References
- Alzheimer’s Association. 2021 Alzheimer’s disease facts and figures. Alzheimers Dement. 2021;17(3):327–406. doi:10.1002/alz.12328.
- World Health Organization. Global action plan on the public health response to dementia 2017–2025. Geneva:World Heal Organ; 2017: 27. Available from: http://www.who.int/mental_health/neurology/dementia/action_plan_2017_2025/en/. Accessed May 14, 2022.
- Lane CA, Hardy J, Schott JM. Alzheimer’s disease. Eur J Neurol. 2018;25(1):59–70. doi:10.1111/ene.13439
- Deture MA, Dickson DW. The neuropathological diagnosis of Alzheimer’s disease. Mol Neurodegener. 2019;14(1):1–18. doi:10.1186/s13024-019-0333-5
- U.S. Food and Drug Administration (FDA). FDA grants accelerated approval for Alzheimer’s drug. FDA News Release; 2021. Available from: https://www.fda.gov/news-events/press-announcements/fda-grants-accelerated-approval-alzheimers-drug. Accessed November 14, 2021.
- Sevigny J, Chiao P, Bussière T, et al. The antibody aducanumab reduces Aβ plaques in Alzheimer’s disease. Nature. 2016;537(7618):50–56. doi:10.1038/nature19323
- Selkoe DJ, Hardy J. The amyloid hypothesis of Alzheimer’s disease at 25 years. EMBO Mol Med. 2016;8(6):595–608. doi:10.15252/emmm.201606210
- Pietro IB, Ippati S, Watling M. Should drug discovery scientists still embrace the amyloid hypothesis for Alzheimer’s disease or should they be looking elsewhere? Expert Opin Drug Discov. 2020;15(11):1241–1251. doi:10.1080/17460441.2020.1793755
- Salloway S, Farlow M, McDade E, et al. A trial of gantenerumab or solanezumab in dominantly inherited Alzheimer’s disease. Nat Med. 2021;27(7):1187–1196. doi:10.1038/s41591-021-01369-8
- Sturchio A, Dwivedi AK, Young CB, et al. High cerebrospinal amyloid-β 42 is associated with normal cognition in individuals with brain amyloidosis. EClinicalMedicine. 2021;38:100988. doi:10.1016/j.eclinm.2021.100988
- Landmark Alzheimer’s MA. drug approval confounds research community. Nature. 2021;594(7863):309–310. doi:10.1038/d41586-021-01546-2
- Rubin R. Recently approved Alzheimer drug raises questions that might never be answered. JAMA. 2021;326(6):469. doi:10.1001/jama.2021.11558
- Walsh S, Merrick R, Milne R, Brayne C. Aducanumab for Alzheimer’s disease? BMJ. 2021;374. doi:10.1136/bmj.n1682.
- Nisticò R, Borg JJ. Aducanumab for Alzheimer’s disease: a regulatory perspective. Pharmacol Res. 2021;171:105754. doi:10.1016/j.phrs.2021.105754
- Alzheimer’s Forum Association. Aducanumab approved to treat Alzheimer’s disease. Alzforum; 2021. Available from: https://www.alzforum.org/news/research-news/aducanumab-approved-treat-alzheimers-disease. Accessed November 11, 2021.
- Hooker JM. FDA Approval of aducanumab divided the community but also connected and united it. ACS Chem Neurosci. 2021;12(15):2716–2717. doi:10.1021/acschemneuro.1c00393
- Cummings J, Aisen P, Lemere C, Atri A, Sabbagh M, Salloway S. Aducanumab produced a clinically meaningful benefit in association with amyloid lowering. Alzheimers Res Ther. 2021;13(1):1–3. doi:10.1186/s13195-021-00838-z
- Alzheimer’s Forum Association. FDA advisory committee throws cold water on aducanumab filing. Alzforum; 2020. Available from: https://www.alzforum.org/news/community-news/fda-advisory-committee-throws-cold-water-aducanumab-filing. Accessed November 11, 2021.
