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Anti-amyloid drugs

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Anti-amyloid drugs, also known as anti-amyloid antibodies (AAA),[1] are a class of monoclonal antibodies developed to treat Alzheimer's disease. The first drug in the class to be developed, in the early 2000s, is bapineuzumab, but it did not show effectiveness in later-stage trials.[2] The first drug to be approved by the US Food and Drug Administration (FDA) is aducanumab—in 2021.[3]

Approved drugs

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As of 2022, none of these drugs has been approved by the European Medicines Agency.[4]

Aducanumab

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This section is an excerpt from Aducanumab.[edit]

Aducanumab, sold under the brand name Aduhelm, is a monoclonal antibody designed to treat Alzheimer's disease.[5][6] It is a monoclonal antibody[6][5] that targets aggregated forms (plaque)[7][8] of amyloid beta (Aβ) found in the brains of people with Alzheimer's disease to reduce its buildup.[9][10] It was developed by Biogen and Eisai.[11] Aducanumab is given via intravenous infusion.[5]

Aducanumab was approved for medical use in the United States by the Food and Drug Administration (FDA) in June 2021,[12] in a controversial decision that led to the resignation of three advisers to the FDA in the absence of evidence that the medication is effective.[13][14][15] The FDA stated that it represents a first-of-its-kind treatment approved for Alzheimer's disease and that it is the first new treatment approved for Alzheimer's since 2003.[6] Aducanumab's approval is controversial for numerous reasons including ambiguous clinical trial results regarding efficacy, the high cost of the medication and the very high rate of serious adverse events.[16][15] The FDA considers it to be a first-in-class medication.[17]

In November 2020, a panel of outside experts for the FDA concluded that a pivotal study of aducanumab failed to show strong evidence that the medication worked, citing questionable efficacy and multiple red flags found with the data analysis.[18] There were also significant health risks associated with the medication; brain swelling or brain bleeding was found in 41% of patients enrolled in the studies.[19] Nevertheless, the medication was approved under the FDA's accelerated approval pathway, and the FDA requires Biogen to perform follow-up reviews to assure the medication is a safe and effective treatment for Alzheimer's disease.[6][20] The Office of Inspector General, US Department of Health and Human Services was asked to investigate interaction between the drug company and the FDA prior to the medication's approval.[21]

Biogen abandoned the drug in January 2024, for financial reasons.[22]

Lecanemab

[edit]
This section is an excerpt from Lecanemab.[edit]

Lecanemab, sold under the brand name Leqembi, is a monoclonal antibody medication used for the treatment of Alzheimer's disease.[23][24] Lecanemab is an amyloid beta-directed antibody.[23] It is given via intravenous infusion to patients with mild cognitive impairment or mild dementia.[23] In clinical trials, it demonstrated modest efficacy in reducing relative cognitive decline compared to placebo.[25] The most common side effects of lecanemab include headache, infusion-related reactions, and amyloid-related imaging abnormalities, a side effect known to occur with the class of antibodies targeting amyloid.[26]

Lecanemab was jointly developed by Eisai and Biogen. It was granted accelerated approval for medical use in the United States in January 2023,[27] and fully approved by the FDA in July 2023.[24][28]

Donanemab

[edit]
This section is an excerpt from Donanemab.[edit]

Donanemab, sold under the brand name Kisunla, is a monoclonal antibody used for the treatment of Alzheimer's disease.[29][30] Donanemab was developed by Eli Lilly and Company.[31][32]

The most common side effects include amyloid-related imaging abnormalities and headache.[30]

Donanemab was approved for medical use in the United States in July 2024 by the Food and Drug Administration.[30] Treatment is intended for patients with mild cognitive impairment or mild dementia stage of disease, which is the same population the treatment was studied in the clinical trials.[33]

Efficacy

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A 2023 review found that "Anti-Aβ drugs have relatively low efficacy in preventing cognitive decline, and they reduce pathological productions with acceptable safety."[34] A 2022 review finds "a statistically significant but slight clinical effect of these drugs emerges in patients with early AD after 18 months" and states, "The risk/benefit ratio of this class of drugs in early AD remains so far questionable after 18 months."[35]

