Since August 2024, the National Institute for Health and Care Excellence (NICE) has published two draft guidance papers relating to new monoclonal antibody treatments for Alzheimer’s disease (AD) – lecanemab (Leqembi; Eisai) and donanemab (Kisunla; Eli Lilly).
While treatments currently offered to people with AD are aimed at managing symptoms, both lecanemab and donanemab are seen as cutting edge for their ability to target the root cause of the disease and slow progression. NICE, which produces guidance for clinicians in England and Wales, estimates that around 70,000 adults in England would have been eligible for treatment with lecanemab and donanemab.
However, both treatments are expensive and are associated with concerning side effects. As a result, NICE declined to recommend them in its draft guidelines, despite both being licensed for use in the UK by the Medicines and Healthcare products Regulatory Agency — lecanemab since August 2024 and donanemab since October 2024.
Clinicians in Scotland are still waiting for the Scottish Medicines Consortium to produce guidance on both lecanemab and donanemab.
Experts in AD have publicised mixed reactions to the news. Hilary Evans-Newton, chief executive of Alzheimer’s Research UK (ARUK), described the lecanemab decision as “deeply disappointing”, while Robert Howard, professor of Old Age Psychiatry at University College London, said the decision “should not come as a surprise”.
Similarly, in response to the donanemab decision, Howard said NICE had made “the correct and responsible decision”, while Evans-Newton said it “risks signalling that the UK is no longer a good place to launch new dementia treatments”.
Here, we unpack everything you need to know about why NICE arrived at its divisive conclusions for these “game-changing” new treatments and what it means for them to be approved by the MHRA but not recommended by NICE.
The decision underlines the need for us to double down on our research efforts to find new, affordable diagnostic tools that the NHS can deliver at scale
Tara Spires-Jones, group leader at the UK Dementia Research Institute at the University of Edinburgh
Who are lecanemab and donanemab licensed for?
Both drugs are licensed by the MHRA for adult patients in the early stages of AD. They can be used by patients who have no copies, or one copy, of the apolipoprotein E4 gene (ApoE4). They cannot be prescribed for patients with two copies of that gene (ApoE4 homozygous patients), who make up around 15% of people diagnosed with AD.
According to the NHS, AD affects an estimated 1 in 14 people aged over 65 years and 1 in 6 people aged over 80 years.
ApoE4 homozygous patients who take the drugs are at higher risk of developing amyloid-related imaging abnormalities (ARIAs), such as temporary swelling in one or more areas of the brain or small spots of bleeding on the brain surface. Homozygous patients also do not show the same level of benefit compared with people with no copies, or one copy, of the ApoE4 gene. For these reasons, the licenses do not cover ApoE4 homozygous patients.
What were NICE’s decisions on lecanemab and donanemab?
In statements on lecanemab and donanemab made in August and October 2024, respectively, NICE said that both drugs can slow the progression of AD; however, at this stage, it is not recommending them for NHS use.
Draft guidance for the two drugs concluded that “more evidence was needed to generate robust cost-effectiveness estimates”.
However, the draft guidance does not apply to patients who are already undergoing treatment with either of these two drugs in clinical trials. They are permitted to continue with the treatment, unless they and their healthcare professional consider it appropriate to stop.
What were the main reasons behind those decisions?
In the case of lecanemab, NICE said that while it had been shown to slow progression of AD by between four and six months, the cost of delivering the drug and of monitoring for side effects, combined with the “relatively small benefits”, meant that it was not considered a cost-effective use of limited NHS funding. While there were some uncertainties around the cost-effectiveness estimates, NICE said in its draft guidance: “All of the cost-effectiveness results seen by the committee are considerably above what NICE considers an acceptable use of NHS resources.”
In regard to donanemab, NICE acknowledged that it can slow AD progression by four to seven months, but said that there were uncertainties around the economic modelling. It concluded that the cost-effectiveness estimate is “likely to be above what NICE normally considers an acceptable use of NHS resources”.
In both cases, NICE has asked NHS England and each manufacturer for more information to explore the uncertainties further. It said it will look at that additional information, together with other stakeholder responses, at a later meeting.
Why were the medicines found to be too expensive?
With donanemab, NICE cited the costs involved in providing monthly infusions of the medicine in hospital and intensive monitoring for side effects as reasons why the medicine could not be considered cost-effective in light of what it described as “relatively small” benefits to patients.
