Aducanumab, a controversial Alzheimer disease therapeutic with questionable efficacy, is under Therapeutic Goods Administration review
Dementia, the second leading cause of death in Australia,1 affects nearly half a million people.2 It is the single greatest cause of disability in Australians aged 65 years and over and cost more than $15 billion in 2018.2 Alzheimer disease (AD) accounts for about two‐thirds of cases.3 The need for disease‐modifying treatment for AD is clearly one of the highest priorities for current medical research.
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- 1. Australian Bureau of Statistics. Causes of death, Australia (Cat. No. 3303.0). Canberra: ABS, 2021; https://www.abs.gov.au/statistics/health/causes‐death/causes‐death‐australia/latest‐release#australia‐s‐leading‐causes‐of‐death‐2020 (viewed Jan 2022).
- 2. Dementia Australia. Dementia statistics: key facts and statistics https://www.dementia.org.au/statistics (viewed Jan 2022).
- 3. World Health Organization. Global, regional, and national burden of Alzheimer’s disease and other dementias, 1990–2016: a systematic analysis for the Global Burden of Disease Study 2016. Lancet Neurol 2019; 18: 88–106.
- 4. Hardy JA, Higgins GA. Alzheimer’s disease: the amyloid cascade hypothesis. Science 1992; 256: 184–185.
- 5. Ayton S, Bush AI. β‐amyloid: the known unknowns. Ageing Res Rev 2021; 65: 101212.
- 6. Herrup K. The case for rejecting the amyloid cascade hypothesis. Nat Neurosci 2015; 18: 794–799.
- 7. US Food and Drug Administration. Highlights of prescribing information: Aduhelm, July 2021. Reference ID: 4807032. https://www.accessdata.fda.gov/drugsatfda_docs/label/2021/761178s003lbl.pdf (viewed July 2021).
- 8. Cavazzoni P. FDA’s decision to approve new treatment for Alzheimer’s disease [media release]. 6 July 2021. https://www.fda.gov/drugs/news‐events‐human‐drugs/fdas‐decision‐approve‐new‐treatment‐alzheimers‐disease (viewed July 2021).
- 9. Fillit H, Green A. Aducanumab and the FDA ‐ where are we now? Nat Rev Neurol 2021; 17: 129–130.
- 10. Joseph A. Third member of FDA expert committee resigns over controversial Alzheimer’s therapy decision. Stat News 2021; 10 June. https://www.statnews.com/2021/06/10/third‐member‐of‐fda‐expert‐committee‐resigns‐over‐controversial‐alzheimers‐therapy‐decision/ (accesed July 2021)
- 11. Gumbrecht J. Acting FDA commissioner calls for independent investigation into approval of Alzheimer’s drug. CNN Health 2021; 9 July. https://edition.cnn.com/2021/07/09/health/aduhelm‐fda‐requests‐inspection/index.html (viewed July 2021).
- 12. Knopman DS, Perlmutter JS. Prescribing aducanumab in the face of meager efficacy and real risks. Neurology 2021; 97: 545–547.
- 13. Lin G, Whittington M, Synnott P, et al. Aducanumab for Alzheimer’s disease: effectiveness and value: draft evidence report. Boston: Institute for Clinical and Economic Review, 2021. https://icer.org/wp‐content/uploads/2020/10/ICER_ALZ_Draft_Evidence_Report_050521.pdf (viewed July 2021).
- 14. Alexander GC, Emerson S, Kesselheim AS. Evaluation of aducanumab for alzheimer disease: scientific evidence and regulatory review involving efficacy, safety, and futility. JAMA 2021; 325: 1717–1718.
- 15. Gleason A, Ayton S, Bush AI. Unblinded by the light: amyloid‐related imaging abnormalities in Alzheimer’s clinical trials. Eur J Neurol 2021; 28: e1.
- 16. Andrews JS, Desai U, Kirson NY, et al. Disease severity and minimal clinically important differences in clinical outcome assessments for Alzheimer’s disease clinical trials. Alzheimers Dement (NY) 2019; 5: 354–363.
- 17. Birks JS, Harvey RJ. Donepezil for dementia due to Alzheimer’s disease. Cochrane Database Syst Rev 2018; (6): CD001190.
- 18. Ackley SF, Zimmerman SC, Brenowitz WD, et al. Effect of reductions in amyloid levels on cognitive change in randomized trials: instrumental variable meta‐analysis. BMJ 2021; 372: n156.
- 19. Egan MF, Kost J, Voss T, et al. Randomized trial of verubecestat for prodromal Alzheimer’s disease. N Engl J Med 2019; 380: 1408–1420.
- 20. Richard E, den Brok M, van Gool WA. Bayes analysis supports null hypothesis of anti‐amyloid beta therapy in Alzheimer’s disease. Alzheimers Dement 2021; 17: 1051–1055.
- 21. Sperling RA, Jack CR, Jr., 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: 367–385.
- 22. US Food and Drug Administration. Statistical review and evaluation: aducanumab (Application No. 761178Orig1s0002021). 7 July 2020. https://www.accessdata.fda.gov/drugsatfda_docs/nda/2021/761178Orig1s000StatR_Redacted.pdf (viewed July 2021).
- 23. VandeVrede L, Gibbs DM, Koestler M, et al. Symptomatic amyloid‐related imaging abnormalities in an APOE ε4/ε4 patient treated with aducanumab. Alzheimers Dement (Amst) 2020; 12: e12101.
- 24. Ryan NS, Lashley T, Revesz T, et al. Spontaneous ARIA (amyloid‐related imaging abnormalities) and cerebral amyloid angiopathy related inflammation in presenilin 1‐associated familial Alzheimer’s disease. J Alzheimers Dis 2015; 44: 1069–1074.
- 25. Piazza F, Greenberg SM, Savoiardo M, et al. Anti‐amyloid β autoantibodies in cerebral amyloid angiopathy‐related inflammation: implications for amyloid‐modifying therapies. Ann Neurol 2013; 73: 449–458.
- 26. Heuer E, Jacobs J, Du R, et al. Amyloid‐related imaging abnormalities in an aged squirrel monkey with cerebral amyloid angiopathy. J Alzheimers Dis 2017; 57: 519–530.
- 27. Greenberg SM, Vernooij MW, Cordonnier C, et al. Cerebral microbleeds: a guide to detection and interpretation. Lancet Neurol 2009; 8: 165–174.
- 28. Pharmaceutical Benefits Scheme. PBS expenditure and prescriptions report 1 July 2019 to 30 June 2020. https://www.pbs.gov.au/info/statistics/expenditure‐prescriptions/pb‐expenditure‐and‐prescriptions‐report‐1‐july‐2019 (viewed July 2021)
- 29. Beach TG, Monsell SE, Phillips LE, Kukull W. Accuracy of the clinical diagnosis of Alzheimer disease at National Institute on Aging Alzheimer Disease Centers, 2005–2010. J Neuropathol Exp Neurol 2012; 71: 266–273.
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This work was supported by funds from the National Health and Medical Research Council of Australia. The Florey Institute also acknowledges support from the Victorian Government Operational Infrastructure Support Program. The funding sources acknowledged provide support to the authors but did not have any direct role in planning, writing or publication of this work.
Ashley Bush is a shareholder in Alterity Ltd, Cogstate Ltd and Mesoblast Ltd. He is a paid consultant for, and has a profit share interest in, Collaborative Medicinal Development Pty Ltd.