From a 2023 statement by the European Association of Neurology and the European Psychiatric Association, "Anti-Aβ antibodies represent a significant advance in the treatment of AD, but their effectiveness is moderate and much work remains to be done to improve their efficacy, safety and accessibility."[2]

In a 2023 commentary, the authors express concern that the results of the trials, which are based on scoring by patients and their caregivers, of these drugs could be confounded by unblinding produced by adverse effects.[36] They also support running studies designed to distinguish between disease-modifying and symptomatic effects.[36]

Adverse effects

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[edit]

Amyloid-related imaging abnormalities are a relatively uncommon but serious adverse effect.[35]

Accelerated brain volume loss

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Brain volume loss is a symptom of Alzheimer's disease and is accelerated by anti-amyloid drugs developed to treat it. One meta-analysis found that people with mild cognitive impairment treated with anti-amyloid drugs would reach the brain volume associated with full Alzheimer's disease eight months earlier than those who received no such treatment. The significance of the brain volume loss caused by these drugs is unknown.[37]

The mechanism is not understood. Amyloid-related imaging abnormalities (ARIA) have been suggested as a possible cause of the accelerated brain volume loss. Others say it may be attributed to the reduction in amyloid plaques.[36]

Accelerated brain volume loss has been reported with lecanemab, aducanumab, donanemab, and other anti-amyloid drugs. Hippocampal, ventricular, and whole brain volumes are reported in studies and declines in all three have been found. However, the affected parts of the brain are not fully understood.[36]

Society and culture

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Drug development

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The approved anti-amyloid drugs were developed after years of unsuccessful attempts to develop a disease-modifying treatment for Alzheimer's disease.[38]

Cost

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Concerns have been raised about the high cost of the drugs and accessibility to patients.[3]

