The European Medicines Agency has recommended the licensing of lecanemab for early Alzheimer’s disease. Catherine Reilly reports on recent developments
Last month, the European Medicines Agency (EMA) recommended the licensing of lecanemab (Leqembi) for early Alzheimer’s disease (AD) following a re-examination of an earlier decision.
The EMA’s new recommendation specifically relates to the drug’s use in a restricted patient population who are less likely to experience amyloid-related imaging abnormalities (ARIA), which involve swelling and potential bleeding in the brain. ARIA is a recognised possible side-effect in patients receiving anti-amyloid monoclonal antibody therapies.
Lecanemab has been shown to have a modest effect in slowing cognitive decline in early AD. If the European Commission proceeds to grant marketing authorisation, it will become the first disease-modifying therapy (DMT) for early AD in the European Union (EU).
The drug was co-developed by Eisai and Biogen. A spokesperson for Eisai told the Medical Independent: “If approved, Eisai will work through the required national reimbursement authority processes to make lecanemab available to eligible people living with early AD in EU countries as soon as possible.”
The EMA is also reviewing an approval application for another DMT for early AD – donanemab (developed by Eli Lilly).
Re-examination
Last July, the EMA’s human medicines committee (CHMP) decided against recommending lecanemab in a broader population of patients with early AD. The CHMP determined that the medication’s effect on delaying cognitive decline did not counterbalance the risk of serious adverse events.
“Although most cases of ARIA in the main study were not serious and did not involve symptoms, some patients had serious events, including large bleeds in the brain which required hospitalisation,” stated the EMA at the time. “The seriousness of this side-effect should be considered in the context of the small effect seen with the medicine.”
In seeking a re-examination, the company proposed to restrict lecanemab’s use to patients with only one or no copy of the ApoE4 gene. These patients are less likely to experience ARIA compared with those with two ApoE4 copies. Notably, however, people with two copies of the gene have a very high risk of developing AD.
The CHMP considered subgroup analyses which excluded data from patients who carried two copies of the ApoE4 gene.
In patients treated with lecanemab, 8.9 per cent of those with only one or no copy of ApoE4 experienced ARIA-Edema, compared with 12.6 per cent of all patients; 12.9 per cent of patients in the restricted population experienced ARIA-Haemorrhage, compared with 16.9 per cent of the broader population.
In regard to patients treated with placebo, the figures were 1.3 per cent (ARIA-E) and 6.8 per cent (ARIA-H) in the restricted population.
Effectiveness
According to the EMA, the benefits of lecanemab in the restricted population were in line with those seen in the broader population. For the re-examination, the company provided a subgroup analysis of data from the main study which included 1,521 patients who had one or no ApoE4 copy out of a total 1,795 patients.
The main measure of effectiveness was a change in cognitive and functional symptoms after 18 months using the Clinical Dementia Rating-Sum of Boxes (CDR-SB). The CDR-SB scale ranges from 0-to-18 and higher scores indicate greater impairment.
The data from the aforementioned 1,521 patients showed that, after 18 months of treatment, patients treated with lecanemab had a smaller increase in CDR-SB score than those who received placebo (1.22 versus 1.75), indicating slower cognitive decline.
The results of other key measures indicated a similar effect to that seen in the CDR-SB score.
The CHMP concluded that lecanemab’s benefits in slowing down progression of early AD symptoms were greater than its risks in patients who had only one or no copy of ApoE4.
Additional safety measures
The EMA recommendation comes with a number of provisos, including the implementation of risk minimisation measures to reduce the risk of severe and symptomatic ARIA.
Patients will require MRI scans to monitor for ARIA prior to initiating treatment and before the fifth, seventh, and 14th dose. Additional MRI scans may be needed during treatment if patients develop symptoms of ARIA.
The company will provide a guide and checklist for healthcare professionals, an alert card for patients, and training programmes on ARIA for healthcare professionals. In addition, it must carry out a post-authorisation safety study to further characterise ARIA-E and ARIA-H and assess the effectiveness of the risk minimisation measures.
Eligibility
The EMA stated that lecanemab will be available through a controlled access programme for the recommended patient population. The medication will also be contraindicated in people receiving anticoagulant treatment, for example.
The benefits vs costs of the drug remain the subject of ongoing debate. In August, the UK’s National Institute for Health and Care Excellence (NICE) published draft guidance which stated the benefits of lecanemab were too small to justify the costs.
According to NICE, lecanemab provided on average four-to-six months slowing in the rate of progression from mild-to-moderate AD. It said this “small but meaningful” effect – based on outcomes at 18 months – was not sufficient to justify the additional cost to the NHS. NICE’s final recommendations are awaited.
‘Significant moment’
A recent statement issued by the Alzheimer Society of Ireland (ASI) on the EMA recommendation captured some of the complexities at play.
It said the fact the EU was on the cusp of its first DMT for AD was a significant moment that “cannot be underestimated”.
The ASI also stated it was “glad to see” the EMA taking a “cautious approach which protects people at the greatest risk of harmful side-effects”.
However, the ASI added that “we cannot forget the 64,000 people already living with dementia in Ireland who need services and supports to live as well as possible for as long as possible”.
“Leqembi will only be suitable for a relatively small number of people who are in the very early stages of Alzheimer’s disease. There are many for whom this drug will not be suitable, including those living with other types of dementia.”
National Dementia Office
The HSE National Dementia Office (NDO) has been preparing for the possible introduction of DMTs for AD. In 2022, it convened an expert reference group on preparedness for potential licensing of such agents.
Aside from the cost of DMTs, considerations for health systems include the structures required to identify patients, deliver the drug, and monitor patients.
Currently, anti-amyloid monoclonal antibody DMTs approved in other jurisdictions, or on the approval pathway, require biomarker confirmation of the diagnosis of AD through PET-ligand neuroimaging, or amyloid-tau ratio cut offs from cerebrospinal fluid, obtained via lumbar puncture.
In addition, delivery of the drug requires intravenous infusion facilities and radiological resourcing to implement serial brain MRI.
A recent paper in BMC Health Services Research, which arose from the NDO’s preparatory work, described a hub-and-spoke model for DMT service delivery. This model would utilise the approach outlined in the HSE’s national model of care for dementia (2023).
The paper also noted that when patients present to memory clinics with subjective memory complaints, or mild cognitive impairment, they are often discharged back to primary care without further support or intervention.
“Thus, it is imperative to consider systematic approaches to managing early-stage cognitive decline, since evidence suggests early interventions are associated with larger clinical benefits, and foster potential for access to DMT.”
It noted the future delivery of DMTs in Irish healthcare was complicated by long-standing capacity constraints, insufficient universal primary care coverage, and growing waiting lists.
The emergence of DMTs for early AD is widely regarded as a significant breakthrough and may also act as a lever to drive enhancements of diagnostic and care pathways.
However, clinicians and patients hope these developments will pave the way for even more advanced and expansive treatment options for all those impacted by dementia over the coming years.
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