Author: Rachael Hansford

In Great Britain, lecanemab is indicated for the treatment of mild cognitive impairment and mild dementia due to Alzheimer’s disease (AD) in adult patients that are apolipoprotein E ε4 (ApoE ε4)* heterozygotes or non-carriers¹

Great Britain becomes the first country in Europe to authorise the medicine, which targets an underlying cause of AD¹

Authorisation based on data from the global Phase 3 trial, Clarity AD, which demonstrated that lecanemab slowed disease progression vs placebo at 18 months^1,2

Eisai is working collaboratively with health technology assessment bodies and the National Health Service to support access for eligible patients

22 August, 2024 – Eisai Europe Ltd. and Biogen International GmbH have announced today that Leqembi^® (lecanemab) has been granted a Marketing Authorisation (MA) by the Medicines and Healthcare products Regulatory Agency (MHRA) in Great Britain. Lecanemab is indicated for the treatment of mild cognitive impairment (MCI) and mild dementia due to Alzheimer’s disease (AD) in adult patients that are apolipoprotein E ε4 (ApoE ε4)* heterozygotes or non-carriers.¹ Great Britain is the eighth country in the world to grant MA, making lecanemab the first monoclonal antibody therapy for early AD (MCI and mild dementia due to AD)² that targets amyloid-beta (Aβ) to be authorised in a country in Europe.¹

The medicine was awarded an Innovative Licensing and Access Pathway (ILAP) passport by the MHRA in February 2023,³ as there is a significant unmet patient need for treatments that alter an underlying cause of the disease for people living with early AD.⁴ Lecanemab is a humanised Aβ monoclonal antibody that selectively binds to Aβ aggregate species with preferential activity for toxic Aβ protofibrils** (as well as fibrils, which are a major component of Aβ plaques).^1,2,5,6 It binds to these aggregate Aβ species to neutralise and clear them from the brain.^1,2,5,6

The approval was primarily based on Phase 3 data from Eisai’s global, placebo-controlled, double-blind, parallel-group, randomised Clarity AD clinical trial, in which the medicine met its primary endpoint (change from baseline in the Clinical Dementia Rating Sum of Boxes [CDR-SB]^† at 18 months) and all key secondary endpoints with statistically significant results.² In the indicated population in Great Britain, the most common adverse reactions were infusion-related reaction, amyloid-related imaging abnormalities with haemorrhage (small spots of bleeding) (ARIA-H)^‡, fall, headache and amyloid-related imaging abnormalities with cerebral oedema (build-up of fluid) (ARIA-E)^‡‡.^1,2

“Today signals a significant moment for the AD community. We are now one step closer to eligible people in Great Britain receiving a much-needed new treatment option that can slow disease progression, as demonstrated through clinical trials, by targeting an underlying cause of Alzheimer’s disease for the first time,” said Gary Hendler, Regional Chairman and CEO, Eisai EMEA, Senior Vice President & Global Corporate Officer, Eisai Co. Ltd, Tokyo. “This could mean maintaining independence and the ability to continue daily activities and hobbies for as long as possible. We are proud that 40 years of AD research has led to this important milestone.”

“The authorisation of lecanemab in Great Britain marks a significant step forward in the pursuit of innovation for AD,” said Wolfram Schmidt, President, Head of Europe, Biogen. “We remain steadfast in our mission to further AD research and bring treatment options to patients.”

In the UK, it is estimated that 982,000 people are living with dementia,⁷  and AD is the cause in 60-70% of people with dementia.⁸ These numbers are expected to rise, as the population ages.^7,8 People living with AD can experience loss of cognition, memory and independence, as well as psychological symptoms such as depression and anxiety.⁹ For care partners, witnessing the changes in their loved ones can be difficult and providing round-the-clock care can impact their own emotional well-being, employment and finances.^7,9

Eisai is working collaboratively with the National Institute for Health and Care Excellence, the Scottish Medicines Consortium and the National Health Service (NHS) to make this medicine available to eligible people living with early AD in Great Britain as soon as possible.

Eisai serves as the lead of lecanemab development and regulatory submissions globally with both Eisai and Biogen co-commercialising and co-promoting the product and Eisai having final decision-making authority. In Great Britain, Eisai and Biogen will co-promote the medicine, with Eisai distributing the product as the MA Holder.

*Apolipoprotein E is a protein involved in the metabolism of fats in humans. It is implicated in AD.

