Bapineuzumab for mild to moderate Alzheimer’s disease: a meta-analysis of randomized controlled trials

Protein translation and folding are tightly controlled processes in all cells, by proteostasis, an important component of which is the unfolded protein response (UPR). During periods of endoplasmic reticulum stress because of protein misfolding, the UPR activates a coordinated response in which the PERK branch activation restricts translation, while a variety of genes involved with protein folding, degradation, chaperone expression and stress responses are induced through signaling of the other branches. Chronic overactivation of the UPR, particularly the PERK branch, is observed in the brains of patients in a number of protein misfolding neurodegenerative diseases, including Alzheimer's, and Parkinson's diseases and the tauopathies. Recently, numerous genetic and pharmacological studies in mice have demonstrated the effectiveness of inhibiting the UPR for eliciting therapeutic benefit and boosting memory. In particular, fine-tuning the level of PERK inhibition to provide neuroprotection without adverse side effects has emerged as a safe, effective approach. This includes the recent discovery of licensed drugs that can now be repurposed in clinical trials for new human treatments for dementia. This review provides an overview of the links between UPR overactivation and neurodegeneration in protein misfolding disorders. It discusses recent therapeutic approaches targeting this pathway, with a focus on treatments that fine-tune PERK signaling.

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“…, ; Abushouk et al . ), researchers are increasingly pursuing other avenues for future therapeutic targets (Morris et al . ).…”

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confidence: 99%

Fine‐tuning PERK signaling for neuroprotection

Halliday

Hughes

Mallucci

2017

Journal of Neurochemistry

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“…The group sizes in that study were small (N = 38–57 evaluable, depending on the measure) but similar to that which was targeted (N = 75) based on power calculations for a 30% reduction in whole‐brain atrophy. In the bapineuzumab studies, no significant difference in whole‐brain atrophy between treated and placebo groups was observed in any of the four phase 3 trials [8,9] nor in a meta‐analysis of six phase 2 and 3 trials [19]. Moreover, no relationship between brain boundary shift integral and drug exposure levels was observed in an analysis of two of the phase 3 trials [20].…”

Section: Discussionmentioning

confidence: 95%

“…However, in a predefined secondary analysis of subjects with mild (baseline MMSE score 20-26) AD only, pooled across both trials, solanezumab-treated subjects declined more slowly on cognitive and functional measures than placebo-treated subjects [4]. No evidence of slowing of cognitive or functional decline was seen in subjects with moderate (baseline MMSE score [16][17][18][19] disease. Amyloid positron emission tomography imaging, performed in a small subset (N 5 251) of the EXPEDITION and EXPEDITION2 participants with mild AD, revealed that approximately 25% of those subjects were amyloid negative and, in the placebo arm, did not show typical disease progression over the trial duration [5,6].…”

Section: Introductionmentioning

confidence: 90%

“…Solanezumab is a humanized monoclonal antibody that preferentially binds soluble amyloid b (Ab) and was designed to slow Alzheimer's disease (AD) progression by increasing soluble Ab clearance from brain [1,2]. Initial phase 3, double-blind clinical trials of solanezumab, at a dose of 400 mg every 4 weeks for 76 weeks, in patients with clinically defined mild-to-moderate (baseline Mini-Mental State Examination [MMSE] score [16][17][18][19][20][21][22][23][24][25][26] AD (EXPEDITION and EXPEDITION2) failed to show a treatment benefit for solanezumab [3]. However, in a predefined secondary analysis of subjects with mild (baseline MMSE score 20-26) AD only, pooled across both trials, solanezumab-treated subjects declined more slowly on cognitive and functional measures than placebo-treated subjects [4].…”

Section: Introductionmentioning

confidence: 99%

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Magnetic resonance imaging measures of brain atrophy from the EXPEDITION3 trial in mild Alzheimer's disease