See also

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References

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  1. ^ Gandy S (2023). "News & views: anti-amyloid antibodies and novel emerging approaches to Alzheimer's disease in 2023". Molecular Neurodegeneration. 18 (1): 66. doi:10.1186/s13024-023-00656-x. PMC 10518943. PMID 37749530.
  2. ^ a b Perneczky R, Dom G, Chan A, Falkai P, Bassetti C (11 September 2023). "Anti-amyloid antibody treatments for Alzheimer's disease". European Journal of Neurology. 31 (2): e16049. doi:10.1111/ene.16049. hdl:10067/1987770151162165141. ISSN 1351-5101. PMC 11235913. PMID 37697714. S2CID 261694703.
  3. ^ a b Brockmann R, Nixon J, Love BL, Yunusa I (1 March 2023). "Impacts of FDA approval and Medicare restriction on antiamyloid therapies for Alzheimer's disease: patient outcomes, healthcare costs, and drug development". Viewpoint. Lancet Regional Health - Americas. 20: 100467. doi:10.1016/j.lana.2023.100467. PMC 9996432. PMID 36908502.
  4. ^ Villain N, Planche V, Levy R (December 2022). "High-clearance anti-amyloid immunotherapies in Alzheimer's disease. Part 2: putative scenarios and timeline in case of approval, recommendations for use, implementation, and ethical considerations in France". Revue Neurologique. 178 (10): 999–1010. doi:10.1016/j.neurol.2022.08.002. PMID 36336488. S2CID 253349289.
  5. ^ a b c "Aduhelm- aducanumab injection, solution". DailyMed. Archived from the original on 14 June 2021. Retrieved 14 June 2021.
  6. ^ a b c d "FDA Grants Accelerated Approval for Alzheimer's Drug". U.S. Food and Drug Administration (FDA) (Press release). 7 June 2021. Archived from the original on 8 June 2021. Retrieved 7 June 2021. Public Domain This article incorporates text from this source, which is in the public domain.
  7. ^ Walsh S, Merrick R, Milne R, Brayne C (July 2021). "Aducanumab for Alzheimer's disease?". BMJ. 374: n1682. doi:10.1136/bmj.n1682. PMC 8258645. PMID 34226181.
  8. ^ Sevigny J, Chiao P, Bussière T, Weinreb PH, Williams L, Maier M, et al. (September 2016). "The antibody aducanumab reduces Aβ plaques in Alzheimer's disease". Nature. 537 (7618): 50–56. Bibcode:2016Natur.537...50S. doi:10.1038/nature19323. PMID 27582220. S2CID 205250312.
  9. ^ Abyadeh M, Gupta V, Gupta V, Chitranshi N, Wu Y, Amirkhani A, et al. (2021). "Comparative Analysis of Aducanumab, Zagotenemab and Pioglitazone as Targeted Treatment Strategies for Alzheimer's Disease". Aging and Disease. 12 (8): 1964–1976. doi:10.14336/AD. PMC 8612603. PMID 34881080.
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  11. ^ Liu A (15 March 2022). "Biogen takes full control of troubled Aduhelm in revamped Eisai deal". Fierce Pharma. Archived from the original on 21 March 2022. Retrieved 21 March 2022.
  12. ^ "Drug Approval Package: Aduhelm (aducanumab-avwa)". U.S. Food and Drug Administration (FDA). 22 June 2021. Archived from the original on 2 September 2021. Retrieved 1 September 2021.
  13. ^ Mahase E (June 2021). "Three FDA advisory panel members resign over approval of Alzheimer's drug". BMJ. 373: n1503. doi:10.1136/bmj.n1503. PMID 34117086. S2CID 235405355.
  14. ^ "3 Experts Have Resigned From An FDA Committee Over Alzheimer's Drug Approval". NPR. 11 June 2021. Archived from the original on 11 June 2021. Retrieved 11 June 2021.
  15. ^ a b Belluck P, Robbins R (10 June 2021). "Three F.D.A. Advisers Resign Over Agency's Approval of Alzheimer's Drug". The New York Times. Archived from the original on 14 November 2021. Retrieved 14 June 2021.
  16. ^ McGinley L (22 June 2021). "FDA releases fresh details on internal debate over controversial Alzheimer's drug". The Washington Post. Archived from the original on 19 November 2021. Retrieved 24 June 2021.
  17. ^ Advancing Health Through Innovation: New Drug Therapy Approvals 2021 (PDF). U.S. Food and Drug Administration (FDA) (Report). 13 May 2022. Archived from the original on 6 December 2022. Retrieved 22 January 2023. Public Domain This article incorporates text from this source, which is in the public domain.
  18. ^ Marchione M, Perrone M (6 November 2020). "FDA panel urges rejection of experimental Alzheimer's drug". Associated Press. Archived from the original on 17 November 2021. Retrieved 8 June 2021.
  19. ^ Belluck P (22 November 2021). "Concerns Grow Over Safety of Aduhelm After Death of Patient Who Got the Drug". The New York Times. ISSN 0362-4331. Archived from the original on 20 July 2022. Retrieved 20 July 2022.