**Protofibrils are thought to be the most toxic Aβ species that contribute to brain damage in AD and play a major role in the cognitive decline of this progressive and devastating disease. Protofibrils can cause neuronal damage in the brain, which can subsequently adversely affect cognitive function through multiple mechanisms.¹⁰ The mechanism by which this occurs has been reported not only by increasing the formation of insoluble Aβ plaques, but also by directly damaging signalling between neurons and other cells. It is believed that reducing protofibrils may reduce neuronal damage and cognitive impairment, potentially preventing the progression of AD.¹¹

^†CDR-SB is a commonly used diagnostic tool, which can help to stage dementia due to AD.¹² It is a global cognitive and functional scale that measures six domains of functioning, including memory, orientation, judgement and problem solving, community affairs, home and hobbies, and personal care.¹²

^‡ARIA-H: amyloid-related imaging abnormalities with haemorrhage (cerebral microhaemorrhages and superficial siderosis).

^‡‡ARIA-E: amyloid-related imaging abnormalities with oedema (oedema/effusion).

References

1. Lecanemab Great Britain Summary of Product Characteristics.
2. van Dyck, H., et al. Lecanemab in Early Alzheimer’s Disease. New England Journal of Medicine. 2023;388:9-21. https://www.nejm.org/doi/full/10.1056/NEJMoa2212948.
3. Eisai. Internal correspondence with MHRA. 17 February 2023.
4. Gov.UK. 2023. Guidance: Innovative Licensing and Access Pathway. Available at: https://www.gov.uk/guidance/innovative-licensing-and-access-pathway. Last accessed: August 2024.
5. Johannesson, M., et al. Lecanemab demonstrates highly selective binding to Aβ protofibrils isolated from Alzheimer’s disease brains. Molecular and Cellular Neuroscience. 2024;130:103949. https://doi.org/10.1016/j.mcn.2024.103949.
6. Sehlin, D., et al. Large aggregates are the major soluble Aβ species in AD brain fractionated with density gradient ultracentrifugation. PLoS One. 2012;7(2):e32014. https://doi.org/10.1371/journal.pone.0032014.
7. Alzheimer’s Society. 2024. The economic impact of dementia. Available at: https://www.alzheimers.org.uk/about-us/policy-and-influencing/dementia-scale-impact-numbers. Last accessed: August 2024. 
8. World Health Organization. 2023. Dementia. Available at: https://www.who.int/news-room/fact-sheets/detail/dementia. Last accessed: August 2024.
9. Koca, E., Taşkapilioğlu, Ö., Bakar, M. Caregiver Burden in Different Stages of Alzheimer’s Disease. Archives of Neuropsychiatry. 2017;54(1):82-86.
10. Amin, L., Harris, D.A. Aβ receptors specifically recognize molecular features displayed by fibril ends and neurotoxic oligomers. Nature Communications. 2021;12:3451. doi:10.1038/s41467-021-23507-z.
11. Ono, K., Tsuji, M. Protofibrils of Amyloid-β are Important Targets of a Disease-Modifying Approach for Alzheimer’s Disease. International Journal of Molecular Sciences. 2020;21(3):952. doi: 10.3390/ijms21030952. PMID: 32023927; PMCID: PMC7037706.
12. Morris, J.C. The Clinical Dementia Rating (CDR): current version and scoring rules. Neurology. 1993;43:2412-2414.
13. U.S. Food and Drug Administration. 2023. FDA Converts Novel Alzheimer’s Disease Treatment to Traditional Approval. Last accessed: August 2024.
14. Reuters. 2023. Japan approves Alzheimer’s treatment Leqembi by Eisai and Biogen. Last accessed: August 2024.
15. The Pharma Letter. 2024. Brief – Alzheimer drug Leqembi now approved in China. Last accessed: August 2024.
16. Pharmaceutical Technology. 2024. South Korea’s MFDS approves Eisai-Biogen’s LEQEMBI for Alzheimer’s. Last accessed: August 2024.
17. Pharmaceutical Technology. 2024. Hong Kong approves Leqembi for Alzheimer’s treatment. Last accessed: August 2024.
18. BioSpace. 2024. Leqembi approved for the treatment of Alzheimer’s disease in Israel. Last accessed: August 2024.
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American clinical-stage biopharmaceutical company Alzheon has recently presented promising interim results from its Phase II Biomarker Trial (NCT04693520) of its oral, brain-penetrant, amyloid-oligomer inhibitor ALZ-801 (valiltramiprosate) at the American Academy of Neurology 2024 annual meeting. ALZ-801 has the potential to be the first oral Aβ-targeting therapy to be approved in the US and EU in early AD, according to GlobalData, a data and analytics company.

