Alzheimer’s disease (AD) is a neurodegenerative disease, contributing to 60% - 70% of cases of dementia. Over time, Alzheimer’s leads to a loss of cognitive function, including the ability to remember and recognise, orientation and also behavioural changes. It is a progressive disorder that damages and destroys nerve cells in the brain, typically affecting (but not limited to) elderly people over the age of 65. Therefore, the disease is becoming more and more common since people are living for longer and the likelihood of developing Alzheimer's rises with age. AD affects over 55 million people worldwide and every year there are 10 million new cases. Thus, Alzheimer’s is at the forefront of biomedical research, especially due to the limited treatment options and understanding of the disease.
However, in recent years there has been remarkable progress in our knowledge of how Alzheimer’s affects the brain, and consequently new treatments for it. Inside the brains of patients with Alzheimer’s, there are abnormal levels of proteins called beta-amyloid and tau, which make up plaques and tangles. While people do generally develop more of this with age, those with AD have significantly more build-up and deposits in the hippocampus and temporal lobe, before spreading to other areas of the brain. They directly contribute to the damage and destruction of synapses that are involved in memory and cognition, as tangles of tau cause brain cells to start producing a specific molecule called MEG3 that provoke death by necroptosis - a process which the body normally uses to get rid of unwanted cells as new ones are made. Scientists at the UK's Dementia Research Institute at University College London and KU Leuven in Belgium found that if MEG3 is blocked off, brain cells survive. This ground-breaking discovery pinpoints the specific cell suicide mechanism that hints at how and why neurones die in patients with AD, which means an opportunity for new lines of drugs to treat the disease.
Lecanemab, one of two drugs used to treat Alzheimer’s disease was very recently fully approved for use by the FDA in July this year (the FDA is the drug regulations body in the USA; this is the MHRA in the UK). Developed by a Japanese pharmaceutical company called Eisai that later worked together with Biogen, it is the second approved anti-amyloid drug (used for treating AD) after Biogen’s aducanumab. Lecanemab, sold under the name Leqembi, was first approved through the FDA’s Accelerated Approval Pathway which allows approval decisions to take place faster for unmet medical treatments for serious conditions. The new drug has been shown to slow down cognitive and functional deterioration during the early stages of the disease by clearing the amyloid plaque.
More specifically, lecanemab is a monoclonal antibody treatment and is given to patients intravenously. Beta-amyloid (a type of protein) exists in various states, including soluble monomers and aggregates of increasing size, insoluble fibrils and plaque. lecanemab has a high selectivity towards soluble beta-amyloid aggregates as they have high levels of neurotoxicity although it works on many different types of beta-amyloid. The drug works by binding to the protein as an immunoglobulin and then triggers an immune response to remove it. Alongside targeting amyloid plaque, lecanemab was also effective in treating some tau tangles in clinical trials.
Lecanemab’s effectiveness is evident in other clinical trials. In an extensive global, double blind, placebo-controlled phase 3 trial involving 1795 participants with early stages, symptomatic Alzheimer’s disease, the promising drug slowed clinical decline on the global cognitive and functional scale by 27% compared to those that received the placebo during those 18 months. In imaging tests like PET or other markers like cerebrospinal fluid, amyloid burden was significantly reduced and usually reached normal levels by the end of the trial. Adverse effects were reported, such as fluid formation on the brain, occurring in 12.6% of participants.
There were incidences of more serious side effects, such as anti-amyloid related imaging abnormalities (ARIA) which showed up in 17.3% of the group. While it’s asymptomatic and self-resolving, and those with Alzheimer’s disease are prone to this anyway, it can cause bleeding in the brain, which poses a significant risk factor. Despite this, the significance of this drug is great as current therapeutic drugs ease symptoms but do not treat the underlying causes. Compared to aducanumab, lecanemab has considerably lower rates of adverse effects - about a third of the rate as explained by Dr van Dyck, a lead author of the study of the drug and Eisai’s consultant, so it seems to be reasonably safe. As the phase 3 clinical trial was limited to 18 months, an extension study is currently going on to look out for possible long term side effects. If it's approved in the UK, it will open up challenges in terms of diagnosis for the NHS, as it's important for the drug to intervene before too much amyloid build-up damages brain cells and causes them to die.
Though this drug will have to wait at least until 2024 for a decision to be made about it in Europe, and it’s uncertain if it will be available on the NHS, lecanemab truly offers hope for those with early stage Alzheimer’s disease. It shows clear signs of slowing down the progression of the disease, and a step in the direction of showing that it is possible, with expectations for even more effective drugs in the future.