Anti-amyloid drugs

Last updated

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]

Contents

Approved drugs

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

Aducanumab

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

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] Lecanemab was approved for medical use in South Korea in May 2024, [29] and in Mexico in December 2024. [30]

Donanemab

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. [31] [32] Donanemab was developed by Eli Lilly and Company. [33] [34]

The most common side effects include amyloid-related imaging abnormalities and headache. [32]

Donanemab was approved for medical use in the United States in July 2024. [32] [35] Treatment is intended for people with mild cognitive impairment or mild dementia stage of disease, which is the same population the treatment was studied in the clinical trials. [36]

Efficacy

A 2023 review found that "Anti-Aβ drugs have relatively low efficacy in preventing cognitive decline, and they reduce pathological productions with acceptable safety." [37] 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." [38]

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. [39] They also support running studies designed to distinguish between disease-modifying and symptomatic effects. [39]

A 2024 study suggests that the cognitive benefits of monoclonal antibody treatments for Alzheimer’s disease may result from increases in Aβ42 levels, rather than solely from the removal of amyloid plaques. [40] This challenges traditional amyloid-focused hypotheses, highlighting the need for further research into the role of Aβ42 and the risk/benefit balance of these treatments.

Adverse effects

Amyloid-related imaging abnormalities (ARIA) are a serious adverse effect; with higher rates of ARIA associated with higher amyloid clearance. [38] There are two categories of ARIA, based on signal changes believed to be associated with vasogenic edema (ARIA-E) and microhemorrhages (ARIA-H).

Accelerated brain volume loss

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. [41]

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. [39]

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. [39]

Society and culture

Drug development

The approved anti-amyloid drugs were developed after years of unsuccessful attempts to develop a disease-modifying treatment for Alzheimer's disease. [42]

Cost

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

See also

Related Research Articles

<span class="mw-page-title-main">Infliximab</span> Biopharmaceutical drug for autoimmune disorders

Infliximab, a chimeric monoclonal antibody, sold under the brand name Remicade among others, is a medication used to treat a number of autoimmune diseases. This includes Crohn's disease, ulcerative colitis, rheumatoid arthritis, ankylosing spondylitis, psoriasis, psoriatic arthritis, and Behçet's disease. It is given by slow injection into a vein, typically at six- to eight-week intervals.

<span class="mw-page-title-main">Biogen</span> Pharmaceutical company

Biogen Inc. is an American multinational biotechnology company based in Cambridge, Massachusetts, United States specializing in the discovery, development, and delivery of therapies for the treatment of neurological diseases to patients worldwide. Biogen operates in Argentina, Brazil, Canada, China, France, Germany, Hungary, India, Italy, Japan, Mexico, Netherlands, Poland, Sweden, and Switzerland.

Daclizumab is a therapeutic humanized monoclonal antibody which was used for the treatment of adults with relapsing forms of multiple sclerosis (MS). Daclizumab works by binding to CD25, the alpha subunit of the IL-2 receptor of T-cells.

<span class="mw-page-title-main">Cancer immunotherapy</span> Artificial stimulation of the immune system to treat cancer

Cancer immunotherapy (immuno-oncotherapy) is the stimulation of the immune system to treat cancer, improving the immune system's natural ability to fight the disease. It is an application of the fundamental research of cancer immunology (immuno-oncology) and a growing subspecialty of oncology.

<span class="mw-page-title-main">Natalizumab</span> Medication used to treat multiple sclerosis and Crohns disease

Natalizumab, sold under the brand name Tysabri among others, is a medication used to treat multiple sclerosis and Crohn's disease. It is a humanized monoclonal antibody against the cell adhesion molecule α4-integrin. It is given by intravenous infusion. The drug is believed to work by reducing the ability of inflammatory immune cells to attach to and pass through the cell layers lining the intestines and blood–brain barrier.

<span class="mw-page-title-main">Ibritumomab tiuxetan</span> Radioimmunotherapy treatment

Ibritumomab tiuxetan, sold under the trade name Zevalin, is a monoclonal antibody radioimmunotherapy treatment for non-Hodgkin's lymphoma. The drug uses the monoclonal mouse IgG1 antibody ibritumomab in conjunction with the chelator tiuxetan, to which a radioactive isotope is added. Tiuxetan is a modified version of DTPA whose carbon backbone contains an isothiocyanatobenzyl and a methyl group.

<span class="mw-page-title-main">Monoclonal antibody therapy</span> Form of immunotherapy

Monoclonal antibodies (mAbs) have varied therapeutic uses. It is possible to create a mAb that binds specifically to almost any extracellular target, such as cell surface proteins and cytokines. They can be used to render their target ineffective, to induce a specific cell signal, to cause the immune system to attack specific cells, or to bring a drug to a specific cell type.

Ocrelizumab, sold under the brand name Ocrevus, is a medication used for the treatment of multiple sclerosis. It is a humanized anti-CD20 monoclonal antibody. It targets CD20 marker on B lymphocytes and is an immunosuppressive drug. Ocrelizumab binds to an epitope that overlaps with the epitope to which rituximab binds. It is administered by intravenous infusion. The fixed-dose combination ocrelizumab/hyaluronidase is administered by subcutaneous injection.