Erela Dana, Director of Neurology at GlobalData, comments: “Amyloid beta (Aβ)-targeting therapies hold promise, with this mechanism of action (MOA) recently seeing some success with the FDA’s approval of Biogen’s anti-Aβ monoclonal antibody (mAb) Aduhelm (aducanumab) in 2021, followed by Eisai/Biogen’s anti-Aβ mAb Leqembi (lecanemab) in January 2023.”

ALZ-801 is currently in Phase III, being evaluated for the treatment of apolipoprotein E 4 (APOE4) carrier patients with early AD.

Key opinion leaders (KOLs) previously interviewed by GlobalData highlight that the ALZ-801 target population of early AD patients, who are homozygous for the APOE4 allele, represent a subgroup that has a strong unmet need for novel disease-modifying approaches.

So far, the results over two years of treatment with ALZ-801 have been presented of the four-year open-label biomarker study. Overall, ALZ-801 treatment demonstrated sustained improvement over two years in plasma biomarkers, hippocampal volume, and cognitive effects in the target population. 

Dana comments: “There is a strong correlation between the biomarker outcomes and ALZ-801’s cognitive benefits. The presented biomarker results support the disease-modifying effects of ALZ-801 in APOE4 carriers with early AD with promising clinical efficacy and favorable safety, with no observed cases of amyloid-related imaging abnormalities related to underlying vasogenic edema (ARIA-E), a known side effect of the anti-Aβ mAbs, to date.”

Further to its Phase II biomarker study, Alzheon plans to announce the topline results of its APOLLOE4 (NCT04770220) Phase III trial in Q3 2024, with a potential NDA submission to the US FDA later this year.

Dana concludes: “Should Phase III outcomes follow the positive outcomes from the two-year Phase II biomarker data and support the hypotheses that by acting upstream of anti-Aβ mAbs, ALZ-801 could provide significantly improved amyloid clearance, it would pave the way for Alzheon to launch its AD asset in 2025 as the first oral anti-Aβ DMT in the US.”

On 25 July 2024 the European Medicines Agency (EMA) rejected a licence for lecanemab to treat Alzheimer’s disease.

The EMA said the benefits did not counterbalance the risk of serious side effects, especially bleeding and swelling in the brain.

The MHRA in the UK is still considering whether to grant a licence, and a decision is expected soon. The drug was approved in the United States earlier this year and has already been approved by regulatory authorities in China, Hong Kong, Israel, Japan and South Korea.

In trials, lecanemab reduced markers of amyloid in early Alzheimer’s disease and resulted in moderately less decline on measures of cognition and function than placebo at 18 months.

Alzheimer’s researchers called the trial results “historic” because no previous drug had convincingly shown that the underlying mechanism of the disease could be slowed.

What were the main reasons for refusing the application?

The main study showed that after 18 months of treatment, the CDR-SB score in patients treated with Leqembi increased by 1.21 compared with 1.66 in those who received placebo. Although patients given Leqembi had lower CDR-SB scores than those given placebo, the difference between the two groups was small. EMA’s human medicines committee, the CHMP, considered that the observed effect of Leqembi on delaying cognitive decline does not counterbalance the risk of serious adverse events associated with the medicine.

The most important safety concern with Leqembi is the frequent occurrence of amyloid-related imaging abnormalities (ARIA), a side effect, seen in brain imaging, that involves swelling and potential bleedings in the brain. 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. The seriousness of this side effect should be considered in the context of the small effect seen with the medicine.

In addition, the CHMP was concerned by the fact that the risk of ARIA is more pronounced in people who have a certain form of the gene for the protein apolipoprotein E called ApoE4. The risk is highest in people with 2 copies of the ApoE4 gene, who are known to be at risk of developing Alzheimer’s disease and would therefore be likely to become eligible for treatment with Leqembi.

In reaching its opinion, the CHMP also considered the views of a scientific advisory group on neurology, which included experts such as neurologists and people living with the disease.

Overall, the CHMP considered that the benefits of treatment are not large enough to outweigh the risks associated with Leqembi. Therefore, it recommended refusing marketing authorisation in the EU.

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