November 2024 • PharmaTimes Magazine • 22-23
// THERAPIES /
Chosen path
The approval of lecanemab – a pharmacovigilance perspective
The Medicines and Healthcare products Regulatory Agency (MHRA) has granted approval of lecanemab.
This particular therapy is a monoclonal antibody treatment for use among patient populations with mild cognitive impairment or mild stages of dementia brought on by Alzheimer’s Disease (AD).
The approval signals further progress in addressing an unmet medical need.
However, the complexity of its benefit-risk profile, and the practical implications of its use, does warrant a long-term pharmacovigilance strategy.
Lecanemab targets and binds to amyloid-beta (Aβ) aggregates in the brain. These aggregates are a hallmark of AD and their reduction is seen as a potential pathway to slow disease progression in a condition that is becoming more prevalent as our communities live longer.
The drug has already received approval from the FDA in the last year and has since been approved in several other countries. These include Japan, China, South Korea, the United Arab Emirates and, most recently, the UK.
Keeping it real
As with many new therapies, there are complexities regarding its risk-benefit profile that need further exploration in real-world settings.
The European Medicines Agency (EMA) rejected its marketing authorisation application, citing concerns over the serious adverse events (SAEs) linked to the drug.
Similarly, the UK’s NICE has not recommended lecanemab for routine NHS use, citing high levels of uncertainty regarding the long-term effectiveness of lecanemab and a requirement for more evidence regarding its cost-effectiveness.
The differences in opinion of regulatory authorities highlights the complexity of evaluating the benefit-risk profile of a drug for an unmet medical need, particularly when limited clinical trial data is available.
‘The differences in opinion of regulatory authorities highlights the complexity of evaluating the benefit-risk profile of a drug’
Lecanemab’s mechanism of selectively targeting toxic soluble aggregated amyloid-beta has shown promise in reducing amyloid burden in AD patients.
Clinical trial data indicated a reduction in amyloid levels after 18 months of treatment when compared with placebo.
However, it is uncertain whether this observed reduction in amyloid burden translates to a clinically meaningful benefit in cognitive function.
Risk assessment
In terms of risks, the most common adverse events arising from the clinical trial data for lecanemab included infusion-related reactions, amyloid-related imaging abnormalities (ARIA) and intracerebral haemorrhage.
ARIA is of particular concern, with the risk increased in patients carrying the ApoE ε4 gene.
The boxed warning for ARIA in US product information underlines the importance of identifying patients with this gene prior to treatment initiation. Ultimately this will minimise the risk of ARIA with possible rare, life-threatening events.
The need for a pharmacovigilance perspective is vital. Those clinical trials that supported lecanemab’s approval were conducted in controlled environments. Furthermore, they were designed to assess the efficacy of the intervention in a strictly defined study population and may not necessarily detect adverse events in a broader real-world population.
For example, the clinical trials excluded patients with exposure to antiplatelet agents or anticoagulants (other than aspirin) and excluded patients with various risk factors for intracerebral haemorrhage.
Consequently, the trial provided limited insights into the safety of lecanemab in patients more commonly seen in routine clinical practice, such as those with diverse ethnic backgrounds or with comorbidities.
This was highlighted by NICE, which noted that people with young-onset dementia, of diverse ethnicity and racial backgrounds, and a high lifetime risk of AD (such as people with Down’s syndrome) were not fully represented in the clinical trials.
Additionally, the relatively short time frame of the clinical trial (18 months) limits a comprehensive understanding of the long-term outcomes of the drug at present.
Class monitor
Given these limitations, a comprehensive pharmacovigilance strategy is essential to monitor lecanemab’s real-world safety and effectiveness.
This strategy should encompass diverse data sources, including spontaneous adverse event reporting, electronic health records, post-authorisation safety and effectiveness studies, and patient-reported outcomes. Systematic reviews and meta-analyses also play a key role in synthesising emerging real-world evidence.
One area that requires particular attention is the routine risk minimisation measures proposed for the safe use of lecanemab, including baseline and periodic brain imaging scans and pharmacogenomic testing for the ApoE ε4 allele.
NICE has pointed out that the implementation of such measures in the NHS would significantly disrupt current diagnostic and treatment pathways.
Furthermore, in the US, where pharmacogenomic testing for ApoE ε4 is required, there is currently no FDA-authorised test available, challenging routine risk minimisation in this population.
Final analysis
While the approval of lecanemab marks an important step forward in the treatment of AD, regulatory bodies have reached different conclusions regarding the current benefit-risk profile of the drug in real-world clinical practice.
A pharmacovigilance perspective involving the continuous monitoring of a range of real-world data sources will be critical in addressing remaining uncertainties going forward.
The effectiveness of routine risk minimisation measures for the safe use of the product is also necessary to minimise the risks of use.
This cautious approach is essential to protect patients and maximise the therapeutic benefit of this new treatment.
Amy Bobbins is a Senior Research Fellow at the Drug Safety Research Unit. Go to drsu.org
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