Committee papers from NICE, published alongside the draft guidance, said the manufacturer assumed a cost of £208 for each infusion; however, submissions from NHS England reference in the papers assumed a cost of £565, related to the healthcare resource group that would be recorded for giving such an infusion.
The estimated cost given by the manufacturer and by NHS England for lecanemab were the same as for donanemab.
In both cases, NHS England said that £565 represents the actual amount that service providers would be paid to deliver the infusions.
In a statement on the lecanemab decision, Samantha Roberts, chief executive of NICE, said: “The reality is that the benefits this first treatment provides are just too small to justify the significant cost to the NHS.
“It is an intensive treatment to give to patients involving a hospital visit every two weeks with skilled staff needed to monitor them for signs of serious side effects, plus the cost of purchasing the drug,” she said.
What side effects are associated with donanemab and lecanemab?
In its draft guidance, NICE highlighted clinical trial evidence that suggested there are significant risks linked to donanemab treatment. Clinical trial data of 1,736 patients submitted by the manufacturer showed that amyloid-related imaging abnormality-edema (ARIA-E) — which presents as brain oedema or sulcal effusion — occurred in 205 participants (24.0%) in the donanemab group and in 18 participants (2.1%) in the placebo group.
The trial results also showed that most were asymptomatic (donanemab: 74.6%, placebo: 94.4%) and mild to moderate (donanemab: 93.1%, placebo: 100%)
Clinical effectiveness data submitted to NICE for lecanemab, following a trial involving 1,795 patients, found that the rate of radiographically identified ARIA-E was 12.6% for lecanemab and 1.7% for placebo. ARIA-E incidence with lecanemab was mostly asymptomatic (lecanemab: 77.9%, placebo: 100.0%) and was mostly radiographically mild or moderate (lecanemab: 91.1% vs placebo: 100.0%). Trial participants were given additional MRIs and safety visits to monitor their condition.
What does this all mean for patient access?
The MHRA’s approval and NICE’s rejection — assuming the draft guidance remains unchanged — mean that both lecanemab and donanemab will only be accessible to patients willing to pay for them privately. While a cost to patients in the UK has not yet been publicly announced by the manufacturer or private providers, lecanemab costs £20,000 per year in the United States, with ARUK estimating that, in total, care could cost “in the hundreds of thousands of pounds”.
“This is due to having to receive the drug intravenously every other week, needing extensive screening tests and ongoing MRI scans to monitor side effects,” it added.
ARUK has also estimated that donanemab may cost less than this because there is a maximum treatment duration of 18 months, whereas patients remain on lecanemab for life. Each vial of donanemab costs US$700 (£540) but ARUK says private patients will also have to pay for “screening tests, consultations and repeated brain scans to monitor for side effects”.
The decision also highlights the problems with the amyloid-targeting drugs — eye-wateringly expensive, difficult to administer and potentially harmful
Paul Morgan, professor of complement biology, division of Infection and Immunity UK at Cardiff University School of Medicine; Dementia Research Institute Cardiff, Cardiff University
Tara Spires-Jones, group leader at the UK Dementia Research Institute at the University of Edinburgh, said NICE’s decision on lecanemab “will see greater inequities emerging in people with dementia, as only those who are able to access private healthcare will be able to receive the drug”.
“It also underlines the need for us to double down on our research efforts to find new, affordable diagnostic tools that the NHS can deliver at scale, and different treatment options that can be implemented more easily in our health system,” she says.
Fiona Carragher, chief policy and research officer at Alzheimer’s Society, said the draft decision not to recommend donanemab was “disheartening”, but added that “we respect the decision of the regulator”.
“In other diseases, like cancer, treatments have become more effective, safer and cheaper over time and we hope to see similar progress in dementia,” she added.
Are these treatments available in other countries?
According to Biogen, its manufacturer in the United States, lecanemab has been approved in the United States, Japan, China, South Korea, Hong Kong and Israel, and is being marketed in the United States, Japan and China. Donanemab has been approved in both the United States and Japan.
On 14 November 2024, the EU’s Committee for Medicinal Products for Human Use issued a positive recommendation for lecanemab in early AD based on data from the global phase III clinical trial, ‘Clarity AD’, which demonstrated that lecanemab slowed disease progression at 18 months. The positive recommendation means that a decision on whether to grant lecanemab marketing authorisation is due from the European Medicines Agency (EMA) within 67 days.
