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Innovative Medicines & Omics Alzheimer’s disease and clinical trials

A B

Figure 1. Neuroinflammatory pathways underlying AD and related dementias, and possible target sites for drug development and clinical trials.
(A) Graphical representation of immune system dysregulation leading to Alzheimer’s disease and related dementias. (B) Potential therapeutic targets.
Abbreviations: Aβ: Amyloid-beta; AD: Alzheimer’s disease; IFNγ: Interferon-gamma; IL-1β: Interleukin-1 beta; IL-6: Interleukin-6; TNFα: Tumor necrosis
factor-alpha.
and tau formation. Despite their potential, the long-term Table 1. List of drugs for Alzheimer’s disease treatment
effectiveness of these drugs remains uncertain. As of now, with approval status by the United States Food and Drug
only lecanemab has been fully approved by the US FDA Administration
for AD treatment on July 6, 2023 (https://www.fda.gov/ Drug name Company Mode of action Approval status
news-events/press-announcements/fda-converts-novel- (brand name) and effect
alzheimers-disease-treatment-traditional-approval). 17 A Aducanumab Biogen, Eliminate Approval in
summary of promising drugs and their approval status by (Aduhelm) Neurimmune aggregated Aβ progress 17,57,94
the US FDA is presented in Table 1. plaques
3.2. Challenges in clinical trials Lecanemab BioArctic AB, Reduce soluble Fully approved 17,57
Biogen, Eisai
(Leqembi)
Aβ protofibrils
Most of the currently designed drugs for AD target Aβ Donanemab Eli Lilly and Eliminate Application for
pathology, aiming to reduce Aβ production, inhibit Aβ (Kisunla) Company aggregated Aβ full approval 17,57
plaque formation, promote Aβ plaque clearance, or develop plaques
Aβ vaccines. 6,57,59,60 Other drug targets have also been Abbreviation: Aβ: Amyloid-beta.
explored for various objectives, including mitigating tau
pathology, reducing inflammation, lowering cholesterol modulation, filament modulation, glutaminyl cyclase
28
61
accumulation, 62,63 improving brain energy utilization, 64-67 inhibition, active immunization, passive immunization,
decreasing vascular burden, enhancing neuroprotectant receptor for advanced glycation end-products inhibition,
68
and antioxidant processes, 69-71 increasing neural growth and metabotropic glutamate receptor 5 modulation, aiming
and regeneration, 72,73 and restoring hormonal balance. to reverse or inhibit Aβ pathology or dementia. A summary
74
Among the 2,695 clinical trials for AD (data available at of the drugs in clinical trials developed for AD treatment is
clinicaltrials.gov), when categorized as disease-modifying provided in Table 2.
versus symptomatic, the failure rates are concerning: 41% Several potential factors contributed to the failures
failed in phase III, while 59% failed in phase II. Of these, in clinical trials, whether by faulty drug development
64% were disease-modifying agents, whereas 36% were processes or the lack of a clear understanding of the
symptomatic agents. 54 complex regulatory mechanisms underlying AD pathology.
Several clinical trials have targeted various drug The main reasons for failures include (i) insufficient
mechanisms, including beta-secretase 1 (BACE1) inhibition, evidence to justify clinical trials, (ii) inadequate clinical
γ-secretase inhibition, γ-Secretase modulation, apolipoprotein trial designs, (iii) inappropriate drug designs that fail
E (ApoE) inhibition, Aβ production inhibition, Aβ aggregation to align with the rational drug development principles
inhibition, Aβ dissociation, synaptic modulation, Aβ toxicity specifically designed for AD therapeutic development,

Volume 2 Issue 2 (2025) 39 doi: 10.36922/IMO025050007