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.

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.

These plaques have been implicated in AD since the disease was first described over 100 years ago. However, it was only through the advent of genetic sequencing and subsequent testing of patients with an early-onset (~30 to 40 years old), aggressive form of AD (called familial AD) that mutations in genes responsible for cleaving APP were found. These mutations cause accelerated production and depositing of the ‘stickier’, more pathogenic Aβ42 species, linking amyloid burden and species to disease development and aggression. A finding supported by the knowledge that individuals with Down syndrome, caused by a triplication in chromosome 21 that harbours APP, present with greater amyloid and prevalence of AD. However, while causative genetic mutations are not found in classical AD (>65-years old), neuroimaging studies including amyloid PET and biomarker studies (Aβ42/ Aβ40 ratio) have shown amyloid deposition is likely the first stage in disease development. This is an understanding that has led to the belief that targeting and reducing amyloid deposition in the brain will slow/prevent AD pathology.

While this approach has been effective, with Leqembi and donanemab showing significant efficacy in slowing disease progression, neither has been a silver bullet. In both cases, disease progression still occurs indicating other mechanisms are likely contributing to AD progression. Academic and clinical research has supported this idea with other hallmark pathologies, including tau and neuroinflammation now seen as integral components of disease progression. Side effects known as amyloid-related imaging abnormalities (ARIA) that are seen in patients treated with Leqembi and (currently unapproved) donanemab have also caused concern. While currently not well understood, it is known ARIA have some safety implications including oedema and haemorrhagic propensities. However, it is unclear whether this side effect is amyloid specific, with Alector’s AL002, which targets the immune-stimulating receptor TREM2, also resulting in ARIA consistent with amyloid therapeutics.

These limitations in current amyloid therapeutics and advances in our understanding of other AD-related pathologies have subsequently led to the expansion of the AD pipeline beyond just amyloid. New drugs targeting tau, an intraneuronal protein associated with maintaining the stability of neuronal structures and forms tangles during AD, have seen a significant growth in interest, while inflammatory pathway and the innate immune system modulators are also contributing to the growing diversity of AD therapeutics.

In addition to amyloid targeting medicines and alternative treatments, successes in the development of novel biomarker assays has also played a part in optimising the treatment of AD.

Biomarkers are naturally occurring molecules, genes or characteristics that allow for a pathological or physiological process to be measured. In AD, biomarkers are used to diagnose and measure disease progression and include the detection of risk-associated genetic mutations, variable Aβ40/42 ratios, p-Tau, neurofilament light and cognitive/neuroimaging assessments. Each biomarker is detected in its own way and together helps healthcare professionals (HCP) provide a patient with a clinical AD diagnosis while also providing context on how far along a patient is.

Cerebral spinal fluid (CSF)-based biomarkers that utilise the fluid that surrounds the central nervous system are one of the most commonly used approaches. Over the last few years, these assays have become significantly more reliable and accurate, allowing for detection of patients at earlier stages of disease. However, CSF collection requires a spinal tap or lumbar puncture, a process that involves a needle being inserted into the spinal cord. This is a painful process and requires a trained professional and time, which limits the accessibility of such tests. Due to this, the development of more accessible biomarkers has been a significant focus for the field. One such advance has been the development of blood-derived biomarkers (BDBM), which include serum- and plasma-based biomarkers. BDBMs, similar to CSF, can measure Aβ40/42 and tau but are more accessible without the need for a specialist with spinal tap training. Such advances in diagnostic accessibility and reliability have contributed to the earlier diagnosis and earlier treatment of patients with less advanced pathologies. This, in turn, has been associated with greater therapeutic efficacy and is seen as a contributing factor in Leqembi and donanemab’s clinical trial success.

For a disease that has historically seen little advancement, it is now entering an exciting phase of development and innovation. There are currently over 50 drugs in phase 1 to 3 of development for AD. These range in their target from amyloid, tau, neuroinflammation, cellular therapies and TREM2, to name but a few. While Leqembi and donanemab are receiving the most limelight, there are several other promising drug developments expected over the course of the next year including data from Alector’s AL002, Eli Lilly’s remternetug, Anavex’s blarcameine and Cassava’s simufilam clinical trials, as well as many more.

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.

Ivo Carre is a Business Analyst at Lifescience Dynamics