The EMA previously refused marketing authorisation approval for lecanemab in July 2024 on the grounds that the observed effect of the treatment “on delaying cognitive decline does not counter balance the risk of serious adverse events associated with the medicine”.
But following the EMA’s decision, Eisai — which manufactures the medicine outside of the United States — requested a re-examination of the opinion.
Could NICE change its decision?
Since both NICE guidance documents are in draft form, the committee’s decisions could change depending on responses to the consultations. A final decision on lecanemab is due in February 2025 and a final decision on donanemab is due in March 2025.
How are people with Alzheimer’s disease currently treated in the UK?
Current treatments for AD are aimed at temporarily reducing the symptoms of the condition and include acetylcholinesterase (AChE) inhibitors, such as donepezil, galantamine and rivastigmine. Memantine, which is a N-methyl-D-aspartate (NMDA) receptor antagonist, can also be prescribed. Both classes of medicines target nerve cell receptors to increase communication between these cells.
People with AD can also be prescribed antipsychotic medicines, such as risperidone and haloperidol, to manage behavioural changes associated with the disease, including aggression or distress.
Are there further new therapies in the pipeline?
The Alzheimer’s Society has highlighted three promising drugs for treating the disease in the future. The first is remternetug, which targets amyloid proteins in a similar way to donanemab and lecanemab. Remternetug, manufactured by Eli Lilly, is currently undergoing clinical trials testing to determine whether it is best administered by IV infusion like donanemab and lecanemab or through a subcutaneous injection. The phase III trial — ‘TRAILRUNNER-ALZ 1’ — is testing the drug in patients with mild AD and is expected to end in 2025.
Buntanetap, which also targets amyloid proteins, is also entering a phase III trial, following a successful phase II/III trial that showed significant improvements in memory and thinking scores after 12 weeks of treatment for patients with early-stage AD.
Lastly, Novo Nordisk, which manufactures semaglutide, is testing its benefits on patients with AD, with results expected by September 2025.
Key quotes
On donanemab:
Paul Morgan, professor of complement biology, division of Infection and Immunity UK at Cardiff University School of Medicine; Dementia Research Institute Cardiff, Cardiff University:
“The decision will be a disappointment to Alzheimer’s sufferers and their carers. It means that there are no disease-modifying drugs for AD currently approved in the UK.
“The decision also highlights the problems with the amyloid-targeting drugs — eye-wateringly expensive, difficult to administer and potentially harmful. Balancing these against a modest impact on the disease, the decision made by NICE is understandable.”
Rob Howard, professor of old age psychiatry at University College London:
“Although there is considerable uncertainty about both the meaningfulness of the very small benefits seen with treatment and any longer term effects beyond the 18 months of data collected in the pivotal trials, NHS access to these new drugs would not have made an appreciable difference to the experience of patients and families affected by dementia.”
Tara Spires-Jones, director of the Centre for Discovery Brain Sciences at the University of Edinburgh, group leader in the UK Dementia Research Institute, and president of the British Neuroscience Association:
“While people living with dementia and their loved ones will undoubtedly be disappointed by the decision not to fund this new treatment on the NHS, the good news that new treatments can slow disease even a small amount is hopeful.
“New research is bringing us closer to treatments that should be safer and more effective.”
On lecanemab:
Liz Coulthard, professor of cognitive neurology at the University of Bristol:
“It has been very difficult for NICE to decide whether the clinical effect of lecanemab is worth the money. My view is that lecanemab should be available on the NHS for patients who may benefit. I hope that we can find a way to make administration of lecanemab more cost-effective.”
John Gallacher, director of Dementias Platform UK and professor of cognitive health at the University of Oxford:
“Whatever your view on the decision taken by MHRA and NICE, the key take-away is that lecanemab has been licensed. This is encouraging for the development of next-generation therapies that will provide greater benefit at less risk. There are grounds for optimism that these next-generation drugs will become available on the NHS. It is crucial, therefore, that the UK remains laser-focused on developing these treatments.”
Vanessa Raymont, associate professor and honorary consultant psychiatrist in the Department of Psychiatry at the University of Oxford; research and development director at Oxford Health NHS Foundation Trust; and associate director, Dementias Platform UK:
“It is clear the NHS still isn’t ready to roll out treatments like this. More groundbreaking treatments are coming and this is a great opportunity for us to offer improved care for all patients with AD.”
- This article was updated on 19 November 2024 to reflect that the EU granted a positive recommendation for lecanemab in November 2024
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