- U.S. Food and Drug Administration (FDA). Combined FDA and applicant PCNS drugs advisory committee briefing document. Peripheral and Central Nervous System (PCNS) Drugs Advisory Committee Meeting. Online; 2020. Available from: https://www.fda.gov/media/143502/download. Accessed November 14, 2021.
- Mahase E. Three FDA advisory panel members resign over approval of Alzheimer’s drug. BMJ. 2021;373:n1503. doi:10.1136/bmj.n1503
- Salloway S, Chalkias S, Barkhof F, et al. Amyloid-related imaging abnormalities in 2 phase 3 studies evaluating aducanumab in patients with early Alzheimer disease. JAMA Neurol. 2021. doi:10.1001/jamaneurol.2021.4161
- European Medicines Agency (EMA). Refusal of the marketing authorisation for Aduhelm (aducanumab). EMA; 2021. Available from: https://www.ema.europa.eu/documents/smop-initial/refusal-marketing-authorisation-aduhelm-aducanumab_en.pdf. Accessed December 17, 2021.
- Lythgoe MP, Jenei K, Prasad V. Regulatory decisions diverge over aducanumab for Alzheimer’s disease. BMJ. 2022;376. doi:10.1136/bmj-2021-069780.
- Eisai. Japan’s first committee on new drugs of the pharmaceutical affairs and food sanitation council seeks additional data; aducanumab remains under review. Eisai Global; 2021. Available from: https://www.eisai.com/news/2021/news2021101.html. Accessed April 9, 2022.
- Long JM, Holtzman DM. Alzheimer disease: an update on pathobiology and treatment strategies. Cell. 2019;179(2):312–339. doi:10.1016/j.cell.2019.09.001
- Vaz M, Silvestre S. Alzheimer’s disease: recent treatment strategies. Eur J Pharmacol. 2020;887:173554. doi:10.1016/j.ejphar.2020.173554
- Penke B, Szucs M, Bogár F. Oligomerization and conformational change turn monomeric β-amyloid and tau proteins toxic: their role in Alzheimer’s pathogenesis. Molecules. 2020;25(7):1659. doi:10.3390/molecules25071659
- Cline EN, Bicca MA, Viola KL, Klein WL. The amyloid-β oligomer hypothesis: beginning of the third decade. J Alzheimers Dis. 2018;64(s1):S567–S610. doi:10.3233/JAD-179941
- Chen XQ, Mobley WC. Alzheimer disease pathogenesis: insights from molecular and cellular biology studies of oligomeric Aβ and tau species. Front Neurosci. 2019;13:(JUN):659. doi:10.3389/fnins.2019.00659
- Arndt JW, Qian F, Smith BA, et al. Structural and kinetic basis for the selectivity of aducanumab for aggregated forms of amyloid-β. Sci Rep. 2018;8(1):1–16. doi:10.1038/s41598-018-24501-0
- Linse S, Scheidt T, Bernfur K, et al. Kinetic fingerprints differentiate the mechanisms of action of anti-Aβ antibodies. Nat Struct Mol Biol. 2020;27(12):1125–1133. doi:10.1038/s41594-020-0505-6
- U.S. Food and Drug Administration (FDA). Aducanumab for the treatment of Alzheimer’s disease: clinical overview of efficacy. Peripheral and Central Nervous System (PCNS) Drugs Advisory Committee Meeting. Online; 2020. Available from: https://www.fda.gov/media/143504/download. Accessed November 14, 2021.
- Bussiere T, Weinreb PH, Dunstan RW, et al. Differential in vitro and in vivo binding profiles of BIIB037 and other anti-abeta clinical antibody candidates. Neurodegener Dis. 2013;11(Suppl1):2576.
- Ferrero J, Williams L, Stella H, et al. First-in-human, double-blind, placebo-controlled, single-dose escalation study of aducanumab (BIIB037) in mild-to-moderate Alzheimer’s disease. Alzheimers Dement Transl Res Clin Interv. 2016;2(3):169–176. doi:10.1016/j.trci.2016.06.002
- Biogen. EMERGE and ENGAGE topline results: two phase 3 studies to evaluate aducanumab in patients with early Alzheimer’s disease. Clinical Trials on Alzheimer’s Disease (CTAD). San Diego; 2019. Available from: https://investors.biogen.com/static-files/ddd45672-9c7e-4c99-8a06-3b557697c06f. Accessed November 14, 2021.
