With 14 million people in Europe expected to suffer from Alzheimer’s and other forms of dementia by 2030, the race is on to find a treatment to not only slow its course, but even prevent the development of the disease.
Historically, market authorisations for neurological diseases have had significantly lower rates of success compared with other indications.
Between 2000 to 2015, the likelihood of approval for neurological drugs that entered phase 1 trials (8.4%) was below the mean across all indications (9.6%) and far below haematology (26.1%) and infectious diseases (19.1%). When considering neurodegenerative diseases and specifically Alzheimer’s disease (AD), the rate is even lower with only four drugs: donepezil; galantamine; memantine, and rivastigmine approved between 1996 and 2020.
These drugs, however, only treat the disease’s symptoms rather than the causes. This has largely been due to a lack of understanding of the mechanisms behind disease pathogenesis, with advances in AD happening at a significantly slower rate relative to other diseases. Despite being first discovered over 100 years ago, the complexity of the brain and limitations surrounding research/diagnostic methods and models have acted as barriers for AD drug development.
Recently, however, this trend has begun to shift. In 2021, while cancer drugs accounted for 30% of all new FDA approvals, neurology saw the second most approvals for the third time in a row (10%).
The AD pipeline in particular saw major advancements with the (controversial) FDA accelerated approval of Biogen’s Aduhelm (aducanumab) in 2021, the first amyloid-targeting antibody for AD. The FDA approval of Eisai’s Leqembi (lecanemab) in July 2023 – with Lilly’s donanemab submitted but awaiting a currently delayed advisory committee meeting in 2024 (both of which also target amyloid) – continue to highlight the advancements happening in AD therapeutics.
A closer look at amyloid targeting treatments and beyond
Amyloid plaques, targeted by the aforementioned therapeutics, form from a protein known as amyloid-beta (Aβ), which is produced through the proteolytic cleavage of amyloid precursor protein (APP). The cleavage of APP has two different pathways known as the non-amyloidogenic and the amyloidogenic pathway. The non-amyloidogenic pathway results in soluble APP (sAPP) and a fragment known as P3 being released, with both being cleared from the brain. Alternatively, the amyloidogenic pathway, which is the main interest in AD, results in the generation of oligomeric Aβ40 or Aβ42, which are deposited within the brain and over time, through a process known as aggregation, form insoluble plaques.
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In the next 12 months, it is also likely there will be the approval of at least one more amyloid drug in Eli Lilly’s donanemab globally. In addition, potential approval of a subcutaneous formulation of Eisai’s Leqembi (currently requesting an FDA Fast Track designation) will offer patients greater accessibility due to not requiring access to a transfusion centre, with data showing increased efficacy and comparable safety to the current intravenous Leqembi.
Beyond 2024, the general consensus among HCPs and key opinion leaders active in the AD clinical space is that combination therapies with existing drugs for AD will start being developed, with therapeutic efficacy further enhanced by doing so. These could manifest in several ways including combining Aβ (Leqembi/donanemab) and TREM2-targeting drugs (AL002) or Aβ and tau (E2814)-targeting combination therapies.
Increased funding and greater public awareness of AD impact on people’s lives will continue to influence future innovation in these areas. The potential financial benefits are also certainly an incentive for drug developers with the Alzheimer’s market estimated to be $4.2bn in 2022 and expected to grow to $15.6bn by 2030. The financial burden on payers and governments has led to the recognition by regulatory bodies of an unmet need and is also contributing to advancements in AD therapeutics. With AD and other dementias responsible for a cost of $2.8trn in 2019 and expected to cost $4.7trn by 2023 globally, the race is truly on.
How the pipeline continues to develop may be dependent on the success of Leqembi, but as the first amyloid drug to be covered for reimbursement, it has paved the way for subsequent developments. While the actual clinical and commercial success of Leqembi is still to be determined, the market remains open, highlighting the requirement for further development.
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