  20. ^ "FDA's Decision to Approve New Treatment for Alzheimer's Disease". U.S. Food and Drug Administration (FDA). 7 June 2021. Archived from the original on 8 June 2021. Retrieved 7 June 2021.
  21. ^ Gumbrecht J (9 July 2021). "Acting FDA commissioner calls for independent investigation into approval of Alzheimer's drug". CNN. Archived from the original on 13 August 2021. Retrieved 1 September 2021.
  22. ^ "Biogen will stop selling its controversial Alzheimer's drug Aduhelm". ABC News. Archived from the original on 31 January 2024. Retrieved 1 February 2024.
  23. ^ a b c "Leqembi – lecanemab injection, solution". DailyMed. 11 January 2023. Archived from the original on 15 January 2023. Retrieved 21 January 2023.
  24. ^ a b "FDA Grants Accelerated Approval for Alzheimer's Disease Treatment" (Press release). U.S. Food and Drug Administration (FDA). 6 January 2023. Archived from the original on 7 January 2023. Retrieved 7 January 2023. Public Domain This article incorporates text from this source, which is in the public domain.
  25. ^ Kwon D (22 August 2024). "Debate rages over Alzheimer's drug lecanemab as UK limits approval". Nature. doi:10.1038/d41586-024-02720-y.
  26. ^ "FDA Converts Novel Alzheimer's Disease Treatment to Traditional Approval". U.S. Food and Drug Administration (FDA) (Press release). 6 July 2023. Archived from the original on 6 July 2023. Retrieved 6 July 2023. Public Domain This article incorporates text from this source, which is in the public domain.
  27. ^ "Drug Approval Package: Leqembi". U.S. Food and Drug Administration (FDA). 6 February 2023. Archived from the original on 9 July 2023. Retrieved 8 July 2023.
  28. ^ "Lecanemab Summary Review" (PDF). Center for Drug Evaluation and Research (CDER). U.S. Food and Drug Administration (FDA). Archived (PDF) from the original on 7 January 2023. Retrieved 7 January 2023.
  29. ^ "Kisunla- donanemab-azbt injection, solution". DailyMed. 2 July 2024. Retrieved 15 August 2024.
  30. ^ a b c "FDA approves treatment for adults with Alzheimer's disease". U.S. Food and Drug Administration (FDA) (Press release). 2 July 2024. Archived from the original on 2 July 2024. Retrieved 2 July 2024. Public Domain This article incorporates text from this source, which is in the public domain.
  31. ^ Mintun MA, Lo AC, Duggan Evans C, Wessels AM, Ardayfio PA, Andersen SW, et al. (May 2021). "Donanemab in Early Alzheimer's Disease". The New England Journal of Medicine. 384 (18): 1691–1704. doi:10.1056/NEJMoa2100708. PMID 33720637.
  32. ^ Long JM, Holtzman DM (October 2019). "Alzheimer Disease: An Update on Pathobiology and Treatment Strategies". Cell. 179 (2): 312–339. doi:10.1016/j.cell.2019.09.001. PMC 6778042. PMID 31564456.
  33. ^ "FDA approves treatment for Alzheimer's disease - The Yucatan Times". 12 July 2024. Retrieved 15 July 2024.
  34. ^ Lyu D, Lyu X, Huang L, Fang B (July 2023). "Effects of three kinds of anti-amyloid-β drugs on clinical, biomarker, neuroimaging outcomes and safety indexes: A systematic review and meta-analysis of phase II/III clinical trials in Alzheimer's disease". Ageing Research Reviews. 88: 101959. doi:10.1016/j.arr.2023.101959. PMID 37217078. S2CID 258808777.
  35. ^ a b Villain N, Planche V, Levy R (1 December 2022). "High-clearance anti-amyloid immunotherapies in Alzheimer's disease. Part 1: Meta-analysis and review of efficacy and safety data, and medico-economical aspects" (PDF). Revue Neurologique. 178 (10): 1011–1030. doi:10.1016/j.neurol.2022.06.012. ISSN 0035-3787. PMID 36184326. Archived (PDF) from the original on 10 January 2024. Retrieved 10 January 2024.
  36. ^ a b c d Liu KY, Villain N, Ayton S, Ackley SF, Planche V, Howard R, et al. (2 May 2023). "Key questions for the evaluation of anti-amyloid immunotherapies for Alzheimer's disease". Commentary. Brain Communications. 5 (3): fcad175. doi:10.1093/braincomms/fcad175. PMC 10306158. PMID 37389302.
  37. ^ Alves F, Kalinowski P, Ayton S (16 May 2023). "Accelerated Brain Volume Loss Caused by Anti–β-Amyloid Drugs: A Systematic Review and Meta-analysis". Neurology. 100 (20): e2114–e2124. doi:10.1212/WNL.0000000000207156. ISSN 0028-3878. PMC 10186239. PMID 36973044.
  38. ^ Perneczky R, Dom G, Chan A, Falkai P, Bassetti C (11 September 2023). "Anti-amyloid antibody treatments for Alzheimer's disease". European Journal of Neurology. 31 (2): e16049. doi:10.1111/ene.16049. hdl:10067/1987770151162165141. ISSN 1351-5101. PMC 11235913. PMID 37697714. S2CID 261694703.
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