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aducanumab-avwa (Aduhelm)

Biogen will stop developing & selling aducanumab [40] Indications: - treatment of mild cognitive impairment or early Alzheimer's disease [14] - for use only in patients with the earliest stages of disease [14] * 2 trials discontinued due to futility [4] - Biogen later reversed its position of futility on one of 2 trials [6] * FDA approval using the accelerated approval pathway June 7, 2021 [6] * accelerated approval includes an FDA mandate for a phase 4 study to verify clinical benefit of aducanumab [19] Contraindications: - patients on anticoagulants were excluded from clinical trials* - 19% of patients treated with Aduhelm developed ARIA-hemorrhage * 91% of patients with Alzheimer's disease & 85% of patients with mild cognitive impairment met at least 1 exclusion criteria from the EMERGE & ENGAGE clinical trials stopped prematurely based on prespecified futility thresholds; most patients with multiple exclusion criteria [27] - the most common exclusion criteria include cardiovascular disease, anticoagulation, anti-platelet therapy (except low-dose aspirin), chronic kidney disease, age > 85 years Dosage: - 1-10 mg/kg monthly administered as IV infusion over 1 hour [1] - dose titration of infusion is required over the initial 6 infusions - infusions 1 & 2 -> 1 mg/kg - infusions 3 & 4 -> 3 mg/kg - infusions 5 & 6 -> 6 mg/kg - treatment dose of 10mg/kg begins on infusion 7 [12] Vials: 170 mg/1.7 mL, 100 mg/mL single dose vials (must be diluted prior to indfusion) Adverse effects: - cerebral edema (vasogenic), seen on PET, occurred in 3-41% (higher at higher doses) with resolution within 4-12 weeks [2] - no new cases of cerebral edema in those who continued on the same dose of aducanumab [3] - case report of 6 amyloid-related imaging abnormality (ARIA) episodes - over 44 months recurrent episodes of asymptomatic mild-moderate ARIA-edema including 1 episode with mild ARIA-hemorrhage [29] - ARIA-related edema (35%) 26% symptomatic [31] - apolipoprotein E4 carriers may be more likely to have ARIA-related edema [38] - cerebral microhemorrhage 19% [29,31] - ARIA siderosis (15%) [31] - headache - falls - diarrhea - confusion/delirium [12] Drug interactions: - antiplatelet drugs increase risk intracerebral hemorrhage - anticoagulants increase risk of intracerebral hemorrhage - thrombolytic agents increase risk of intracerebral hemorrhage Radiology: - may require amyloid PET scan for eligibility & CMS does not cover amyloid PET unless performed as part of a CMS-approved clinical trial [19] - 3 screening MRI of brain* [12] - prior to beginning infusion (within the past year) - prior to infusion 7 - prior to infusion 12 * looking for Amyloid Related Imaging Abnormalities edema or hemorrhage (ARIA-E, ARIA-H) Mechanism of action: - monoclonal IgG1 directed against aggregated soluble & insoluble forms of beta-amyloid [6] - removes amyloid plaques (PET scan confirmed in 100%) - dose-dependent reductions in amyloid plaques through 36 months of treatment [3] - slows cognitive decline in some, but not all studies [1] Notes: - industry-funded investigators report [1,2] - advisory committee concludes that study 302 EMERGE does not support strong evidence of aducanumab effectiveness in treatment of Alzheimer's disease [5] - many scientists disagree with FDA approval [7] - 3 FDA advisors resign over FDA's approval of Aduhelm [9] - Public Citizen's Health Research Group calls for removal of FDA's acting commissioner & 2 other FDA officials for reckless approval of Aduhelm [10] - 87% of US-based physicians & 89% of neurologists disagree with the FDA's approval of aducanumab [13] - ex-FDA advisor calls decision to approve Aduhelm probably the worst decision in U.S. history [28] - no net benefit [19] - FDA acting commissioner calls for investigation into FDA approval of Aduhelm [15] - CMS opened a National Coverage Determination analysis to review & determine whether Medicare will establish a national coverage policy for monoclonal Ab targeting beta-amyloid for treatment of Alzheimer's Disease [17] - FDA-defends decision of accelerated approval of Aduhelm [22] - Biogen pulled Aduhelm paper after JAMA demanded edits [23] - Biogen launches controversial infomercial campaign directed at consumers [24] - Veterans Administration decides not to add Aduhelm to its formulary & recommends against using it [25] - FDA broke with its own protocols in reviewing & subsequently approving aducanumab (Aduhelm), by inappropriately collaborating with drugmaker Biogen on briefing documents, holding unreported meetings, & failing to obtain internal consensus before engaging in such collaborations [39] - average annual cost of aducanumab treatment is > $75,000 [38] - annual cost of Aduhelm will be $56,000/year with no cost increase for 4 years [8] - Biogen has reduced the price of Aduhelm to 28,200/year as the drug has sold poorly since its approval in June 2021 due to concerns about its safety, effectiveness & cost [33] - Medicare copayments for Aduhelm may be ~$11,500 [11] - Aduhelm coverage & cost [32] - public & private payers may check on the FDA's decision, by refusing to cover the drug - CMS has upheld its proposed plan to cover aducanumab (Aduhelm) only for people in randomized controlled trials [37]