- Biogen. Biogen and eisai to discontinue phase 3 ENGAGE and EMERGE trials of aducanumab in Alzheimer’s disease. Biogen; 2019. Available from: https://investors.biogen.com/news-releases/news-release-details/biogen-and-eisai-discontinue-phase-3-engage-and-emerge-trials. Accessed November 8, 2021.
- Knopman DS, Jones DT, Greicius MD. Failure to demonstrate efficacy of aducanumab: an analysis of the EMERGE and ENGAGE trials as reported by Biogen, December 2019. Alzheimers Dement. 2021;17(4):696–701. doi:10.1002/alz.12213
- Biogen. Biogen plans regulatory filing for aducanumab in Alzheimer’s disease based based on new analysis of larger dataset from phase 3 studies. Biogen. 2019. Available from: https://investors.biogen.com/news-releases/news-release-details/biogen-plans-regulatory-filing-aducanumab-alzheimers-disease. Accessed November 20, 2021.
- Tampi RR, Forester BP, Aducanumab: AM. Evidence from clinical trial data and controversies. Drugs Context. 2021;10:1–9. doi:10.7573/dic.2021-7-3
- Belluck P, Robbins R. Three F.D.A. advisers resign over approval of Alzheimer’s drug. The New York Times; 2021. Available from: https://www.nytimes.com/2021/06/10/health/aduhelm-fda-resign-alzheimers.html. Accessed April 9, 2022.
- U.S. Food and Drug Administration (FDA). Accelerated Approval; 2021. Available from: https://www.fda.gov/patients/fast-track-breakthrough-therapy-accelerated-approval-priority-review/accelerated-approval. Accessed April 10, 2022.
- Biogen. European medicines agency accepts Biogen’s aducanumab marketing authorization application for Alzheimer’s disease. Biogen; 2020. Available from: https://investors.biogen.com/news-releases/news-release-details/european-medicines-agency-accepts-biogens-aducanumab-marketing. Accessed November 23, 2021.
- Mahase E. Aducanumab: European agency rejects Alzheimer’s drug over efficacy and safety concerns. BMJ. 2021;375:n3127. doi:10.1136/bmj.n3127
- Biogen. Update on regulatory review of aducanumab in the European Union. Biogen. Available from: https://investors.biogen.com/news-releases/news-release-details/update-regulatory-submission-aducanumab-european-union.; 2021. Accessed April 9, 2022.
- Castrillo-Viguera C, Chalkias S, Burkett P, et al. EMBARK: a Phase 3b, open-label, single-arm, safety study to evaluate the long-term safety and efficacy of aducanumab in eligible participants with Alzheimer’s disease (2448). Neurology. 2021;96(15Supplement):2448.
- ClinicalTrials.gov. A study to evaluate safety and tolerability of aducanumab in participants with Alzheimer’s disease who had previously participated in the aducanumab studies 221AD103, 221AD301, 221AD302 and 221AD205; 2020. Available from: https://clinicaltrials.gov/ct2/show/NCT04241068?term=aducanumab&draw=2&rank=3. Accessed November 13, 2021.
- Biogen. ADUHELM ICARE AD-US study, the first real-world observational phase 4 study in Alzheimer’s disease at AAIC 2021. Biogen; 2021. Available from: https://investors.biogen.com/news-releases/news-release-details/biogen-and-eisai-announce-design-aduhelm-icare-ad-us-study-first. Accessed November 13, 2021.
- ClinicalTrials.gov. An observational study of aducanumab-avwa in participants with Alzheimer’s disease in the US - full text view - ClinicalTrials.gov; 2021. Available from: https://clinicaltrials.gov/ct2/show/NCT05097131?term=aducanumab&draw=2&rank=10. Accessed November 13, 2021.
- Biogen. Update on the phase 4 confirmatory study of ADUHELM®. Biogen; 2021. Available from: https://investors.biogen.com/news-releases/news-release-details/update-phase-4-confirmatory-study-aduhelmr. Accessed December 17, 2021.
