A breakthrough in Alzheimer’s disease: the new wave of therapeutic antibodies

The long-standing absence of disease-modifying therapies for Alzheimer’s disease has often left patients and families with limited prospects of cognitive recovery. Over the years, established treatments (such as acetylcholinesterase inhibitors) have been directed towards alleviating symptoms of Alzheimer’s disease, rather than addressing its underlying pathophysiology.
 
Cause for optimism remains, however. Researchers harnessing the innate affinity and highly versatile nature of monoclonal antibodies have recently ended the wait for a disease-modifying therapy for Alzheimer’s disease in the U.S. Between 2021 and 2024, the FDA approved aducanumab, lecanemab and donanemab, marking a pivotal advance in antibody therapies which improve neural function through the targeted clearance of pathological beta-amyloid (Aβ) deposits in the brain. In this article, we look at how these three pioneering antibodies have transformed the therapeutic landscape in Alzheimer’s disease.
 

Breaking barriers: antibodies and the Aβ challenge

The Amyloid Beta (Aβ) Hypothesis in Alzheimer's disease has been a focal point in the search for disease-modifying treatments. The theory – now well-established – posits that the misprocessing of amyloid precursor protein (APP) facilitates a cascade of downstream events, resulting in the production of neurotoxic, extracellular Aβ deposits. The build-up of these deposits in critical neural centres disrupts synaptic connectivity and causes neuronal damage, ultimately leading to cognitive decline and neuronal atrophy.
 
Targeting the removal of Aβ, or inhibiting its production, has been a logical approach to halt disease progression. In the past however, small molecule drugs aiming to achieve this have faced challenges related to effectiveness and safety. Now, new classes of monoclonal antibodies targeting specific forms of Aβ have the potential to directly address these shortcomings.
 

Aducanumab: the first US-approved monoclonal antibody Alzheimer’s treatment

Aducanumab (Aduhelm®) is a recombinant, fully human IgG1 monoclonal antibody targeting a conformational N-terminal epitope of Aβ. Though its exact mechanism of action remains unclear, imaging studies showed that aducanumab induces clearance of Aβ plaques. Aducanumab achieved FDA approval for use in Alzheimer’s disease in June 2021, and was touted by Biogen and Eisai at the time as the first and only drug to address this defining pathology of the disease. 
 
The patents covering aducanumab in the US and Europe were filed by the University of Zurich and were licensed to Biogen. The claims of the European patent (EP2099826 B1) are fairly typical, with claim 1 defining the antibody by its six CDRs. The US patent (US10131708 B2) uses the same definition, which should help to avoid the enablement issues that have plagued functionally defined antibody patents in the US. Notably, Biogen brought patent infringement proceedings in the US against Creative Biolabs, although the case was settled out of court in 2020. 
 

Regulatory hurdles for Aducanumab in Europe

Despite approval in the US, attempts to secure regulatory approval for aducanumab in Europe through the European Medicines Agency (EMA) proved unsuccessful. The EMA cited conflicting clinical trial data which allegedly failed to convincingly demonstrate efficacy of treatment. Aducanumab’s safety profile was also scrutinised due to alleged incidences of amyloid-related imaging abnormalities (ARIA), a side-effect that causes swelling and bleeding of the brain. Biogen ultimately withdrew their marketing authorisation application in April 2022.
 
It seems these regulatory issues echoed broader concerns about aducanumab. In January 2024, Biogen announced they will discontinue the development and commercialisation of aducanumab (including an on-going phase 3b/4 clinical trial). Resources were subsequently directed to other drugs in their Alzheimer’s disease pipeline.
 

Lecanemab: a mixed global reception

The shortcomings of aducanumab presented an opportunity for a new frontrunner in the Alzheimer’s therapy field. In 2022, Eisai, in collaboration with Biogen, published clinical trial results showing that lecanemab (Leqembi^®), their new humanised monoclonal IgG1 antibody, slowed cognitive decline in patients with early Alzheimer’s. Lecanemab works by selectively binding and clearing Aβ aggregate species, preventing build-up of toxic extracellular Aβ deposits.
 