Interactions

drug adverse effects of anti-Alzheimer monoclonal antibody

Related

investigational therapies for treatment of Alzheimer's disease

General

anti-Alzheimer monoclonal antibody

References

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  2. Sevigny J, Chiao P, Bussiere T et al The antibody aducanumab reduces Abeta plaques in Alzheimer's disease. Nature. 2016 Aug 31;537(7618):50-6 PMID: 27582220 - Reiman EM Alzheimer's disease: Attack on amyloid-beta protein. Nature. 2016 Aug 31;537(7618):36-7. doi: 10.1038/537036a. PMID: 27582214
  3. Fiore K NeuroBreak: More Aducanumab Data; AI to Aid in Parkinson's Drug Discovery MedPage Today. August 29, 2017 https://www.medpagetoday.com/Neurology/GeneralNeurology/67585
  4. Biogen and Eisai to Discontinue Phase 3 ENGAGE and EMERGE Trials of aducanumab in Alzheimer's Disease. Independent data monitoring committee advises aducanumab unlikely to meet primary endpoints, leading to decision to discontinue the trials. Biogen News Release. March 29, 2019 http://investors.biogen.com/news-releases/news-release-details/biogen-and-eisai-discontinue-phase-3-engage-and-emerge-trials - Gutis PS. An Alzheimer's drug trial gave me hope, and then it ended. New York Times. Mar 22, 2019. https://www.nytimes.com/2019/03/22/well/mind/alzheimers-drug-trial-study-biogen-dementia-treatment-cure.html
  5. Alexander GC, Emerson S, Kesselheim AS Evaluation of Aducanumab for Alzheimer Disease Scientific Evidence and Regulatory Review Involving Efficacy, Safety, and Futility. JAMA. Published online March 30, 2021. PMID: 33783469 https://jamanetwork.com/journals/jama/fullarticle/2778191
  6. George J Controversial Alzheimer's Drug Wins FDA Approval. Aducanumab is first treatment directed at Alzheimer's pathophysiology. https://www.medpagetoday.com/neurology/alzheimersdisease/92960 - Brauser D FDA Approves Controversial Alzheimer's Drug Aducanumab (Aduhelm) Medscape - Jun 07, 2021. https://www.medscape.com/viewarticle/952502
  7. Mullard A Landmark Alzheimer's drug approval confounds research community. Nature 2021. June 8. News. https://www.nature.com/articles/d41586-021-01546-2
  8. Lovelace B Jr Biogen CEO says $56,000 annually for Alzheimer's drug is 'fair,' promises not to hike price for at least 4 years. CNBC Health & Science. 2021, June 7.
  9. Belluck P, Robbins R Three F.D.A. Advisers Resign Over Agency's Approval of Alzheimer's Drug. New York Times. June 10, 2021 https://www.msn.com/en-us/news/us/three-fda-advisers-resign-over-agencys-approval-of-alzheimers-drug/ar-AAKVatC - Hughes S Two FDA Panel Members Resign Over Alzheimer's Drug Approval Medscape - Jun 09, 2021. https://www.medscape.com/viewarticle/952802 - Bagley M The Drug That Could Break American Health Care. The Atlantic. June 11, 2021 https://www.msn.com/en-us/news/us/the-drug-that-could-break-american-health-care/ar-AAKWqZV - Feuerstein A, Garde D FDA grants historic approval to Alzheimer's drug designed to slow cognitive decline. STAT. June 7, 2021 https://www.statnews.com/2021/06/07/fda-grants-historic-approval-to-alzheimers-drug-designed-to-slow-cognitive-decline/ - Fiore K Will Insurers Pay for New Alzheimer's Drug? All eyes are on CMS, which could issue a Medicare National Coverage Determination. MedPage Today June 8, 2021 https://www.medpagetoday.com/special-reports/exclusives/92990
  10. Ault A Watchdog Group Demands Removal of FDA Leaders After Aducanumab Approval Medscape - Jun 16, 2021. https://www.medscape.com/viewarticle/953172
