Abstract
Background: While phase III clinical trials for the treatment of Alzheimer’s disease (AD) keep failing regardless of the target, more and more data suggest that the toxic protein assemblies of amyloid-beta protein (Aβ) and tubulin binding protein (TAU) behave like prions. Irrespective of the question of whether AD is theoretically or practically contagious, the presence of a self-replicating toxic etiologic agent in the brains of AD patients must have decisive consequences for drug development programs and clinical trial designs. Objectives: We intend to challenge the hypothesis that the underlying etiologic agent of AD is behaving prion-like. We want to discuss whether the outcome of clinical trials could have been predicted based on this hypothesis, and whether compounds that directly disassemble the toxic prion could be more beneficial for AD treatment. Method: We collected publicly accessible pre-clinical efficacy data of Aβ targeting compounds that failed or still are in phase III clinical trials. We describe the desired properties of an anti-prionic compound and compare it the properties of past and current phase III drug candidates. Results: We could not find convincing and reproducible pre-clinical efficacy data of past and current phase III drug candidates on cognition other than in preventive treatment settings. The desired properties of an anti-Aβ-prionic compound are fulfilled by the drug candidate RD2, which has been developed to directly disassemble toxic Aβ oligomers. Conclusion: RD2 is the first anti-prionic drug candidate. It is able to enhance cognition and impede neurodegeneration in three different transgenic AD mouse models, even under truly non-preventive conditions and even when applied orally. In addition, it is safe in humans.
Highlights
While phase III clinical trials for the treatment of Alzheimer’s disease (AD)keep failing regardless of the target, more and more data suggest that the toxic protein assemblies of amyloid-beta protein (Aβ) and tubulin binding protein (TAU) behave like prions
Alzheimer’s disease (AD) is a progressive neurodegenerative disorder which is associated with cognitive deficits, neurodegeneration as well as the aggregation of amyloid-beta protein (Aβ) and aggregation of TAU
On the basis of this theory, disease-modifying treatments were developed which should interrupt early pathologic events by reducing Aβ42 production (β- and γ-secretase inhibitors), increasing amyloid plaque clearance and decreasing plaque formation (Aβ42 lowering agents like tarenflurbil and inhibitors of amyloid aggregation tramiprosate), preventing later pathologic processes. Despite this enormous scientific and economic effort, none of the drug candidates which were developed based on the amyloid hypothesis were successful in phase III clinical trials with beneficial effects on cognition decline
Summary
Alzheimer’s disease (AD) is a progressive neurodegenerative disorder which is associated with cognitive deficits, neurodegeneration as well as the aggregation of amyloid-beta protein (Aβ) and aggregation of TAU. On the basis of this theory, disease-modifying treatments were developed which should interrupt early pathologic events by reducing Aβ42 production (β- and γ-secretase inhibitors), increasing amyloid plaque clearance (immunotherapy) and decreasing plaque formation (Aβ42 lowering agents like tarenflurbil and inhibitors of amyloid aggregation tramiprosate), preventing later pathologic processes. Despite this enormous scientific and economic effort, none of the drug candidates which were developed based on the amyloid hypothesis were successful in phase III clinical trials with beneficial effects on cognition decline. Besides the missing efficacy to significantly decelerate cognitive decline or to ameliorate memory deficits, so-called amyloid-related imaging abnormalities (ARIA-E or ARIA-H) occurred in several cases (potentially indicating for example microhemorrhages or meningoencephalitis), representing some of the major severe side effects of Aβ-immunotherapy for Alzheimer’s disease [26,27], which is of concern especially because the prospective treatment is envisioned as life-long
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