Obinutuzumab, sold under the brand name Gazyva among others, is a humanized anti-CD20 monoclonal antibody used as a treatment for cancer. It was originated by GlycArt Biotechnology AG and developed by Roche.

Mogamulizumab, sold under the brand name Poteligeo, is a humanized, afucosylated monoclonal antibody targeting CC chemokine receptor type 4 (CCR4). It is given by injection into a vein.

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

<span class="mw-page-title-main">Amyloid-related imaging abnormalities</span> Medical condition

Amyloid-related imaging abnormalities (ARIA) are abnormal differences seen in magnetic resonance imaging of the brain in patients with Alzheimer's disease. ARIA is associated with anti-amyloid drugs, particularly human monoclonal antibodies such as aducanumab. There are two types of ARIA: ARIA-E and ARIA-H. The phenomenon was first seen in trials of bapineuzumab.

Lecanemab, sold under the brand name Leqembi, is a monoclonal antibody medication used for the treatment of Alzheimer's disease. Lecanemab is an amyloid beta-directed antibody. It is given via intravenous infusion to patients with mild cognitive impairment or mild dementia. In clinical trials, it demonstrated modest efficacy in reducing relative cognitive decline compared to placebo. 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.

Dostarlimab, sold under the brand name Jemperli, is a monoclonal antibody used as an anti-cancer medication for the treatment of endometrial cancer. Dostarlimab is a programmed death receptor-1 (PD-1)–blocking monoclonal antibody.

Satralizumab, sold under the brand name Enspryng, is a humanized monoclonal antibody medication that is used for the treatment of neuromyelitis optica spectrum disorder (NMOSD), a rare autoimmune disease. The drug is being developed by Chugai Pharmaceutical, a subsidiary of Roche.

Belantamab mafodotin, sold under the brand name Blenrep, is a monoclonal antibody conjugated with a cytotoxic agent for the treatment of relapsed and refractory multiple myeloma.

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

Frunevetmab, sold under the brand name Solensia, is a monoclonal antibody used to treat pain associated with osteoarthritis in cats. It is the first monoclonal antibody drug approved by the US Food and Drug Administration for animal use. Frunevetmab is the international nonproprietary name.

Mosunetuzumab, sold under the brand name Lunsumio, is a monoclonal antibody used for the treatment of follicular lymphoma. It bispecifically binds CD20 and CD3 to engage T-cells. It was developed by Genentech.

<span class="mw-page-title-main">Tofersen</span> Medication

Tofersen, sold under the brand name Qalsody, is a medication used for the treatment of amyotrophic lateral sclerosis (ALS). Tofersen is an antisense oligonucleotide that targets the production of superoxide dismutase 1, an enzyme whose mutant form is commonly associated with amyotrophic lateral sclerosis. It is administered as an intrathecal injection.

References

  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. 1 2 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. 1 2 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. 1 2 3 "Aduhelm- aducanumab injection, solution". DailyMed. Archived from the original on 14 June 2021. Retrieved 14 June 2021.
  6. 1 2 3 4 "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.PD-icon.svg 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.
  10. ↑ Toyn J (May 2015). "What lessons can be learned from failed Alzheimer's disease trials?". Expert Review of Clinical Pharmacology. 8 (3): 267–269. doi: 10.1586/17512433.2015.1034690 . PMID   25860157. S2CID   35158630.
  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. 1 2 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.PD-icon.svg 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. 1 2 3 "Leqembi – lecanemab injection, solution". DailyMed. 11 January 2023. Archived from the original on 15 January 2023. Retrieved 21 January 2023.
  24. 1 2 "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.PD-icon.svg 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.PD-icon.svg 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. ↑ "Leqembi launched in South Korea" (Press release). BioArctic. 27 November 2024. Retrieved 6 December 2024– via PR Newswire.
  30. ↑ "Leqembi approved in Mexico" (Press release). BioArctic. 4 December 2024. Retrieved 6 December 2024– via PR Newswire.
  31. ↑ "Kisunla- donanemab-azbt injection, solution". DailyMed. 2 July 2024. Retrieved 15 August 2024.
  32. 1 2 3 "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.PD-icon.svg This article incorporates text from this source, which is in the public domain.
  33. ↑ 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.
  34. ↑ 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.
  35. ↑ "Novel Drug Approvals for 2024". U.S. Food and Drug Administration (FDA). 1 October 2024. Retrieved 29 November 2024.
  36. ↑ "FDA approves treatment for Alzheimer's disease - The Yucatan Times". 12 July 2024. Retrieved 15 July 2024.
  37. ↑ 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.
  38. 1 2 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.
  39. 1 2 3 4 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.
  40. ↑ Dolan EW (9 December 2024). "Neuroscientists just turned a major Alzheimer's theory on its head". PsyPost - Psychology News. Retrieved 13 December 2024.
  41. ↑ 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.
  42. ↑ 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.
This page is based on this Wikipedia article
Text is available under the CC BY-SA 4.0 license; additional terms may apply.
Images, videos and audio are available under their respective licenses.