deposition influence the efficacy of donanemab in treating Alzheimer's disease?
  5. What are the implications of the observed amyloid-related cerebral edema in patients receiving donanemab, and how should this affect clinical practice?

Key Findings ​

Key Insights: ​

  1. Research Background and Objective: Alzheimer's disease is characterized by the accumulation of amyloid-β (Aβ) peptide, which contributes to cognitive decline. Donanemab is an investigational antibody designed to target a modified form of deposited Aβ. This study aimed to evaluate the efficacy and safety of donanemab in patients with early symptomatic Alzheimer's disease who exhibit both tau and amyloid deposition as confirmed by positron-emission tomography (PET).

  2. Main Methods and Findings: The study was a phase 2 trial involving 257 patients diagnosed with early Alzheimer's disease. Participants were randomly assigned to receive either donanemab or a placebo, with intravenous infusions occurring every four weeks for up to 72 weeks. The primary outcome measure was the change in the Integrated Alzheimer's Disease Rating Scale (iADRS) score at 76 weeks. Secondary outcomes included several cognitive and functional assessment scales, as well as changes in amyloid and tau levels on PET scans. Results indicated that the change in the iADRS score was -6.86 for the donanemab group compared to -10.06 for the placebo, with a statistically significant difference of 3.20 (P = 0.04). Moreover, donanemab led to a reduction in amyloid plaque levels and tau burden, although the differences in secondary outcomes were not substantial. Adverse events related to amyloid were noted, primarily asymptomatic cerebral edema.

  3. Core Conclusions: Donanemab demonstrated a modest improvement in cognitive and functional abilities compared to placebo over a 76-week period in patients with early Alzheimer's disease. Although the primary outcome showed a statistically significant benefit, the mixed results in secondary outcomes underscore the complexity of treatment effects in Alzheimer's disease. Furthermore, safety concerns, particularly regarding amyloid-related cerebral edema, must be carefully considered.

  4. Research Significance and Impact: This study contributes to the growing body of evidence regarding the potential of amyloid-targeting therapies in Alzheimer's disease. The findings suggest that donanemab may offer a meaningful benefit in cognitive function and daily living activities for early-stage patients, supporting the continued exploration of amyloid modulation as a therapeutic strategy. However, the necessity for larger and longer-term trials is imperative to fully understand the efficacy and safety profile of donanemab, which could significantly influence treatment paradigms and improve outcomes for individuals with early Alzheimer's disease. The research also highlights the importance of monitoring for side effects, which is crucial in the clinical management of Alzheimer's therapies.

Literatures Citing This Work ​

  1. Strategies to reduce sample sizes in Alzheimer's disease primary and secondary prevention trials using longitudinal amyloid PET imaging. - Isadora Lopes Alves;Fiona Heeman;Lyduine E Collij;Gemma Salvadó;Nelleke Tolboom;Natàlia Vilor-Tejedor;Pawel Markiewicz;Maqsood Yaqub;David Cash;Elizabeth C Mormino;Philip S Insel;Ronald Boellaard;Bart N M van Berckel;Adriaan A Lammertsma;Frederik Barkhof;Juan Domingo Gispert - Alzheimer's research & therapy (2021)
  2. Alzheimer's Disease-Rationales for Potential Treatment with the Thrombin Inhibitor Dabigatran. - Klaus Grossmann - International journal of molecular sciences (2021)
  3. Aducanumab produced a clinically meaningful benefit in association with amyloid lowering. - Jeffrey Cummings;Paul Aisen;Cynthia Lemere;Alireza Atri;Marwan Sabbagh;Stephen Salloway - Alzheimer's research & therapy (2021)
  4. Alzheimer disease. - David S Knopman;Helene Amieva;Ronald C Petersen;Gäel Chételat;David M Holtzman;Bradley T Hyman;Ralph A Nixon;David T Jones - Nature reviews. Disease primers (2021)
  5. Neuroprotective Natural Products for Alzheimer's Disease. - Xin Chen;Joshua Drew;Wren Berney;Wei Lei - Cells (2021)
  6. Safety and Tolerability of Active Immunotherapy Targeting α-Synuclein with PD03A in Patients with Early Parkinson's Disease: A Randomized, Placebo-Controlled, Phase 1 Study. - Werner Poewe;Dieter Volc;Klaus Seppi;Rossella Medori;Petra Lührs;Alexandra Kutzelnigg;Atbin Djamshidian;Caroline Thun-Hohenstein;Wassilios G Meissner;Olivier Rascol;Achim Schneeberger;Günther Staffler; ; ;Werner Poewe;Klaus Seppi;Atbin Djamshidian;Roberto deMarzi;Beatrice Heim;Stephanie Mangesius;Raphaela Stolz;Katarzyna Wachowicz;Dieter Volc;Caroline Thun-Hohenstein;Constanze Riha;Achim Schneeberger;Vera Bürger;Gergana Galabova - Journal of Parkinson's disease (2021)
  7. New Hope for Alzheimer's Disease. - B Vellas;P Aisen - The journal of prevention of Alzheimer's disease (2021)
  8. Critical Appraisal of Amyloid Lowering Agents in AD. - Boris Decourt;Fadel Boumelhem;Evans D Pope;Jiong Shi;Zoltan Mari;Marwan Noel Sabbagh - Current neurology and neuroscience reports (2021)
  9. Effect of Age on Clinical Trial Outcome in Participants with Probable Alzheimer's Disease. - Steven D Targum;Lisa Fosdick;Kristen E Drake;Paul B Rosenberg;Anna D Burke;David A Wolk;Kelly D Foote;Wael F Asaad;Marwan Sabbagh;Gwenn S Smith;Andres M Lozano;Constantine G Lyketsos - Journal of Alzheimer's disease : JAD (2021)
  10. A trial of gantenerumab or solanezumab in dominantly inherited Alzheimer's disease. - Stephen Salloway;Martin Farlow;Eric McDade;David B Clifford;Guoqiao Wang;Jorge J Llibre-Guerra;Janice M Hitchcock;Susan L Mills;Anna M Santacruz;Andrew J Aschenbrenner;Jason Hassenstab;Tammie L S Benzinger;Brian A Gordon;Anne M Fagan;Kelley A Coalier;Carlos Cruchaga;Alison A Goate;Richard J Perrin;Chengjie Xiong;Yan Li;John C Morris;B Joy Snider;Catherine Mummery;G Mustafa Surti;Didier Hannequin;David Wallon;Sarah B Berman;James J Lah;Ivonne Z Jimenez-Velazquez;Erik D Roberson;Christopher H van Dyck;Lawrence S Honig;Raquel Sánchez-Valle;William S Brooks;Serge Gauthier;Douglas R Galasko;Colin L Masters;Jared R Brosch;Ging-Yuek Robin Hsiung;Suman Jayadev;Maité Formaglio;Mario Masellis;Roger Clarnette;Jérémie Pariente;Bruno Dubois;Florence Pasquier;Clifford R Jack;Robert Koeppe;Peter J Snyder;Paul S Aisen;Ronald G Thomas;Scott M Berry;Barbara A Wendelberger;Scott W Andersen;Karen C Holdridge;Mark A Mintun;Roy Yaari;John R Sims;Monika Baudler;Paul Delmar;Rachelle S Doody;Paulo Fontoura;Caroline Giacobino;Geoffrey A Kerchner;Randall J Bateman; - Nature medicine (2021)

... (707 more literatures)

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