- Biogen. Update on the Phase 4 ENVISION confirmatory study of ADUHELM® | biogen. Biogen; 2022. Available from: https://investors.biogen.com/news-releases/news-release-details/update-phase-4-envision-confirmatory-study-aduhelmr. Accessed January 29, 2022.
- U.S. Food and Drug Administration (FDA). ADUHELM: full prescribing information; 2021. Available from: https://www.accessdata.fda.gov/drugsatfda_docs/label/2021/761178s003lbl.pdf. Accessed November 14, 2021.
- Greenberg SM, Bacskai BJ, Hernandez-Guillamon M, Pruzin J, Sperling R, van Veluw SJ. Cerebral amyloid angiopathy and Alzheimer disease — one peptide, two pathways. Nat Rev Neurol. 2020;16(1):30–42. doi:10.1038/s41582-019-0281-2
- Sperling RA, Jack CR, Black SE, et al. Amyloid-related imaging abnormalities in amyloid-modifying therapeutic trials: recommendations from the Alzheimer’s Association Research Roundtable Workgroup. Alzheimers Dement. 2011;7(4):367–385. doi:10.1016/j.jalz.2011.05.2351
- Salloway S, Sperling R, Fox NC, et al. Two phase 3 trials of bapineuzumab in mild-to-moderate Alzheimer’s disease. N Engl J Med. 2014;370(4):322–333. doi:10.1056/nejmoa1304839
- Avgerinos KI, Ferrucci L, Kapogiannis D. Effects of monoclonal antibodies against amyloid-β on clinical and biomarker outcomes and adverse event risks: a systematic review and meta-analysis of Phase III RCTs in Alzheimer’s disease. Ageing Res Rev. 2021;68:101339. doi:10.1016/j.arr.2021.101339
- Penninkilampi R, Brothers HM, Eslick GD. Safety and efficacy of anti-amyloid-β Immunotherapy in Alzheimer’s disease: a systematic review and meta-analysis. J Neuroimmune Pharmacol. 2017;12(1):194–203. doi:10.1007/s11481-016-9722-5
- Gleason A, Ayton S, Bush AI. Unblinded by the light: amyloid-related imaging abnormalities in Alzheimer’s clinical trials. Eur J Neurol. 2021;28(1):e1. doi:10.1111/ene.14484
- Biogen. New phase 3 data show positive correlation between ADUHELMTM treatment effect on biomarkers and reduction in clinical decline in Alzheimer’s disease | biogen. Biogen; 2021. Available from: https://investors.biogen.com/news-releases/news-release-details/new-phase-3-data-show-positive-correlation-between-aduhelmtm?cid=osm-lkdn-ctad-um-alz-111121. Accessed November 28, 2021.
- Fleck LM. Alzheimer’s and aducanumab: unjust profits and false hopes. Hastings Cent Rep. 2021;51(4):9–11. doi:10.1002/hast.1264
- Alexander GC, Knopman DS, Emerson SS, et al. Revisiting FDA approval of Aducanumab. N Engl J Med. 2021;385(9):769–771. doi:10.1056/nejmp2110468
- La JR, Visani AV, Baker SL, et al. Prospective longitudinal atrophy in Alzheimer’s disease correlates with the intensity and topography of baseline tau-PET. Sci Transl Med. 2020;12:524. doi:10.1126/scitranslmed.aau5732
- Leuzy A, Smith R, Cullen NC, et al. Biomarker-based prediction of longitudinal tau positron emission tomography in Alzheimer disease. JAMA Neurol. 2021;79(2):149–158. doi:10.1001/jamaneurol.2021.4654
- Mukhopadhyay S, Banerjee D. A primer on the evolution of aducanumab: the first antibody approved for treatment of Alzheimer’s disease. J Alzheimers Dis. 2021;83(4):1537–1552. doi:10.3233/JAD-215065
- Alexander GC, Emerson S, Kesselheim AS. Evaluation of aducanumab for Alzheimer disease: scientific evidence and regulatory review involving efficacy, safety, and futility. J Am Med Assoc. 2021;325(17):1717–1718. doi:10.1001/jama.2021.3854
- Alzheimer’s Forum Association. Aducanumab approved to treat Alzheimer’s disease. Alzforum; 2021. Available from: https://www.alzforum.org/news/research-news/aducanumab-approved-treat-alzheimers-disease. Accessed January 6, 2022.
