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, was bapineuzumab, but it did not show effectiveness in later-stage trials. [2] The first drug to be FDA approved was aducanumab in 2021. [3]

Contents

Approved drugs

As of 2022 none of these drugs have been approved by the European Medicines Agency. [5]

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." [6] 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." [7]

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 article in Brain Communications, 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. They also support running studies designed to distinguish between disease-modifying and symptomatic effects. [8]

Adverse effects

Amyloid-related imaging abnormalities are a relatively uncommon but serious adverse effect. [7]

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. [9]

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. [8]

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. [8]

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. [10]

Cost

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

Related Research Articles

<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.

Neurotoxicity is a form of toxicity in which a biological, chemical, or physical agent produces an adverse effect on the structure or function of the central and/or peripheral nervous system. It occurs when exposure to a substance – specifically, a neurotoxin or neurotoxicant– alters the normal activity of the nervous system in such a way as to cause permanent or reversible damage to nervous tissue. This can eventually disrupt or even kill neurons, which are cells that transmit and process signals in the brain and other parts of the nervous system. Neurotoxicity can result from organ transplants, radiation treatment, certain drug therapies, recreational drug use, exposure to heavy metals, bites from certain species of venomous snakes, pesticides, certain industrial cleaning solvents, fuels and certain naturally occurring substances. Symptoms may appear immediately after exposure or be delayed. They may include limb weakness or numbness, loss of memory, vision, and/or intellect, uncontrollable obsessive and/or compulsive behaviors, delusions, headache, cognitive and behavioral problems and sexual dysfunction. Chronic mold exposure in homes can lead to neurotoxicity which may not appear for months to years of exposure. All symptoms listed above are consistent with mold mycotoxin accumulation.

Pittsburgh compound B (PiB) is a radioactive analog of thioflavin T, which can be used in positron emission tomography scans to image beta-amyloid plaques in neuronal tissue. Due to this property, Pittsburgh compound B may be used in investigational studies of Alzheimer's disease.

<span class="mw-page-title-main">Familial amyloid polyneuropathy</span> Medical condition

Familial amyloid polyneuropathy, also called transthyretin-related hereditary amyloidosis, transthyretin amyloidosis abbreviated also as ATTR, or Corino de Andrade's disease, is an autosomal dominant neurodegenerative disease. It is a form of amyloidosis, and was first identified and described by Portuguese neurologist Mário Corino da Costa Andrade, in 1952. FAP is distinct from senile systemic amyloidosis (SSA), which is not inherited, and which was determined to be the primary cause of death for 70% of supercentenarians who have been autopsied. FAP can be ameliorated by liver transplantation.

<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.

Bapineuzumab is a humanized monoclonal antibody that acts on the nervous system and may have potential therapeutic value for the treatment of Alzheimer's disease and possibly glaucoma. However, in 2012 it failed to produce significant cognitive improvements in patients in two major trials, despite lowering key biomarkers of AD, amyloid brain plaque and hyperphosphorylated tau protein in CSF.

<span class="mw-page-title-main">Alzheimer's disease</span> Progressive neurodegenerative disease

Alzheimer's disease (AD) is a neurodegenerative disease that usually starts slowly and progressively worsens, and is the cause of 60–70% of cases of dementia. The most common early symptom is difficulty in remembering recent events. As the disease advances, symptoms can include problems with language, disorientation, mood swings, loss of motivation, self-neglect, and behavioral issues. As a person's condition declines, they often withdraw from family and society. Gradually, bodily functions are lost, ultimately leading to death. Although the speed of progression can vary, the typical life expectancy following diagnosis is three to nine years.

Solanezumab is a monoclonal antibody being investigated by Eli Lilly as a neuroprotector for patients with Alzheimer's disease. The drug originally attracted extensive media coverage proclaiming it a breakthrough, but it has failed to show promise in Phase III trials.

The Alzheimer's disease biomarkers are neurochemical indicators used to assess the risk or presence of the disease. The biomarkers can be used to diagnose Alzheimer's disease (AD) in a very early stage, but they also provide objective and reliable measures of disease progress. It is imperative to diagnose AD disease as soon as possible, because neuropathologic changes of AD precede the symptoms by years. It is well known that amyloid beta (Aβ) is a good indicator of AD disease, which has facilitated doctors to accurately pre-diagnose cases of AD. When Aβ peptide is released by proteolytic cleavage of amyloid-beta precursor protein, some Aβ peptides that are solubilized are detected in CSF and blood plasma which makes AB peptides a promising candidate for biological markers. It has been shown that the amyloid beta biomarker shows 80% or above sensitivity and specificity, in distinguishing AD from dementia. It is believed that amyloid beta as a biomarker will provide a future for diagnosis of AD and eventually treatment of AD.

Crenezumab is a fully humanized monoclonal antibody against human 1-40 and 1-42 beta amyloid, which is being investigated as a treatment of Alzheimer's disease. Crenezumab is highly homologous to solanezumab, another monoclonal antibody targeting amyloid-β peptides. In June 2022, the US National Institutes of Health announced that the drug failed as a medication for early-onset Alzheimer's disease following the results of a decade-long clinical trial.