Two European patents cover lecanemab, with two further pending divisional applications. The selective binding of lecanemab  is reflected in the claims of the earlier European patent (EP2448968 B1). Claim 1 functionally defines lecanemab, and is directed to antibodies that bind the Aβ aggregate species – which is a truncated Aβ form called Aβ3(pE)-42 – but exhibit no or substantially no binding with the non-N-terminal truncated monomer. The equivalent US application (US20230295283 A1) uses the same functional definition and is still in examination, although it seems it could be challenging to have this claim granted in the wake of the US Supreme Court’s decision in Amgen vs. Sanofi. The later granted US patent, (US9573994 B2), defines the antibody by its variable light chain and may prove more resilient if challenged.
 
Like aducanumab, concerns regarding the safety profile of lecanemab were raised due to alleged incidences of ARIA – but, promisingly, clinical trials also indicated that lecanemab could slow disease progression by 7 months, and slow decline in quality of life by up to 56%. After the publication of phase 3 clinical trial results in January 2023, lecanemab was approved by the FDA via an accelerated pathway in July 2023.
 
However, recent reception of the drug in the EU and the UK has been notably different. In July 2024, the EMA recommended refusing marketing authorisation for lecanemab, stating that “the observed effect of Leqembi^® on delaying cognitive decline does not counterbalance the risk of serious adverse events”. Just a month later, in August 2024, the UK's Medicines and Healthcare products Regulatory Agency (MHRA) approved the drug for private use but not for provision through the NHS, ruling that high costs (£20,000 p/a per patient) and relatively small benefits “cannot be considered good value for the taxpayer”.
 

Donanemab: Eli Lilly’s late contender

In June 2024, Eli Lilly’s donanemab (Kisunla^®) received FDA approval for the treatment of early Alzheimer’s disease, following promising phase 3 clinical trial results published in July 2023. Like lecanemab, the relative latecomer demonstrated efficacy in significantly slowing cognitive decline in early-stage Alzheimer’s – and even outperformed lecanemab with a 35% versus 27% reduction in cognitive decline.
 
The two antibodies have different mechanisms of action, which may account for the apparent difference in performance; donanemab targets existing Aβ plaques via an oligomer-specific epitope (N-terminally, pyroglutamate-modified amyloid β proteins), whereas lecanemab aims to inhibit plaque formation. It remains to be seen which will win out commercially in the US, while in Europe, donanemab will be looking to obtain the coveted “first-to-market” advantage in view of lecanemab’s regulatory difficulties.
 
Of the original composition of matter patents, Lilly’s patents (e.g., EP2603523 B1) also appear to have the later filing dates (August 2011 for donanemab vs June 2010 for lecanemab), potentially providing a further competitive advantage when it comes to patent term. Of course, both Lilly and Eisai will no doubt be busy filing further applications directed to new formulations, therapeutic indications and treatment regimens in order to maximise the coverage for these assets.
 

Conclusion

Table: overview of approval status for aducanumab, lecanemab and donanemab.

The FDA approval of aducanumab marked the beginning of a transformative phase in disease-modifying Alzheimer’s therapeutics. However, with discontinuation of aducanumab set for later in 2024, focus turns to the promising impact of Eisai/Biogen’s lecanemab and Eli Lilly’s donanemab. Clinical trial data suggests that donanemab may offer improved efficacy over lecanemab, positioning it as leader in the field. However, the true test will be whether donanemab can achieve widespread regulatory approval across the US, UK, and Europe.
 
Now, after decades of treatment failures and disappointing clinical trial results, patients and clinicians will certainly look forward with optimism to this new chapter in the treatment of Alzheimer’s disease.

If you have any questions or require further information, please do not hesitate to contact Trevor Eve, Sarah Lau, Jess Duncombe, or your regular advisor at Kilburn & Strode.