Kaylee Stella Harris MBChB V
Dementia (major neurocognitive disorder) is a plague that impacts the ever-aging population currently having over 55 million victims worldwide. Majority of dementia patients also suffer from Alzheimer’s disease which accounts for 60% to 80% of cases.1 Alzheimer’s disease causes catastrophic damage to memory and a patient’s mental functions. It is a disease that continues to baffle scientists as to its exact cause, however it is thought that a build-up of an abnormal protein called amyloids around neurones leads to plaque build-up around the cells. Tau neurofibrillary tangles (NFTs) can also be seen within cells and is known as the primary biomarker of the disease.2 The NFTs are made up of hyperphosphorylated tau proteins and are important in staging the disease. Typical progression starts from the trans-entorhinal region towards the neocortex and allocortex.3 There are also many other causes of major neurocognitive disorders including traumatic brain injury, prion disease, substance abuse, HIV, tertiary syphilis, and metabolic disorders. On 6 January 2023, Lecanemab, a drug that treats this condition was granted accelerated approval by the Food and Drug Administration (FDA) in the United States of America. Its efficacy is still under deliberation.
Clinical Studies
Double-blind, placebo-controlled, parallel-group, dose finding studies were used to determine the efficacy of Lecanemab. 856 patients with mild dementia stage of Alzheimer’s disease or amyloid pathology and mild cognitive impairment were involved in the study. By week 79 there was a change from baseline in amyloid beta Positron Emission Tomography (PET) composite, standardised uptake value ratio (SUVR) and centiloids.4
Figure 1: A graph showing the reduction in brain amyloid beta plaques (adjusted mean change from baseline in amyloid beta PET composite, SUVR and centiloids)4
Mechanism of action
Lecanemab is unique as it not only targets the devastating symptoms of Alzheimer’s Disease, but also targets the underlying disease progression. Lecanemab is classified as a recombinant humanised immunoglobulin gamma 1 (IgG1) monoclonal antibody. They are man-made proteins that will attach to a specific antigen on the surface of the cell that they are targeting. This helps the body’s immune system to identify and destroy these damaged cells.5 The antibody is directed against both soluble and insoluble aggregated forms of amyloid beta (Aβ). Lecanemab is highly selective to Aβ protofibrils and prevents Aβ deposits in the brain. Aβ causes neuronal death, synaptic impairment, and progressive neurodegeneration. Soluble Aβ is the preferred target of Lecanemab and works on Aβ oligomers, insoluble and protofibrils.6
Pharmacokinetics
The steady state concentration of Lecanemab is reached at six weeks after initiation of treatment with 10mg/kg doses every two weeks.6 The peak concentration (Cmax) and area under the curve versus time (AUC) of Lecanemab after a single dose (0.3 – 15 mg/kg) increased proportionally. The mean volume of distribution is 3.22L. The half-life is five to seven days and is degraded by proteolytic enzymes. No studies to date have been conducted with regards to patients with hepatic or renal impairments, but the drug is not expected to undergo renal elimination or hepatic metabolism.4
Side effects
ARIA (Amyloid Related Imaging Abnormalities) are abnormalities found on magnetic resonance imaging (MRI) with regards to anti-amyloid treatment of Alzheimer’s disease. These signs include vasogenic oedema and cerebral microhaemorrhages. Vasogenic oedema stems from the identification of an increased MRI signal on fluid attenuation inversion recovery (FLAIR) sequences. This depicts an increase in cellular permeability to serum proteins by capillary endothelial cells in the leptomeningeal and sulcal spaces. This high intracellular osmolality results from cellular damage. On the images below, it is seen that there is effusion of proteinaceous fluid from meningeal vessels into the sulcal space.7
Fatal complications (intracerebral haemorrhages)
The complications of Lecanemab will be explained using a case study.
A 65-year-old patient that was part of the Lecanemab trial underwent the randomised phase where he received either a placebo or doses of Lecanemab, the treatment assignment was unknown. During the open-label phase the patient was to receive three intravenous Lecanemab over a six-week period. Four days after the last transfusion, the patient presented to the emergency room with aphasia and a left horizontal gaze preference. The patient had an ischemic stroke.
A Magnetic Resonance Imaging (MRI) done 81 days before the stroke showed mild small-vessel disease with no microhaemorrhages, oedema or amyloid-related pathology. However, when the patient presented to the emergency department, a Computerised Tomography (CT) was done which revealed multiple intraparenchymal haemorrhages that were extensive. The patient’s condition began to worsen as they soon sustained nonconvulsive seizures that were picked up on Electroencephalography (EEG) as well as a global aphasia. Three days later the patient had to be intubated and a MRI revealed an acute right sided thalamocapsular infarction and many multifocal cortical and subcortical haemorrhages as well as oedema surrounding these areas.
