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lecanemab (Leqembi)

Indications: - treatment of Alzheimer's disease (FDA-approved) [11]* - may not benefit women or patients < 65 years [8,16,17] - treatment effect may be smaller in men than women [8,16,17,18] - European drug agency rejects lecanemab due to issues of efficacy & safety [25] - benefits too small to justify cost (NICE) [26] * first beta-amyloid monoclonal antibody to receive traditional approval from the US Food & Drug Administration (FDA) [16] * unlike aducanumab,there was no formal FDA advisory committee meeting on lecanemab prior to approval [11] Contraindications: - 2 groups of patients not likely to benefit* - amyloid-negative patients - amyloid-positive with a high plasma phospho-tau burden * plasma ptau217 useful for identifying patients unlikely to benefit [5] Dosage: - bi-weekly intravenous infusion of 10 mg/kg - subcutaneous dosing investigational [23] Injection for intravenous infusion: 500 mg/5 mL & 200 mg/2 mL single use vials * it takes a multidisciplinary team to administer lecanemab [20,21] - this team should include: - a behavioral neurologist who can distinguish mild cognitive impairment from depression - a neuropsychologist to interpret cognitive testing & make the correct diagnosis - a neuroradiologist to look for cerebral microbleeds at baseline - a social worker to handle financial issues [20,21] Adverse effects: - infusion-related reactions (24%) [8] - amyloid-related imaging abnormality-edema or effusions (ARIA-E) 12.6% - patients homozygous for apo E4 are > 6 times more likely to experience symptomatic ARIA with edema or effusions & 3 times more likely to experience cerebral microhemorrhages than those homozygous for apo E3 [19] * Black-box warning: - rare cases of serious & life-threatening events [14] Complications: - complications of ARIA manifested as headache the day after infusion may not be recognized by emergency medicine physicians at a local hospital - even if they do, they not not be able to facilitate an emergency MRI - thus the importance of 24/7 access to a multidisciplinary team as described above (see Dosage: section) Drug interactions: - concurrent use of lecanemab & SSRI may increase risk of intracerebral hemorrhage within the first 30 days of combination therapy [15] - antiplatelet drugs increase risk intracerebral hemorrhage - anticoagulants increase risk of intracerebral hemorrhage - thrombolytic agents increase risk of intracerebral hemorrhage Mechanism of action: - humanized IgG1 monoclonal antibody - binds with high affinity to amyloid-beta soluble protofibrils Clinical trials: - small phase 2b trial [1] - reportedly completely clears amyloid within 18 months in 80% patients with early Alzheimer's disease [2] - granted breakthrough therapy designation [1] - small but significant reduction in cognitive decline in early Alzheimer's disease in a phase III trial [3] - the National Institute on Aging (NIA) eagerly awaits publication of this data in a peer-reviewed scientific journal [4] - volunteer died during the study; unclear if death caused by lecanemab [6] - a 2nd death in a lecanemab trial participant occurred [7] - lecanemab may have interacted with tissue plasminogen activator used to treat a stroke in this participant with cerebral amyloid angiopathy [7] - lecanemab associated with lower increase in Clinical Dementia Rating - Sum of Boxes score at 18 months than placebo (1.21 vs 1.66, baseline 3.2) in patients with early Alzheimer's disease, but associated with adverse events [8] - Institute for Clinical & Economic Review (ICER) found lecanemab failed to show benefit compared to supportive care for adults with early Alzheimer' disease [13] * summary of 3 deaths in lecanemab trial participants [10] Notes: - Eisai & Biogen - list price for lecanemab (Leqembi)...would be $26,500 per year [12,13] - Medicare says it would cover much of its cost [14] - treatment expense & complexity may preclude traditionally marginalized populations [16] - apoE genotype was not revealed to any patients, insurance companies, employers, families or other doctor treating the patients [27] - thus no dislosure of added risk of apoE genotype for ARIA-E