- Institute for Clinical and Economic Review. ICER issues statement on the FDA’s approval of aducanumab for Alzheimer’s disease. ICER; 2021. Available from: https://icer.org/news-insights/press-releases/icer-issues-statement-on-The-fdas-approval-of-aducanumab-for-alzheimers-disease/. Accessed November 11, 2021.
- Biogen. Biogen announces reduced price for ADUHELM® to improve access for patients with early Alzheimer’s disease | biogen. Biogen; 2021. Available From: https://investors.biogen.com/news-releases/news-release-details/biogen-announces-reduced-price-aduhelmr-improve-access-patients. Accessed January 9, 2022.
- Whittington MD, Campbell JD, Rind D, Fluetsch N, Lin GA, Pearson SD. Cost-effectiveness and value-based pricing of aducanumab for patients with early Alzheimer disease. Neurology. 2022;98(9):e968–e977. doi:10.1212/WNL.0000000000013314
- Cummings J, Aisen P, Apostolova LG, Atri A, Salloway S, Weiner M. Aducanumab: appropriate use recommendations. J Prev Alzheimers Dis. 2021;8(4):398–410. doi:10.14283/jpad.2021.41
- Centers for Medicare & Medicaid Services. Monoclonal antibodies directed against amyloid for the treatment of Alzheimer’s disease; 2022. Available from: https://www.cms.gov/newsroom/press-releases/cms-finalizes-medicare-coverage-policy-monoclonal-antibodies-directed-against-amyloid-treatment. Accessed April 11, 2022.
- Belluck P. Medicare officially limits coverage of aduhelm to patients in clinical trials. The New York Times; 2022. Available from: https://www.nytimes.com/2022/04/07/health/aduhelm-medicare-alzheimers.html. Accessed April 10, 2022.
- Butcher L. Mixed response to the CMS decision on coverage for aducanumab. Neurol Today. 2022;22(3):1,16–17. doi:10.1097/01.nt.0000821676.02301.7a
- Association AF. On aduhelm, medicare agency gets pressure from all sides | ALZFORUM. Alzforum; 2022. Available from: https://www.alzforum.org/news/community-news/aduhelm-medicare-agency-gets-pressure-all-sides. Accessed January 27, 2022.
- Association AF. CMS plans to limit aduhelm coverage to clinical trials | ALZFORUM. Alzforum; 2022. Available from: https://www.alzforum.org/news/research-news/cms-plans-limit-aduhelm-coverage-clinical-trials. Accessed January 27, 2022.
- Bednar MM. Combination therapy for Alzheimer’s disease and related dementias. In: Progress in Molecular Biology and Translational Science. Academic Press; Vol. 168. 2019:289–296. doi:10.1016/bs.pmbts.2019.10.001
- Lythgoe MP, Prasad V. How the US Food and Drug Administration’s approval of aducanumab for Alzheimer’s disease has implication for oncology and beyond. Eur J Cancer. 2021;157:68–70. doi:10.1016/j.ejca.2021.08.012
- Gyawali B, Ross JS, Kesselheim AS. Fulfilling the mandate of the US Food and Drug Administration’s accelerated approval pathway: the need for reforms. JAMA Intern Med. 2021;181(10):1275–1276. doi:10.1001/jamainternmed.2021.4604
- Silvestro S, Valeri A, Mazzon E. Aducanumab and its effects on tau pathology: is this the turning point of amyloid hypothesis? Int J Mol Sci. 2022;23(4):2011. doi:10.3390/ijms23042011
- Association AF. Aduhelm lowers tau; registry to track real-world performance | ALZFORUM. Alzforum; 2021. Available from: https://www.alzforum.org/news/conference-coverage/aduhelm-lowers-tau-registry-track-real-world-performance. Accessed February 1, 2022.