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Aducanumab produced a clinically meaningful benefit in association with amyloid lowering

Aducanumab is a monoclonal antibody targeting amyloid beta protein (Aß), a defining feature of the biology of Alzheimer’s disease (AD) [1]. Laboratory studies showed high affinity of aducanumab for the neurotoxic oligomeric species of Aß [2]. Following a promising phase 1B trial [3], the sponsor (Biogen) implemented two phase 3 studies—EMERGE and ENGAGE. A planned futility analysis concluded that the treatment was not beneficial, and the trials were terminated. With the accrual of additional blinded data, the prespecified analysis of the primary outcome—Clinical Dementia Rating Sum of Boxes (CDR-sb)—showed that the EMERGE trial met its primary outcome and the ENGAGE trial did not. Biogen submitted the data to the US Food and Drug Administration (FDA) for review and possible marketing approval, setting the stage for a vigorous dialogue on aducanumab [4, 5].

The CDR-sb, comprising the primary outcome of ENGAGE and EMERGE, is a composite measure with cognitive and functional components including home activities, problem solving, and community engagement—skills highly valued by patients [6]. In EMERGE, aducanumab treatment resulted in a significant 22% slowing of decline on the CDR-sb [7]. This instrument has a restricted range (0–18); small changes reflect meaningful clinical alterations. In both trials, participants who received at least 14 doses of the highest dose of aducanumab showed similar levels of slowing on the CDR-sb (30% in EMERGE, 27% in ENGAGE). In EMERGE, all secondary measures including the Mini Mental State Examination, Alzheimer’s Disease Assessment Scale-cognitive subscale, and the Alzheimer’s Disease Cooperative Study Activities of Daily Living (ADCS ADL) scale showed statistically significant drug-placebo differences. The ADCS-ADL scale showed a robust 40% slowing of functional decline in the treatment group compared to the placebo group [7]. The Neuropsychiatric Inventory (NPI) that assesses an array of behavioral changes common in AD showed an 87% reduction from baseline scores in the high dose group of EMERGE [8]. There was a corresponding 84% reduction in caregiver distress. Disease-modifying therapies change the trajectory of disease progression; benefits observed in trials are anticipated to increase with long-term treatment. Extending the mild cognitive impairment stage of AD and delaying the dementia stage is very meaningful for a 68-year-old grandmother seeking to preserve daily activities, hobbies, and community and family engagement.

Amyloid plaques measured by amyloid positron emission tomography (PET) were markedly decreased by aducanumab in both trials. Phosphorylated tau (p-tau) in the cerebrospinal fluid (CSF) and medial temporal neurofibrillary tangles measured by tau PET in a small subset of patients were reduced as predicted by “the amyloid hypothesis.” Phosphorylated tau is closely linked to cognitive decline [1]. Statistically significant correlations were present between Aß reduction and the clinical outcomes of EMERGE and between Aß reduction and CSF p-tau changes [8].

An argument marshaled against accepting the EMERGE trial as evidence of efficacy is that previous clinical trials of drugs targeting Aß have been negative [4]. This view fails to account for recent promising clinical trials specifically involving anti-Aß monoclonal antibodies including lecanemab [9], gantenerumab [10], and donanemab [11] and the many learnings that have occurred concerning dose, targeting specific types of Aß, and treating patients earlier in the disease [12]. Doses of monoclonal antibodies have more than quadrupled from those used in previous trials as more evidence has informed exposure requirements, and study populations have shifted toward earlier intervention prior to extensive irreversible neurodegeneration. The recently reported positive donanemab phase 2 trial, linking reduction of brain amyloid with cognitive/functional benefit [11], provides particularly strong support for the therapeutic approach of aducanumab. In view of these recent findings, EMERGE results can be considered consistent with other similar studies rather than as an anomaly.

Aducanumab and several other monoclonal antibodies are associated with amyloid-related imaging abnormalities (ARIA) thought to represent effusion through the blood-brain barrier (ARIA-E) or hemorrhages (ARIA-H) associated with blood-brain barrier compromise. ARIA-E occurred in 34% and 35.5% of those receiving high-dose aducanumab in EMERGE and ENGAGE respectively. Most (80%) ARIA events are without symptoms. When symptoms occur, they include headache, dizziness, visual disturbances, and nausea. ARIA is a manageable side effect of treatment with aducanumab and far less compromising than complications of many routinely used cancer therapies.

Although not directly relevant to determining the efficacy and safety of aducanumab, criticism has been directed at the FDA for working too closely with Biogen in the submission process [13]. FDA has provided written guidance for regularly scheduled meetings with all sponsors and works closely with sponsors to ensure clear communication regarding trial expectations and outcome interpretations [14]. The FDA decision regarding aducanumab carries great significance for patients with AD and their families; close communication is required to reassure those whose lives could be altered by such a therapy that all due considerations have been observed.