Interactions

drug adverse effects of anti-Alzheimer monoclonal antibody

Related

investigational therapies for treatment of Alzheimer's disease

General

anti-Alzheimer monoclonal antibody

References

  1. EISAI and Biogen Inc. Announce U.S. FDA Grants Breakthrough Therapy Designation for LECANEMAB (BAN2401), an Anti-Amyloid Beta Protofibril Antibody for the Treatment of Alzheimer's Disease. Biogen Investor Relations. June 23, 2021 https://investors.biogen.com/news-releases/news-release-details/eisai-and-biogen-inc-announce-us-fda-grants-breakthrough-therapy
  2. Anderson P Lecanemab Effective in Clearing Amyloid in Early Alzheimer's. Medscape. November 23, 2021 https://www.medscape.com/viewarticle/963516 - Swanson CJ, Zhang Y, Dhadda S 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 Apr 17;13(1):80. PMID: 33865446 PMCID: PMC8053280 Free PMC article. Clinical Trial. - Swanson CJ, Zhang Y, Dhadda S et al Correction to: 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. 2022 May 21;14(1):70. PMID: 35598024 PMCID: PMC9123682 Free PMC article.
  3. Biogen LECANEMAB CONFIRMATORY PHASE 3 CLARITY AD STUDY MET PRIMARY ENDPOINT, SHOWING HIGHLY STATISTICALLY SIGNIFICANT REDUCTION OF CLINICAL DECLINE IN LARGE GLOBAL CLINICAL STUDY OF 1,795 PARTICIPANTS WITH EARLY ALZHEIMER'S DISEASE. Investor Relations. September 27, 2022 https://investors.biogen.com/news-releases/news-release-details/lecanemab-confirmatory-phase-3-clarity-ad-study-met-primary
  4. National Institute on Aging NIA statement on report of lecanemab reducing cognitive decline in Alzheimer's clinical trial. Announcement. Oct 3, 2022 https://www.nia.nih.gov/news/nia-statement-report-lecanemab-reducing-cognitive-decline-alzheimers-clinical-trial
  5. Prillaman M Alzheimer's s drug slows mental decline in trial - but is it a breakthrough? Researchers are cautiously optimistic following companies' announcement of positive results for lecanemab. Nature News 2022. Sept 29. https://www.nature.com/articles/d41586-022-03081-0
  6. Walker J Volunteer Dies Testing Eisai-Biogen Alzheimer's Drug During Study. Wall Street Journal. 2022. Oct 28 https://www.doximity.com/articles/6227441f-a4f0-46e8-a500-dc2ec1b9c701
  7. George J Second Trial Participant Dies in Alzheimer's Drug Study. "All eyes are on lecanemab," a closely watched anti-amyloid treatment. MedPage Today November 28, 2022 https://www.medpagetoday.com/neurology/alzheimersdisease/101945 - Piller C Second death linked to potential antibody treatment for Alzheimer's disease. Woman's brain hemorrhage while receiving Eisai's widely heralded lecanemab heightens concerns overs its safety. ScienceInsider. Nov 27, 2022 https://www.science.org/content/article/second-death-linked-potential-antibody-treatment-alzheimer-s-disease
  8. George J Alzheimer's Drug Slows Decline, Trial Data Show. Lecanemab met primary and secondary endpoints, but was associated with adverse events. MedPage Today November 30, 2022 https://www.medpagetoday.com/neurology/alzheimersdisease/101972 - van Dyck CH, Swanson CJ, Aisen P Lecanemab in Early Alzheimer's Disease. N Engl J Med 2023 Jan 5;388(1):9-21 . ePub: Nov 29, 2022 PMID: 36449413 https://www.nejm.org/doi/full/10.1056/NEJMoa2212948 - Supplement: https://www.nejm.org/doi/suppl/10.1056/NEJMoa2212948/suppl_file/nejmoa2212948_appendix.pdf - Dhadda S, Kanekiyo M, Li D et al Consistency of efficacy results across various clinical measures and statistical methods in the lecanemab phase 2 trial of early Alzheimer's disease. Alzheimers Res Ther. 2022 Dec 9;14(1):182. PMID: 36482412 PMCID: PMC9733166 Free PMC article. Clinical Trial. - McDade E, Cummings JL, Dhadda S et al Lecanemab in patients with early Alzheimer's disease: detailed results on biomarker, cognitive, and clinical effects from the randomized and open-label extension of the phase 2 proof-of-concept study. Alzheimers Res Ther. 2022 Dec 21;14(1):191. doi: 10.1186/s13195-022-01124-2. PMID: 36544184 PMCID: PMC9768996 Free PMC article. Clinical Trial. - Reish NJ et al. Multiple cerebral hemorrhages in a patient receiving lecanemab and treated with t-PA for stroke. N Engl J Med 2022 Jan 4; [e-pub]. https://www.nejm.org/doi/10.1056/NEJMc2215148 - Sabbagh M, van Dyck CH. Response to: Multiple cerebral hemorrhages in a patient receiving lecanemab and treated with t-PA for stroke. N Engl J Med 2023 Jan 4; [e-pub]. https://www.nejm.org/doi/10.1056/NEJMc2215907
  9. Editorial Lecanemab for Alzheimer's disease: tempering hype and hope Lancet. 2022. Dec 2. https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(22)02480-1/fulltext
  10. Lou N Scattered Brain Bleeds, Vasculitis in Alzheimer's Trial Death. Case report is published days ahead of FDA lecanemab decision. MedPage Today January 4, 2023. https://www.medpagetoday.com/neurology/alzheimersdisease/102505
