What is the new drug - Lecanemab - and how will this breakthrough change the future of the Alzheimer’s landscape?
During the Clinical Trials on Alzheimer’s Disease conference (CTAD) held last year in San Francisco, one drug, lecanemab, dominated the panels and caused major discussion across the board. In recent news, the FDA has announced the approval of this drug through its accelerated approval program. Lecanemab has been discovered as the first disease-modifiable drug for Alzheimer's disease, as opposed to a treatment to simply dampen symptoms.
What is Alzheimer’s?
Alzheimer’s disease (AD) is a progressive neurodegenerative disease. It is associated with both cognitive and functional decline, initially causing deficits to memory, and in later stages leading to changes in behaviour and movement ability. There are three main stages in its progression:
Early-stage: The primary symptom is short-term memory loss.
Mid-stage: More frequent memory problems, mood changes, confusion and disorientation are commonly experienced.
Late-stage: Symptoms are more severe and include both hallucinations and delusions, possibly rendering violence towards others or paranoia in their surroundings.
The neuropathology of AD is complicated as many factors can contribute to its progression, however, one of the most notable biomarkers is aggregation of certain proteins in the brain. The two most important types of aggregates are amyloid beta and tau, forming amyloid plaques and neurofibrillary tangles respectively.
What is lecanemab?
Lecanemab is a humanised monoclonal antibody, a protein designed by cloning a white blood cell and then used to bind to specific protein sequences (antigens) in the body. Lecanemab is designed to combat AD progression by selectively binding to amyloid-beta aggregates to assist the immune system in neutralising and eliminating these potentially toxic species. The aim of lecanemab is to slow progression and so is best administrated with an early diagnosis.
Clinical trial results
In an 18 – month clinical trial with 1795 participants with mild dementia caused by AD, half of the patients received 10mg/kg intravenous lecanemab every two weeks, whilst the other 50% received a placebo. The main findings of the clinical trial can be summarised as an average of 27% slowing of cognitive decline across the participants over 8 months. These results demonstrate that lecanemab achieved its main goal of slowing cognitive decline, showing for the first time that amyloid-beta removal can improve cognitive function clinically.
Despite this success, it is important to note that the clinical trial was on a limited sample of 1795 people with early-stage AD from North America and Asia, and so, the clinical benefit may be less significant if applied to the wider global population.
Safety of the drug
As with other anti–amyloid agents, lecanemab also has its safety concerns. Throughout the trial, several of the cohort receiving the drug experienced amyloid-related imaging abnormalities (ARIA), brain swelling and bleeding. ARIA occurred in more than 21% of those who were on the drug, and; 17% experienced brain haemorrhages, although, EISAI, one of the pharmaceutical companies behind the development of lecanemab, determined these cases were non-life-threatening and mostly asymptomatic. During the main trial, there were 13 deaths, with 7 of those in the placebo group.
Unfortunately, many patients with Alzheimer’s also suffer from a myriad of other ailments, for example, cerebral amyloid angiopathy (CAA), a condition where amyloid plaque deposits slowly replace the smooth muscles of the blood vessels. This can be seen in one case linked to the clinical trial: a 65-year-old participant with CAA and related heart conditions being treated with blood thinners in addition to lecanemab. The patient experienced an ischemic stroke soon after their final dose of lecanemab. After receiving blood thinners, the patient experienced cerebral haemorrhages and unfortunately died. In this patient’s case, CAA is likely to have weakened blood vessels in the brain, leaving them vulnerable to rupture when the blood clot-dissolving treatment interfered. It is possible that Lecanemab contributes to an increased risk of stroke and brain inflammation in patients with amyloid plaques in the brain who receive blood thinning medication.
To offset the safety concerns, before prescribing lecanemab, screening should be done before and during treatment to rule out the use of blood thinners and the development of CAA or ARIA, and to inform both the patient and their support network about the potential risks of the drug.
Availability of lecanemab
Since its FDA approval, lecanemab is set to be available in the US soon, although it is likely to be very expensive. Lecanemab could be offered to slow cognitive decline for patients in the early stages of AD, provided they are not on blood thinners or show signs of ARIA. However, due to the lack of distinctive clinical features of AD, there is often a delayed diagnosis, leading to currently irreversible biological damage.
Women benefit from lecanemab less than men
Alzheimer’s Association UK states that “‘women are disproportionately affected by Alzheimer’s disease.” Alzheimer's Research UK has said that “dementia has been UK women’s leading cause of death for a decade”. Despite this, and the fact that women experience adverse drug reactions more often than men, clinical trials are less likely to include women. Currently, it is unclear how sex or gender relate to an increased risk, however, there is research to suggest it may be caused by underlying biological factors. Considering this information, we can delve into the figures presented during the CTAD conference.
The clinical trial cohort comprised a large range of characteristics, including different genders. Results show that lecanemab administered similar effects over most of the subgroups, however, there were some disparities. According to a figure published from the trial, females experienced a 12% slowing of cognitive decline with lecanemab treatment, compared to 43% in men. The reasoning for this difference in response, as suggested by Dr. Maria Teresa Ferretti from the University of Zurich, might be that females experiencing dementia seem to have greater amyloid burden (more amyloid plaques) on average than men. Therefore, even if amyloid clearance rate induced by the drug is presumed equal between genders, males would have lower amyloid presence overall after drug treatment, and this is thought to relate to slower cognitive decline in males than the females in the study.
Effects of Alzheimer’s risk gene, ApoE e4, are not mitigated by lecanemab
As well as environmental factors, there is a genetic component to the risk of developing AD. Less than 5% of AD is caused by a single genetic mutation, known as early-onset familial Alzheimer’s disease (EOFAD). In these cases, children of affected parents are very likely to develop AD. However, there are also risk factors, which are less definitive than familial factors, but still contribute to the risk of developing AD. APOE ε4 is a gene that affects the brain’s ability to process lipids and is a risk factor for AD in certain populations, but not equally in all; populations of African ancestry show lower ε4-related risk than those of European or Asian descent. Approximately 15 – 25% of the general population are carriers for APOE ε4, meaning they have either one or two APOE ε4 alleles. Two-thirds of the clinical cohort were carriers for APOE ε4, all of whom, as may be expected, saw less benefit from lecanemab than non-carriers across the duration of the trial. Professor Colin Masters from the University of Melbourne commented on these results, “We know APOE4 leads to amyloid deposition starting earlier in life than in E4 noncarriers. I suspect the ncarriers had a better result because they started with a lower amyloid burden.”
Future work
AD involves complex pathology, and there is still much left to understand. Lecanemab is a gateway drug for slowing cognitive decline, as opposed to a miracle drug that will dramatically alter the disease outcome. After the initial presentation, there has been a lot of excitement that an anti-amyloid drug has finally proven effective, validating years of research into amyloid aggregation and inspiring scientists to look further into these mechanisms.
In response to the approval, Alzheimer’s Research UK released a statement stating, “Today’s decision by the regulators in the US, who have deemed the Alzheimer’s drug lecanemab sufficiently safe and effective, marks another important milestone in the global effort to bring about treatments that target the underlying diseases of dementia”.
Lecanemab has unlocked hope for additional disease-modifying AD treatments: less expensive treatments with similar amyloid-beta target mechanisms, or with different but complementary targets for greater clinical benefit. Perhaps in the future, as more is known about early diagnosis, anti-amyloid drugs will be even more clinically beneficial, however, this discovery is still a great step forward.
This article was written by Rebecca Parker and Lizzie English, and edited by Julia Dabrowska. Interested in writing for WiN UK yourself? Contact us through the blog page and the editors will be in touch!
Commenti