In the EMERGE trial, aducanumab met its primary outcome and had beneficial effects on cognition, function, and behavior. Benefits were observed in ENGAGE participants who were treated with the high dose for longer periods. A decision not to approve aducanumab in spite of these outcomes will adversely affect the field of AD treatment research, discouraging biopharmaceutical companies from investing in this area [15]. The first treatment of AD, tacrine, had flaws, but it was a breakthrough that demonstrated the possibility of improving cognition in AD and was soon followed by improved and now widely used agents. We anticipate a similar reinvigoration of AD treatment research if aducanumab becomes publicly available.

An FDA Advisory Committee voted to recommend that the Agency not approve aducanumab based on a single positive study [4]. We believe that the perspective of the panel was too narrow, ignoring important scientific and clinically meaningful considerations. Based on the review of the totality of the data and our extensive experience with AD trials, research, and clinical care of patients and families, we conclude that aducanumab achieves the standard of meaningful efficacy with adequate safety in early AD. We support providing persons with AD, who face a progressive and incurable disease, with the option of making informed choices about their health and lives with respect to a first-generation drug with aducanumab’s risk-burden/benefit profile.

Availability of data and materials

Not applicable.

Abbreviations

Aβ:

Amyloid beta protein

AD:

Alzheimer’s disease

ADCS-ADL:

Alzheimer’s Disease Cooperative Study Activities of Daily Living

ARIA:

Amyloid-related imaging abnormalities

ARIA-E:

Amyloid-related imaging abnormalities—effusion

ARIA-H:

Amyloid-related imaging abnormalities—hemorrhages

CDR-sb:

Clinical Dementia Rating Sum of Boxes

CSF:

Cerebrospinal fluid

FDA:

US Food and Drug Administration

NPI:

Neuropsychiatric Inventory

PET:

Positron emission tomography

p-tau:

Phosphorylated tau

References

  1. 1.

    Jack CR Jr, Bennett DA, Blennow K, Carrillo MC, Dunn B, Haeberlein SB, et al. NIA-AA Research Framework: toward a biological definition of Alzheimer’s disease. Alzheimers Dement. 2018;14(4):535–62. https://doi.org/10.1016/j.jalz.2018.02.018.

    Article  PubMed  PubMed Central  Google Scholar 

  2. 2.

    Arndt JW, Qian F, Smith BA, Quan C, Kilambi KP, Bush MW, et al. Structural and kinetic basis for the selectivity of aducanumab for aggregated forms of amyloid-beta. Sci Rep. 2018;8(1):6412. https://doi.org/10.1038/s41598-018-24501-0.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  3. 3.

    Sevigny J, Chiao P, Bussiere T, Weinreb PH, Williams L, Maier M, et al. The antibody aducanumab reduces Abeta plaques in Alzheimer’s disease. Nature. 2016;537(7618):50–6. https://doi.org/10.1038/nature19323.

    CAS  Article  PubMed  Google Scholar 

  4. 4.

    Alexander GC, Emerson S, Kesselheim AS. Evaluation of aducanumab for Alzheimer disease: scientific evidence and regulatory review involving efficacy, safety, and futility. JAMA. 2021. https://doi.org/10.1001/jama.2021.3854.

  5. 5.

    Sabbagh MN, Cummings J. Open Peer Commentary to “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):702–3. https://doi.org/10.1002/alz.12235.

    Article  PubMed  Google Scholar 

  6. 6.

    Watson J, Saunders S, Muniz Terrera G, Ritchie C, Evans A, Luz S, et al. What matters to people with memory problems, healthy volunteers and health and social care professionals in the context of developing treatment to prevent Alzheimer’s dementia? A qualitative study. Health Expect. 2019;22(3):504–17. https://doi.org/10.1111/hex.12876.

    Article  PubMed  PubMed Central  Google Scholar 

  7. 7.

    Haeberlein SB, von Hehn C, Tian Y, et al., editors. EMERGE and ENGAGE topline results: two phase 3 studies to evaluate aducanumab in patients with early Alzheimer’s disease. San Diego, CA: 12th Clinical Trials on Alzheimer's Disease; 2019.

    Google Scholar 

  8. 8.

    Haeberlein SB. Aducanumab for the treatment of Alzheimer’s disease: Presentation. US Food and Drug Administration. Peripheral and Central Nervous System Drugs Advisory Board; 2020.

  9. 9.

    Swanson CJ, Zhang Y, Dhadda S, Wang J, Kaplow J, Lai RYK, et al. A randomized, double-blind, phase 2b proof-of-concept clinical trial in early Alzheimer’s disease with lecanemab, an anti-Abeta protofibril antibody. Alzheimers Res Ther. 2021;13(1):80. https://doi.org/10.1186/s13195-021-00813-8.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  10. 10.