Figure 3: Image A shows extensive multifocal cortical intraparenchymal haemorrhages. Image B shows extensive cerebral cortical and subcortical oedema on MRI T2 fluid-attenuated inversion recovery (FLAIR) sequence.8
The patient then subsequently died. An autopsy was conducted which revealed extensive multifocal intraparenchymal haemorrhages, diffuse histiocytic vasculitis with necrotising vasculopathy with amyloid depositions within blood vessel walls, cerebral amyloid angiopathy as well as Alzheimer’s disease neuropathic changes.8 These neuropathic changes included classical positive lesions of abundant amyloid plaques, neurofibrillary tangles, hyperphosphorylated tau within dystrophic neurites, astrogliosis and microglial cell activation. The negative features include neuron loss, neuropil loss and loss of synaptic elements.9
Figure 4: Coronal section of cerebral hemispheres showing numerous cortical intracerebral haemorrhages.8
Figure 5: Image D is a haematoxylin and eosin-stained section of the left parietal cortex showing histiocytic infiltration of the blood vessel with amyloid angiopathy. Image E shows an amyloid-β immunohistochemical stained cortical blood vessel displaying lymphocyte and histocyte infiltration.8
Compare to Aducanumab and Gantenerumab
According to Dr K. D. Sullivan (a neuropsychologist), Lecanemab has shown to be superior to the two drugs Aducanumab and Gantenerumab as it “intervenes earlier in the pathological process that contributes to Alzheimer’s”.
Evidence of this is shown through a clinical trial consisting of 1800 patients with early Alzheimer’s disease between the ages of 50 and 90. The study found that over a period of 18 months, the cognitive decline of patients that took Lecanemab was slowed by 27% as compared to patients that received the placebo.1 Even though this drug may not be the new “wonder drug”, according to Dr R. Petersen (a neurologist at Mayo Clinic), it will bring stability to patients in need making it “clinically meaningful”.
Conclusion
Thus, there are no contra-indications to the use of Lecanemab, however there are precautions to its use. These being ARIAs with oedema and hemosiderin deposition.4 But still Lecanemab shows promising efficacy and could turn the tide on the war against major neurocognitive disorders caused by Alzheimer’s disease.
Bibliography
- Alzheimer’s: Is lecanemab the next great weapon against it? [Internet]. www.medicalnewstoday.com. 2022. Available from: https://www.medicalnewstoday.com/articles/lecanemab-why-a-new-alzheimers-drug-has-drawn-praise-and-some-concern
- NHS. Causes – Alzheimer’s Disease [Internet]. NHS. 2021. Available from: https://www.nhs.uk/conditions/alzheimers-disease/causes/
- Naseri NN, Wang H, Guo J, Sharma M, Luo W. The complexity of tau in Alzheimer’s disease. Neuroscience Letters. 2019 Jul;705:183–94.
- HIGHLIGHTS OF PRESCRIBING INFORMATION These highlights do not include all the information needed to use LEQEMBI TM safely and effectively. See full prescribing information for LEQEMBI [Internet]. Available from: https://www.accessdata.fda.gov/drugsatfda_docs/label/2023/761269s000lbl.pdf
- American Cancer Society. Monoclonal Antibodies and Their Side Effects [Internet]. Cancer.org. American Cancer Society; 2015. Available from: https://www.cancer.org/treatment/treatments-and-side-effects/treatment-types/immunotherapy/monoclonal-antibodies.html
- Lecanemab [Internet]. go.drugbank.com. Available from: https://go.drugbank.com/drugs/DB14580
- Sperling RA, Jack CR, Black SE, Frosch MP, Greenberg SM, Hyman BT, et al. Amyloid-related imaging abnormalities in amyloid-modifying therapeutic trials: Recommendations from the Alzheimer’s Association Research Roundtable Workgroup. Alzheimer’s & Dementia. 2011 Jul;7(4):367–85.
- Reish NJ, Jamshidi P, Stamm B, Flanagan ME, Sugg E, Tang M, et al. Multiple Cerebral Hemorrhages in a Patient Receiving Lecanemab and Treated with t-PA for Stroke. New England Journal of Medicine. 2023 Jan 4;388:478–9.
- Serrano-Pozo A, Frosch MP, Masliah E, Hyman BT. Neuropathological Alterations in Alzheimer Disease. Cold Spring Harbor Perspectives in Medicine [Internet]. 2011 Sep 1;1(1):a006189–9. Available from: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3234452/