  11. Associated Press Medicare Copays For New Alzheimer's Drug Could Reach $11,500 Annually. NPR. 2021. June 10 https://www.npr.org/2021/06/10/1005319693/medicare-copays-for-new-alzheimers-drug-could-reach-11-500-annually
  12. Alexander GC, Karlawish J The Problem of Aducanumab for the Treatment of Alzheimer Disease. Ann Intern Med. 2021 June 17 PMID: 34138642 https://www.acpjournals.org/doi/10.7326/M21-2603
  13. Brooks M Alzheimer's Drug Approval an FDA Blunder? Our Readers Weigh In Medscape - Jun 30, 2021. https://www.medscape.com/viewarticle/953996
  14. Brooks M FDA Updates Label for Controversial Alzheimer's Drug Aducanumab (Aduhelm). Medscape - Jul 08, 2021. https://www.medscape.com/viewarticle/954403
  15. Brauser D FDA Head Calls for Investigation Into Agency's Approval of Aducanumab (Aduhelm) Medscape - Jul 09, 2021. https://www.medscape.com/viewarticle/954544 - Salloway S, Cummings J Aducanumab, amyloid lowering, and slowing of Alzheimer disease. Neurology 2021. July 7 Neurology. 2021 https://n.neurology.org/content/early/2021/07/07/WNL.0000000000012451 - Knopman DS, Perlmutter JS Prescribing aducanumab in the face of meager efficacy and real risks Neurology 2021. July 7 PMID: 34233938 https://n.neurology.org/content/early/2021/07/07/WNL.0000000000012452
  16. Brooks M FDA Defends Alzheimer Drug Approval, Others Call It a '9/11 Moment' for Medicare. Medscape - Jul 14, 2021 https://www.medscape.com/viewarticle/954785 - Dunn B, Stein P, Cavazzoni P. Approval of Aducanumab for Alzheimer Disease - the FDA's Perspective. JAMA Intern Med. Published online July 13, 2021. PMID: 34254984 https://jamanetwork.com/journals/jamainternalmedicine/fullarticle/2782119 - Crosson FJ, Covinsky K, Redberg RF Medicare and the Shocking US Food and Drug Administration Approval of Aducanumab: Crisis or Opportunity? JAMA Intern Med. Published online July 13, 2021. PMID: 34254992 https://jamanetwork.com/journals/jamainternalmedicine/fullarticle/2782118 - Steinbrook R The Accelerated Approval of Aducanumab for Treatment of Patients With Alzheimer Disease. JAMA Intern Med. Published online July 13, 2021. PMID: 34254991 https://jamanetwork.com/journals/jamainternalmedicine/fullarticle/2782122
  17. Centers for Medicare & Medicaid Services (CMS) CMS Opens National Coverage Determination Analysis on Treatment for Alzheimer's Disease. CMS.gov Press Release. July 12, 2021 https://www.cms.gov/newsroom/press-releases/cms-opens-national-coverage-determination-analysis-treatment-alzheimers-disease
  18. Lin KW Why Primary Care Physicians Should Worry About the Approval of Aducanumab. Medscape - Jul 12, 2021. https://www.medscape.com/viewarticle/954556 - Hung WH Alzheimer's s Disease Treatment on the Horizon or False Dawn? Medscape - Jul 14, 2021. https://www.medscape.com/viewarticle/954015
  19. Dooley Young K No Net Benefit of Aducanumab for Alzheimer's Disease, Expert Panel Rules. Medscape - Jul 16, 2021. https://www.medscape.com/viewarticle/954909
  20. Schulman KA, Greicius MD, Richman B Will CMS Find Aducanumab Reasonable and Necessary for Alzheimer Disease After FDA Approval? JAMA. Published online July 19, 2021 PMID: 34279572 https://jamanetwork.com/journals/jama/fullarticle/2782333
  21. Rubin R Recently Approved Alzheimer Drug Raises Questions That Might Never Be Answered. JAMA. Published online July 21, 2021 PMID: 34287610 https://jamanetwork.com/journals/jama/fullarticle/2782427
