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Innovative Medicines & Omics Alzheimer’s disease and clinical trials

edema, and amyloid-related imaging abnormalities Although most drug candidates have failed to
with microhemorrhages. Phase III clinical trials for demonstrate efficacy, the positive outcomes of a few drugs
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donanemab are currently ongoing. keep the hope of success alive. Current clinical trials
On the other hand, LY3202626 and most BACE1 primarily focus on disease-modifying therapies. To enable
inhibitors were excluded from further trials due to preventive interventions before irreversible brain damage
insufficient evidence of safety and efficacy, except occurs, early-stage participant recruitment is crucial. This
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lenalidomide. The US FDA granted traditional approval highlights the importance of fundamental research on
for lecanemab under the brand name Leqembi, in July AD pathology in its early stages. Most drug designs have
focused on inhibiting toxic Aβ and pTau aggregation.
2023 for the treatment of AD. Lecanemab, a humanized However, expanding research has introduced new
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IgG1 antibody derived from mAb158, selectively binds therapeutic possibilities, including the promising outcomes
to soluble Aβ protofibrils. 91,92 In phase II clinical trials of aducanumab, lecanemab, and donanemab, which
involving AD patients with MCI or mild dementia, successfully clear Aβ plaques and protofibrils. A vast number
confirmed by amyloid pathology through amyloid of studies have demonstrated that modulating chronic
positron emission tomography scan or CSF Aβ(1-42) neuroinflammation, regulating microglial phagocytosis,
levels, the results showed a significant dose-dependent and promoting myelination improve Aβ clearance. These
reduction in Aβ plaque. Positive outcomes were observed findings suggest that passive immunotherapy targeting
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across all primary and secondary measures, including the neuroinflammatory responses holds significant therapeutic
AD Assessment Scale–Cognitive Subscale, AD Composite potential. Moreover, early detection of AD could allow for
Score, and AD Cooperative Study-MCI-Activities of Daily timely therapeutic intervention.
Living Inventory scores. The phase III clinical trial for
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lecanemab is currently ongoing. These findings suggest Other monoclonal antibody drugs currently in phase
that while a definitive drug or treatment for dementia III trials are remternetug (ClinicalTrials.gov identifier:
related to AD and RD remains unavailable, there is still NCT05463731) and solanezumab (ClinicalTrials.gov
hope for progress in the field. identifier: NCT01760005). Inflammatory pathways
involving inflammasomes that are associated with potential
4. Discussion AD biomarkers, such as nuclear factor kappa B, NLR

The regulatory mechanisms underlying the pathology family pyrin domain-containing 3, and triggering receptor
of dementia in AD and RD are highly complex, and no expressed on myeloid cells 2, have emerged as potential
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effective treatment is currently available. A more detailed drug targets for AD. Given that multiple pathways
contribute to neurodegeneration, leading to cognitive
investigation is needed to uncover unknown pathways that deficits in AD and RD, single-target drug approaches
could facilitate drug design for the treatment of cognitive have proven insufficient. A more effective strategy would
impairments caused by AD and RD. Despite significant involve the simultaneous application of multiple drugs
efforts and extensive studies aimed at understanding targeting different regulatory pathways.
disease pathology and finding a cure, no breakthrough
therapy has been established. However, research has greatly Research has also revealed common disease pathways
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expanded our knowledge of the regulatory mechanisms among neurodegenerative diseases, suggesting that
involved, identifying multiple potential pathways that the findings from AD studies may be applicable to
contribute to mild, moderate, or severe cognitive deficits in other dementias. Understanding the histopathologic
AD and RD. Although several drugs have been developed changes underlying neurodegenerative diseases is crucial
to target cognitive impairment, the challenges remain for advancing AD and RD research and developing
profound due to the intricate regulatory pathways of these effective treatment, as it can reveal key mechanisms
diseases. In addition to gaps in understanding disease of neurodegeneration that contribute to dementia.
pathology, the design and methodology of clinical trials Furthermore, the persistent failures in AD clinical trials
have been critically examined and debated as contributing necessitate a thorough reassessment of drug design strategies
factors to drug development failures. Three promising and clinical trials methodologies. Moving forward, both
drugs – aducanumab, lecanemab, and donanemab – are basic and clinical research must be expanded, integrating
still undergoing phase III clinical trials to assess their diverse approaches to unravel the complex causes of AD
preventive effects. While lecanemab has received US FDA and RD and develop more effective treatments.
approval, aducanumab and donanemab are still in the 5. Conclusion
process of regulatory review. Comparing the therapeutic
effects across these trials is expected to guide future AD AD and RD are complex neurodegenerative diseases that
drug development. severely affect the lives of millions globally, with mortality

Volume 2 Issue 2 (2025) 42 doi: 10.36922/IMO025050007