<span class="mw-page-title-main">Rudolph E. Tanzi</span> American geneticist

Rudolph Emile 'Rudy' Tanzi a professor of Neurology at Harvard University, vice-chair of neurology, director of the Genetics and Aging Research Unit, and co-director of the Henry and Allison McCance Center for Brain Health at Massachusetts General Hospital (MGH).

Florbetapir (18F), sold under the brand name Amyvid, is a PET scanning radiopharmaceutical compound containing the radionuclide fluorine-18 that was approved for use in the United States in 2012, as a diagnostic tool for Alzheimer's disease. Florbetapir, like Pittsburgh compound B (PiB), binds to beta-amyloid, however fluorine-18 has a half-life of 109.75 minutes, in contrast to PiB's radioactive half life of 20 minutes. Wong et al. found that the longer life allowed the tracer to accumulate significantly more in the brains of people with AD, particularly in the regions known to be associated with beta-amyloid deposits.

Aducanumab, sold under the brand name Aduhelm, is a medication designed to treat Alzheimer's disease (AD). 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">PD-1 and PD-L1 inhibitors</span> Class of anticancer drugs

PD-1 inhibitors and PD-L1 inhibitors are a group of checkpoint inhibitor anticancer drugs that block the activity of PD-1 and PDL1 immune checkpoint proteins present on the surface of cells. Immune checkpoint inhibitors are emerging as a front-line treatment for several types of cancer.

<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. 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.

<span class="mw-page-title-main">Phenserine</span> Chemical compound

Phenserine is a synthetic drug which has been investigated as a medication to treat Alzheimer's disease (AD), as the drug exhibits neuroprotective and neurotrophic effects.

<span class="mw-page-title-main">David M. Holtzman</span> Medical researcher

David M. Holtzman is an American physician-scientist known for his work exploring the biological mechanisms underlying neurodegeneration, with a focus on Alzheimer's disease. Holtzman is former Chair of the Department of Neurology, Scientific Director of the Hope Center for Neurological Disorders, and associate director of the Knight Alzheimer's Disease Research Center at Washington University School of Medicine in St. Louis, Missouri. Holtzman's lab is known for examining how apoE4 contributes to Alzheimer's disease as well as how sleep modulates amyloid beta in the brain. His work has also examined the contributions of microglia to AD pathology.

Donanemab is a biological drug in Phase III clinical trials to determine whether it slows the progression of early Alzheimer's disease. There is currently no cure or disease-modifying treatment for Alzheimer's disease except for lecanemab. Donanemab has shown positive results in its first trials. Donanemab was developed by the Eli Lilly and Co. and is under clinical development as a possible treatment for Alzheimer's disease.

Remternetug is an experimental anti-amyloid monoclonal antibody that targets pyroglutamate Aβ. It is developed by Eli Lilly and Company.

References

  1. ↑ Gandy, Sam (2023). "News & views: anti-amyloid antibodies and novel emerging approaches to Alzheimer's disease in 2023". Molecular Neurodegeneration. 18 (1). doi: 10.1186/s13024-023-00656-x . PMC   10518943 .
  2. 1 2 Perneczky, Robert; Dom, Geert; Chan, Andrew; Falkai, Peter; Bassetti, Claudio (11 September 2023). "Anti‐amyloid antibody treatments for Alzheimer's disease". European Journal of Neurology. doi: 10.1111/ene.16049 . hdl: 10067/1987770151162165141 . ISSN   1351-5101. PMID   37697714. S2CID   261694703.
  3. 1 2 3 Brockmann, Rouen; Nixon, Joanna; Love, Bryan L.; Yunusa, Ismaeel (1 March 2023). "Impacts of FDA approval and Medicare restriction on antiamyloid therapies for Alzheimer's disease: patient outcomes, healthcare costs, and drug development". Lancet Regional Health - Americas. 20: 100467. doi:10.1016/j.lana.2023.100467. ISSN   2667-193X. PMC   9996432 . PMID   36908502.
  4. ↑ Hamilton, Jon (2023-07-06). "Alzheimer's drug Leqembi gets full FDA approval. Medicare coverage will likely follow". NPR. Retrieved 2023-11-26.
  5. ↑ 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.
  6. ↑ Lyu, Diyang; Lyu, Xuanxin; Huang, Li; Fang, Boyan (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.
  7. 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.
  8. 1 2 3 Liu, Kathy Y; Villain, Nicolas; Ayton, Scott; Ackley, Sarah F; Planche, Vincent; Howard, Robert; Thambisetty, Madhav (2 May 2023). "Key questions for the evaluation of anti-amyloid immunotherapies for Alzheimer's disease". Brain Communications. 5 (3). doi: 10.1093/braincomms/fcad175 . PMID   37389302.
  9. ↑ Alves, Francesca; Kalinowski, Pawel; Ayton, Scott (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.
  10. ↑ Perneczky, Robert; Dom, Geert; Chan, Andrew; Falkai, Peter; Bassetti, Claudio (11 September 2023). "Anti‐amyloid antibody treatments for Alzheimer's disease". European Journal of Neurology. doi: 10.1111/ene.16049 . hdl: 10067/1987770151162165141 . ISSN   1351-5101. 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.