  22. Gever J Aducanumab Glass Half Empty. No, It's s Half Full. Sparring over new Alzheimer's drug continues between FDA, critics MedPage Today July 28, 2021 https://www.medpagetoday.com/neurology/alzheimersdisease/93789 - Alexander GC, Knopman DS, Emerson SS et al Perspective. Revisiting FDA Approval of Aducanumab. N Engl J Med. 2021. July 28. PMID: 34320282 https://www.nejm.org/doi/full/10.1056/NEJMp2110468 - Rabinovici GD Perspective. Controversy and Progress in Alzheimer's Disease - FDA Approval of Aducanumab. N Engl J Med. 2021. July 28. PMID: 34320284 https://www.nejm.org/doi/full/10.1056/NEJMp2111320 - Dunn B, Stein P, Temple R, Cavazzoni P. U.S. Food and Drug Administration An Appropriate Use of Accelerated Approval - Aducanumab for Alzheimer's Disease. N Engl J Med. 2021. July 28. PMID: 34320283 https://www.nejm.org/doi/full/10.1056/NEJMc2111960
  23. Herman B Biogen pulled Aduhelm paper after JAMA demanded edits. Axios. 2021. July 27 https://www.axios.com/biogen-jama-aduhelm-clinical-trial-results-publish-fc7c2876-a684-4bfc-8462-4165f57d735a.html
  24. Appleby J Facing Headwinds on New Alzheimer's Drug, Biogen Launches Controversial Campaign. Kaiser Health News. July 23, 2021 https://khn.org/news/article/new-alzheimers-drug-aduhelm-biogen-launches-controversial-marketing-campaign/
  25. Brennan Z Scoop: VA decides against adding Biogen's Aduhelm to its formulary as PBM shuns controversial Alzheimer's drug. Endpoint News. August 11, 2021 https://endpts.com/exclusive-va-decides-against-adding-biogens-aduhelm-to-its-formulary-as-pbm-shuns-controversial-alzheimers-drug/
  26. Karlawish J Aducanumab and the Business of Alzheimer Disease - Some Choice JAMA Neurol. Published online August 19, 2021 PMID: 34410302 https://jamanetwork.com/journals/jamaneurology/fullarticle/2783263 - Manly JJ, Glymour MM. What the Aducanumab Approval Reveals About Alzheimer Disease Research. JAMA Neurol. 2021;78(11):1305-1306 PMID: 34605885 https://jamanetwork.com/journals/jamaneurology/fullarticle/2784441 - Planche V, Villain N US Food and Drug Administration Approval of Aducanumab - Is Amyloid Load a Valid Surrogate End Point for Alzheimer Disease Clinical Trials? JAMA Neurol. 2021;78(11):1307-1308 PMID: 34515750 https://jamanetwork.com/journals/jamaneurology/fullarticle/2784255
  27. Anderson TS, Ayanian JZ, Souza J et al Representativeness of Participants Eligible to Be Enrolled in Clinical Trials of Aducanumab for Alzheimer Disease Compared With Medicare Beneficiaries With Alzheimer Disease and Mild Cognitive Impairment. JAMA. Published online September 9, 2021 PMID: 34499725 https://jamanetwork.com/journals/jama/fullarticle/2784225
  28. Toobin J The road to Aduhelm: What one ex-FDA adviser called 'probably the worst drug approval decision in recent US history' for an Alzheimer's treatment. CNN. September 27, 2021 https://www.cnn.com/2021/09/26/politics/alzheimers-drug-aduhelm-fda-approval/index.html
  29. George J One Aducanumab Patient, Six Brain Edema Episodes "Uniquely complicated course" for patient treated with new Alzheimer's drug. MedPage Today November 8, 2021 https://www.medpagetoday.com/neurology/alzheimersdisease/95523 - Hall JN, Mormino E, Ng A et al Six Recurrent Amyloid-Related Imaging Abnormality Episodes in a Patient Treated With Aducanumab. JAMA Neurol. Published online November 8, 2021 PMID: 34747986 https://jamanetwork.com/journals/jamaneurology/article-abstract/2785856
  30. George J Let Ethics Guide Aducanumab Prescribing, AAN Says. Don't rely on FDA approval alone to make best choices for Alzheimer's patients. MedPage Today November 18, 2021 https://www.medpagetoday.com/neurology/alzheimersdisease/95759 - Chiong W, Tolchin BD, Bonnie RJ et al Decisions With Patients and Families Regarding Aducanumab in Alzheimer Disease, With Recommendations for Consent: AAN Position Statement. Neurology. 2021 November 17. PMID: 34789544 https://n.neurology.org/content/early/2021/11/17/WNL.0000000000013053