Schwarz

Sundell

Charil

et al. 2019

A&D Transl Res & Clin Interv

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Introduction Solanezumab is a humanized monoclonal antibody that preferentially binds to soluble amyloid β and promotes its clearance from the brain in preclinical studies. The objective of this study was to assess the effect of solanezumab in slowing global and anatomically localized brain atrophy as measured by volumetric magnetic resonance imaging (MRI). Methods In the EXPEDITION3 phase 3 trial, participants with mild Alzheimer's disease were randomized to receive intravenous infusions of either 400 mg of solanezumab or placebo every 4 weeks for 76 weeks. Volumetric MRI scans were acquired at baseline and at 80 weeks from 275 MRI facilities using a standardized imaging protocol. A subset of 1462 patients who completed both MRI and 14-item Alzheimer's Disease Assessment Scale–Cognitive Subscale assessments at both time points were selected for analysis. Longitudinal MRI volume changes were analyzed centrally by tensor-based morphometry with a standard FreeSurfer brain parcellation. Prespecified volumetric measures, including whole brain and ventricles, along with anatomically localized regions in the temporal, parietal, and frontal lobes were evaluated in those participants. Results Group-mean differences in brain atrophy rates were directionally consistent across a number of brain regions but small in magnitude (1.3–6.9% slowing) and not statistically significant when corrected for multiple comparisons. The annualized rates of change of the volumetric measures and the correlation of these changes with cognitive changes in placebo-treated subjects were similar to those reported previously. Discussion In the EXPEDITION3 trial, solanezumab did not significantly slow down rates of global or anatomically localized brain atrophy. Brain volume changes and their relationship to cognition were consistent with previous reports.

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“…Alzheimer's disease (AD) is a globally prevalent neurodegenerative condition, clinically characterized by progressive impairment of memory and cognitive functions . At present, there were approximately 36 million AD patients in the world, and it is expected to double every 20 years in future.…”

Section: Introductionmentioning

confidence: 99%

Efficacy and safety of anti‐amyloid‐β immunotherapy for Alzheimer's disease: a systematic review and network meta‐analysis

Yang

et al. 2017

Ann Clin Transl Neurol

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To review the optimality and safety of different anti‐Amyloid‐β(Aβ) immunotherapies for Alzheimer's disease (AD). Published randomized controlled trials were comprehensively reviewed from electronic databases (Cochrane library, Embase, Pubmed, and Google scholar). Pooled outcomes as mean difference or odds ratio values with 95% confidence interval were reported. The network estimates with confidence and predictive intervals for all pairwise relative effects was evaluated. Optimal intervention was ranked by benefit‐risk ratio based on the surface under the cumulative ranking curve. Eleven eligible RCTs from 9 literatures, including 5141 patients and 5 interventions were included. The quality of evidence was rated low in comparisons. For efficacy, in terms of Mini‐Mental State Examination, aducanumab and solanezumab are significantly effective than placebo. For safety, in terms of Amyloid‐Related Imaging Abnormalities (ARIA), bapineuzumab and aducanumab are significantly worse than placebo. There were no significant differences in outcomes of Alzheimer's disease Assessment Scale‐Cognitive subscale, Disability Assessment for Dementia, Adverse Events, and mortality. Given the clinical therapeutic effects of anti‐Aβ immunotherapies for AD, aducanumab and solanezumab improve the cognitive function, while aducanumab and bapineuzumab may increase the risks of ARIA.

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Bapineuzumab for mild to moderate Alzheimer’s disease: a meta-analysis of randomized controlled trials

Cited by 68 publications

References 34 publications

Fine‐tuning PERK signaling for neuroprotection

Fine‐tuning PERK signaling for neuroprotection

Magnetic resonance imaging measures of brain atrophy from the EXPEDITION3 trial in mild Alzheimer's disease

Efficacy and safety of anti‐amyloid‐β immunotherapy for Alzheimer's disease: a systematic review and network meta‐analysis

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