  11. Brooks M FDA Approves Second Anti-Amyloid for Alzheimer's Disease. Medscape. Jan 6, 2022 https://www.medscape.com/viewarticle/986625 - George J Alzheimer's Drug Lecanemab Wins FDA Approval. Anti-amyloid showed modest benefit in phase III trial, but was linked to adverse events. MedPage Today. January 6, 2023 https://www.medpagetoday.com/neurology/alzheimersdisease/102546
  12. AMA Morning Roungs. Jan 9, 2023 American Medical Association
  13. Twenter P New Alzheimer's drug lacks a 'net health benefit,' ICER says. Becker's Hospital Review. 2023, April 18. https://www.beckershospitalreview.com/pharmacy/new-alzheimers-drug-lacks-a-net-health-benefit-icer-says.html
  14. AMA Morning Rounds. July 7, 2023 American Medical Association
  15. George J Experts Warn on Mixing New Alzheimer's Drug and Antidepressants. Patients starting SSRIs and lecanemab may warrant close monitoring. MedPage Today August 18, 2023 https://www.medpagetoday.com/neurology/alzheimersdisease/105944 - Pozuelo Moyano B, Salvioni P, Zullo L et al Antidepressants and the risk of bleeding in the era of anti-amyloid drugs. Alzheimer's & Dementia. 2023. Aug 16 PMID: 37587609 https://alz-journals.onlinelibrary.wiley.com/doi/10.1002/alz.13435
  16. Rubin R Who Should - and Can - Get Lecanemab, the New Alzheimer Disease Drug? JAMA. Published online September 27, 2023. PMID: 37755935 https://jamanetwork.com/journals/jama/fullarticle/2810237
  17. Buckley RF, Gong J, Woodward M. A Call to Action to Address Sex Differences in Alzheimer Disease Clinical Trials. JAMA Neurol. 2023;80(8):769-770. PMID: 37155156 https://jamanetwork.com/journals/jamaneurology/fullarticle/2804753
  18. Zeng BS, Tseng PT, Liang CS. Lecanemab in Early Alzheimer's Disease. N Engl J Med 2023; 388:1630-1632. April 27. PMID: 37099351 https://www.nejm.org/doi/10.1056/NEJMc2301380 - Brenman JE. Lecanemab in Early Alzheimer's Disease. N Engl J Med. 2023 Apr 27;388(17):1631. PMID: 37099354 No abstract available. - Pomara N, Imbimbo BP. Lecanemab in Early Alzheimer's Disease. N Engl J Med. 2023 Apr 27;388(17):1630-1631. PMID: 37099353 No abstract available. - Valenzuela MJ, Pascual-Leone A. Lecanemab in Early Alzheimer's Disease. N Engl J Med. 2023 Apr 27;388(17):1630. PMID: 37099352
  19. Thambisetty M, Howard R Lecanemab and APOE Genotyping in Clinical Practice - Navigating Uncharted Terrain. JAMA Neurol. 2023;80(5):431-432 PMID: 3691285 https://jamanetwork.com/journals/jamaneurology/fullarticle/2802272 - Herper M, DeAngelis A 'This is not a cure': Consensus begins to emerge on new Alzheimer's drug. STAT. Dec 6, 2022. https://www.statnews.com/2022/12/06/lecanemab-consensus-prescription/
  20. Pittock RR, Aakre J, Castillo AM et al Eligibility for Anti-Amyloid Treatment in a Population-Based Study of Cognitive Aging. Neurology. 2023 Aug 16:10.1212/WNL.0000000000207770. PMID: 37586881 https://n.neurology.org/content/early/2023/08/16/WNL.0000000000207770
  21. Cummings J, Apostolova L, Rabinovici GD et al Lecanemab: Appropriate Use Recommendations. J Prev Alzheimers Dis. 2023;10(3):362-377. PMID: 37357276 https://link.springer.com/article/10.14283/jpad.2023.30
  22. CMS.gov June 22, 2023 CMS announces new details of plan to cover new Alzheimer's drugs. https://www.cms.gov/newsroom/fact-sheets/cms-announces-new-details-plan-cover-new-alzheimers-drugs
  23. George J Subcutaneous Alzheimer's Drug May Be on the Horizon Investigational version of lecanemab shows promise, but questions about safety persist. MedPage Today October 27, 2023 https://www.medpagetoday.com/neurology/alzheimersdisease/107057
  24. George J Alzheimer's Blood Test Predicts Who Might Benefit Most From Anti-Amyloid Drugs. Novel two-cutoff approach may reduce need for confirmatory PET scans. MedPage Today December 5, 2023 https://www.medpagetoday.com/neurology/alzheimersdisease/107691 - Mattsson-Carlgren N, Collij LE, Stomrud E et al Plasma Biomarker Strategy for Selecting Patients With Alzheimer Disease for Antiamyloid Immunotherapies. JAMA Neurol. Published online December 4, 2023. PMID: 38048096 https://jamanetwork.com/journals/jamaneurology/article-abstract/2812432
  25. Mahase E Lecanemab: European drug agency rejects Alzheimer's drug amid debate over efficacy and safety. BMJ. 2024 Jul 29;386:q1692 PMID: 39074878 https://www.bmj.com/content/386/bmj.q1692
  26. Kmietowicz Z, Mahase E Lecanemab: Benefits of Alzheimer's drug are "just too small" to justify cost, says NICE. BMJ 2024 Aug 22:386:q1853 PMID: 39174291 https://www.bmj.com/content/386/bmj.q1853
  27. Bogdanich W, Kessler C What Drugmakers Did Not Tell Volunteers in Alzheimer's Trials New York Times. Oct 23, 2024 https://www.nytimes.com/2024/10/23/health/alzheimers-drug-brain-bleeding.html