  31. George J Brain Inflammation Seen in Four of 10 Alzheimer's Aducanumab Patients. Details about edema, hemorrhage ARIA published. MedPage Today November 22, 2021 https://www.medpagetoday.com/neurology/alzheimersdisease/95801 - Smith J Microbleeds, Age Contribute to ARIA Risk With Aducanumab. Medscape. November 30, 2021 https://www.medscape.com/viewarticle/963828 - 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; Published online November 22, 2021 PMID: 34807243 https://jamanetwork.com/journals/jamaneurology/fullarticle/2786606
  32. Robinson JC Perspective: Why Is Aducanumab Priced at $56,000 per Patient? Lessons for Drug-Pricing Reform. N Engl J Med 2021; 385:2017-2019. Nov 25 PMID: 34797614 https://www.nejm.org/doi/full/10.1056/NEJMp2113679 - Sachs RE, Bagley N Perspective: Medicare Coverage of Aducanumab - Implications for State Budgets. N Engl J Med 2021; 385:2019-2021. Nov 25 PMID: 34797617 https://www.nejm.org/doi/full/10.1056/NEJMp2115297
  33. Walker J Biogen Cuts Price for Alzheimer's Drug Aduhelm by Half. Wall Street Journal. December 20, 2021 https://www.wsj.com/articles/biogen-cuts-price-for-alzheimers-drug-aduhelm-by-half-11640001661
  34. Gusmano MK Can We Limit the Consequences of FDA's Aduhelm Approval? Public and private payers may act as checks on the controversial decision. MedPage Today. December 28, 2021 https://www.medpagetoday.com/opinion/second-opinions/96411
  35. George J Medicare Plans to Restrict Coverage of New Alzheimer's Drug. Proposal would cover aducanumab (Aduhelm) in patients on qualifying clinical trials. MedPage Today January 11, 2022 https://www.medpagetoday.com/neurology/alzheimersdisease/96613 - Dooley Young K Medicare to Limit Payment for Controversial Alzheimer's Drug. Medscape. January 11, 2022 https://www.medscape.com/viewarticle/966428
  36. George J Aducanumab Data Finally Published, but Alzheimer's Experts Spot Problems. Questions raised about secondary endpoints. MedPage Today March 23, 2022 https://www.medpagetoday.com/neurology/alzheimersdisease/97839 - Budd Haeberlein S, Aisen P, Barkhof F et al. Two Randomized Phase 3 Studies of Aducanumab in Early Alzheimer's Disease. J Prev Alzheimers Dis 2022. Feb 14 Not indexed in PubMed https://link.springer.com/article/10.14283/jpad.2022.30
  37. George J Medicare Finalizes Limits on Aducanumab Coverage. But decision allows flexibility for some anti-amyloid Alzheimer's drugs. MedPage Today April 8, 2022 https://www.medpagetoday.com/neurology/alzheimersdisease/98116
  38. Day GS et al. Aducanumab use in symptomatic Alzheimer disease evidence in focus: Report of the AAN guidelines subcommittee. Neurology 2022 Feb 23; [e-pub] PMID: 35197360 https://n.neurology.org/content/98/15/619
  39. Firth S Congressional Probe of Alzheimer's Drug Approval Finds Fault With FDA Actions. Investigation reveals Biogen's "aggressive launch and marketing plans MedPage Today December 30, 2022 https://www.medpagetoday.com/washington-watch/fdageneral/102464
  40. George J Controversial Alzheimer's Drug Abandoned. Biogen will stop developing and selling aducanumab MedPage Today January 31, 2024 https://www.medpagetoday.com/neurology/alzheimersdisease/108514
  41. HIGHLIGHTS OF PRESCRIBING INFORMATION ADUHELM (aducanumab-avwa) injection, for intravenous use https://www.accessdata.fda.gov/drugsatfda_docs/label/2021/761178s000lbl.pdf