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Innovative Medicines & Omics Alzheimer’s disease and clinical trials

Table 2. (Continued)
Drug name Mode of action and effect Trial phase status Side effects/outcome
PF-06648671 γ-secretase inhibition, brain Aβ42 reduction Discontinued phase I Pfizer ended R&D in neurology 112,136
Semagacestat γ-secretase inhibition, soluble Aβ, and plaque reduction Discontinued phase II Clinical worsening/adverse events 126
Azeliragon γ-secretase modulation, Aβ load reduction, behavioral Discontinued phase III Lack of efficacy 137
improvement
Tarenflurbil γ-secretase modulation, Aβ reduction Discontinued phase III Lack of efficacy 94
Ibuprofen γ-secretase modulation, Aβ reduction Discontinued phase II Lack of efficacy 138
Clioquinol Aβ aggregation inhibition, amyloid deposition reduction Discontinued phase III Toxic contaminants in manufacturing
process 139,140
ELND005 Aβ aggregation inhibition, amyloid pathology reduction, Discontinued phase II Lack of efficacy 141
learning deficit restored
Tramiprosate Aβ aggregation inhibition, Aβ40 reduction Discontinued phase III Lack of efficacy 142,143
Abbreviations: Aβ: Amyloid-beta; BACE1: Beta-secretase 1; CSF: Cerebrospinal fluid; mGluR5: Metabotropic glutamate receptor 5;
pGlu-Aβ: Pyroglutamate Aβ; RAGE: Receptor for advanced glycation end-products; R&D: Research and development.

and (iv) limited therapeutic efficacy. For example, the ENGAGE trial did not meet the primary endpoint.
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17
bapineuzumab and solanezumab advanced to phase III Based on these results, the US FDA approved aducanumab,
trials despite unconvincing phase II results, ultimately through an “accelerated approval pathway,” for the
leading to failure. 75-77 A critical human error that could treatment of MCI and mild dementia in AD patients in
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have been avoided is the lack of learning from past clinical June 2021, under the brand name Aduhelm by Biogen.
trials, leading to recurring challenges, negative outcomes, Both trials showed intermediate effects on biomarkers,
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and diminished confidence in AD drug development. including amyloid removal, which may contribute to the
Additional factors such as delayed intervention in clinical benefit of aducanumab. The phase phase IIIb/IV
symptomatic dementia, inappropriate therapeutic ENVISION trial (ClinicalTrials.gov ID: NCT05310071) is
targets, and flawed clinical methodologies have further currently ongoing. 17,57
impeded success in AD clinical trials. To overcome these Donanemab is another humanized IgG1 monoclonal
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challenges, both clinical and basic research, along with a antibody developed from mouse mE8-IgG2a, which
more intelligent and holistic approach, are crucial in the targets the Aβ (3 – 42), a pyroglutamate form of Aβ, that
search for effective treatment of AD and RD. is abundant in the brains of AD patients. 83,84 Interestingly,

3.3. Current progress in clinical trials donanemab can bind to approximately one-third of
Aβ plaques in post-mortem AD and Down syndrome
While most drugs have failed, a few continue to show brains, strongly reacting with plaque cores. In the
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promising signs and hold hope for success. Three phase II TRAILBLAZER-ALZ study (https://clinicaltrials.
FDA-approved drugs – aducanumab, lecanemab, and gov/study/NCT04437511), combination therapy using
donanemab – that target Aβ plaques and protofibrils donanemab and BACE1 inhibitor LY3202626 was
are still undergoing phase III clinical trials to further administered to target the pyroglutamate form of Aβ.
examine preventive effects. Comparing the therapeutic The treatment met the primary endpoint of delaying
effects and data from these trials is expected to help guide cognitive decline as assessed by the Integrated AD
future AD drug development. Aducanumab, a human Rating Scale. 17,57 Reduction of Aβ burden was correlated
immunoglobulin gamma 1 (IgG1) monoclonal antibody with improvement in the scores but only in APOE4
derived from aged donors resistant to AD, binds to the carriers. Donanemab also reduced tau aggregation in
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N-terminus of Aβ fibrils but not to Aβ monomers, thereby the temporal, parietal, and frontal lobes and significantly
blocking Aβ aggregation. 80,81 Initially, further clinical trials lowered plasma pTau217 levels. Phase I clinical trials of
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of aducanumab were terminated due to failure to meet donanemab demonstrated sustained reduction in cortical
the primary endpoint in Clinical Dementia Rating Scale amyloid load, with the treatment being well tolerated.
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Sum of Boxes scores. However, two recent phase III While phase II trials of donanemab replicated phase
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clinical trials, the ENGAGE and EMERGE studies, showed I results with no adverse effects, patients were more
significant slowing of cognitive decline at the highest dose. likely to exhibit amyloid-related imaging abnormalities
While the EMERGE trial reached statistical significance, amyloid-related imaging abnormalities with vasogenic

Volume 2 Issue 2 (2025) 41 doi: 10.36922/IMO025050007