Current trends and the renaissance of Alzheimer’s drug development
Historically, market authorisations for neurological diseases have had significantly lower rates of success than other indications. Between 2000 to 2015, the likelihood of approval for neurological drugs (8.4%) was below the mean across all indications (9.6%) and far below haematology (26.1%) and infectious diseases (19.1%). When considering specifically neurodegenerative diseases, this rate is even lower. In Alzheimer’s disease (AD) for example, only donepezil, galantamine, memantine and rivastigmine were approved before 2021.
Recently this trend has shifted: in 2021, although 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. Advancements in the AD pipeline are continuing through the recent FDA full approval of Eisai’s Leqembi in July 2023, the likely approval of Lilly’s donanemab in late 2023 and the >50 assets in clinical development.
What is the cause of this “renaissance” in AD drug development? The potential financial benefits are certainly an incentive for drug developers. Governments and healthcare providers are seeing rising financial burdens, with AD and other dementias costing $2.8 trillion in 2019 – a cost expected to rise to $4.7 trillion by 2023.
Successes in the development of CSF and serum-based biomarkers such as Aβ40:42 ratio, p-Tau level, t-Tau level and NfL level biomarkers have also played a part. Utilising these biomarkers has allowed for the earlier detection and diagnosis of AD, in turn resulting in clinical enrolment of patients with less advanced pathologies, an advancement highlighted in part by Leqembi’s success. Further biomarker advances, such as using blood-derived biomarkers, will also address current limitations and continue to drive AD pipeline advances.
The expansion of the AD pipeline beyond amyloid has also been no small contributor, an effect stemming from advances in our understanding of AD pathoetiology. The importance of developing therapies that target AD pathways other than amyloid is also underscored by the fact that, whilst anti-amyloids like Leqembi offer promising treatments that can slow disease progression, they are not cures. Safety concerns associated with amyloid therapies, including amyloid-related imaging abnormalities, further highlight the importance of AD pipeline diversification. New drugs targeting tau, inflammatory pathways, and the innate immune system all aim to improve treatment outcomes for patients eligible for anti-amyloids, whilst providing much needed options for patients ineligible for anti-amyloids, such as late-stage patients.
While other factors ranging from increased funding and greater public perception of AD have also contributed, how the pipeline continues to develop may also be in part 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. However, with the actual clinical and commercial success of Leqembi still to be determined, the market remains open, highlighting the requirement for further development.