    Klein G, Delmar P, Voyle N, Rehal S, Hofmann C, Abi-Saab D, et al. Gantenerumab reduces amyloid-beta plaques in patients with prodromal to moderate Alzheimer’s disease: a PET substudy interim analysis. Alzheimers Res Ther. 2019;11(1):101. https://doi.org/10.1186/s13195-019-0559-z.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  11. 11.

    Mintun MA, Lo AC, Duggan Evans C, Wessels AM, Ardayfio PA, Andersen SW, et al. Donanemab in early Alzheimer’s disease. N Engl J Med. 2021.

  12. 12.

    Cummings J, Feldman HH, Scheltens P. The “rights” of precision drug development for Alzheimer’s disease. Alzheimers Res Ther. 2019;11(1):76. https://doi.org/10.1186/s13195-019-0529-5.

    Article  PubMed  PubMed Central  Google Scholar 

  13. 13.

    Public Citizen’s Health Research Group. Request for an Office of Inspector General investigation of the Food and Drug Administration’s inappropriate close collaboration with Biogen before and after the submission of the biologics license application for aducanumab for treatment of Alzheimer’s disease; Public Citizen’s Health Research Group; 2020 accessed 02/19/2021; Available from: https://mkus3lurbh3lbztg254fzode-wpengine.netdna-ssl.com/wp-content/uploads/2660.pdf.

  14. 14.

    Food and Drug Administration, Center for Drug Evaluation and Research. Formal meetings between the FDA and sponsors or applicants of PDUFA Products Guidance for Industry. Silver Spring, MD: Office of Communictions, Division of Drug Information, Center for Drug Evaluation and Research, Food and Drug Administration; 2017.

    Google Scholar 

  15. 15.

    Editorial Board. The battle over an Alzheimer’s treatment; Biogen’s promising drug is caught in the FDA’s political and bureaucratic limbo. Wall Street J. 2021.

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Acknowledgements

JC and MS have the following research support: NIGMS P20GM109025 and NIA P20AG068053; JC has the following research support: NINDS U01NS093334; NIA R01AG053798 and R35AG71476.

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PA has received research funding from NIA, FNIH, the Alzheimer’s Association, Janssen, Lilly, and Eisai and personal fees from Biogen, Merck, Roche, Abbvie, ImmunoBrain Checkpoint, Rainbow Medical, and Shionogi. CL has provided consultation to Acumen Pharmaceutical, Apellis Pharmaceutical, Biogen (ADvance Medical Education International Working Group), Cambridge Healthcare Research, and Cognition Therapeutics. She received in-kind research support from Vivoryon Therapeutics. JC has provided consultation to Acadia, Alkahest, AriBio, Avanir, Axsome, Behren Therapeutics, Biogen, Cassava, Cerecin, Cerevel, Cortexyme, EIP Pharma, Eisai, GemVax, Genentech, Green Valley, Grifols, Janssen, Jazz, Karuna, Merck, Novo Nordisk, Otsuka, ReMYND, Resverlogix, Roche, Signant Health, Sunovion, Suven, United Neuroscience, and Unlearn AI pharmaceutical and assessment companies. Dr. Cummings has stock options in ADAMAS, AnnovisBio, MedAvante, BiOasis, and United Neuroscience. Dr. Cummings owns the copyright of the Neuropsychiatric Inventory. Dr Cummings has the following research support: NIGMS P20GM109025; NINDS U01NS093334; NIA R01AG053798; NIA P20AG068053; NIA R35AG71476. AA has received honoraria for consulting; participating in independent data safety monitoring boards; providing educational lectures, programs, and materials; or serving on advisory boards for AbbVie, Acadia, Allergan, the Alzheimer’s Association, Axovant, AZ Therapies, Biogen, Grifols, Harvard Medical School Graduate Continuing Education, JOMDD, Lundbeck, Merck, Roche/Genentech, Novo Nordisk, Sunovion, and Suven. MS has provided consultation to Alzheon, Biogen, Cortexyme, Roche-Genentech, Stage 2 Innovations/Renew Research, Acadia, T3D, Eisai, and KeifeRx. He is on the Speaker’s Bureau for Health and Wellness Partners. He holds stock/options in rain Health Inc, NeuroTau, Optimal Cognitive Health Company, uMethod Health, Versanum, Athira, and Cognoptix. SS was a site PI and co-chair of the investigator steering committee for the ENGAGE trial, and he receives research support and consultancy fees from Lilly, Biogen, Avid, Eisai, Genentech, and Roche.

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Cummings, J., Aisen, P., Lemere, C. et al. Aducanumab produced a clinically meaningful benefit in association with amyloid lowering. Alz Res Therapy 13, 98 (2021). https://doi.org/10.1186/s13195-021-00838-z

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Keywords

  • Aducanumab
  • FDA
  • Clinical trials
  • Monoclonal antibodies
  • Lecanemab
  • Donanemab
  • Gantenerumab