A phase 3 trial of IV immunoglobulin for Alzheimer disease

Relkin, Norman; Thomas, Ronald G.; Rissman, Robert A.; Brewer, James B.; Rafii, Michael S.; Dyck, Christopher H. van; Jack, Clifford R.; Sano, Mary; Knopman, David S.; Raman, Rema; Szabo, Paul; Gelmont, David; Fritsch, Sandor; Aisen, Paul S.

doi:10.1212/wnl.0000000000003904

Cited by 137 publications

(97 citation statements)

References 29 publications

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“…The presence of natural anti-Aβ antibodies have been reported in IV immunoglobulin (IVIg), thus IVIg has been proposed as a potential AD treatment. IVIg is derived from plasma of healthy donors and contains a majority of the human IgG-type antibodies [19,22]. Nevertheless, the first completed phase 3 trial of IVIg for AD, showed good tolerability but lack of efficacy of the agent on cognition or function of participants with mild to moderate AD [22].…”

Section: Inadequate Understanding Of the Complex Pathophysiology Of Amentioning

confidence: 99%

“…IVIg is derived from plasma of healthy donors and contains a majority of the human IgG-type antibodies [19,22]. Nevertheless, the first completed phase 3 trial of IVIg for AD, showed good tolerability but lack of efficacy of the agent on cognition or function of participants with mild to moderate AD [22]. In this phase 3, double-blind, placebo-controlled trial, IVIg (Gammagard Liquid; Baxalta, Bannockburn, IL, USA) was administered intravenously (IV) at doses of 0.2 or 0.4 g/kg every two weeks for 18 months.…”

Section: Inadequate Understanding Of the Complex Pathophysiology Of Amentioning

confidence: 99%

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Reasons for Failed Trials of Disease-Modifying Treatments for Alzheimer Disease and Their Contribution in Recent Research

et al. 2019

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Despite all scientific efforts and many protracted and expensive clinical trials, no new drug has been approved by FDA for treatment of Alzheimer disease (AD) since 2003. Indeed, more than 200 investigational programs have failed or have been abandoned in the last decade. The most probable explanations for failures of disease-modifying treatments (DMTs) for AD may include late initiation of treatments during the course of AD development, inappropriate drug dosages, erroneous selection of treatment targets, and mainly an inadequate understanding of the complex pathophysiology of AD, which may necessitate combination treatments rather than monotherapy. Clinical trials’ methodological issues have also been criticized. Drug-development research for AD is aimed to overcome these drawbacks. Preclinical and prodromal AD populations, as well as traditionally investigated populations representing all the clinical stages of AD, are included in recent trials. Systematic use of biomarkers in staging preclinical and prodromal AD and of a single primary outcome in trials of prodromal AD are regularly integrated. The application of amyloid, tau, and neurodegeneration biomarkers, including new biomarkers—such as Tau positron emission tomography, neurofilament light chain (blood and Cerebrospinal fluid (CSF) biomarker of axonal degeneration) and neurogranin (CSF biomarker of synaptic functioning)—to clinical trials allows more precise staging of AD. Additionally, use of Bayesian statistics, modifiable clinical trial designs, and clinical trial simulators enrich the trial methodology. Besides, combination therapy regimens are assessed in clinical trials. The above-mentioned diagnostic and statistical advances, which have been recently integrated in clinical trials, are relevant to the recent failures of studies of disease-modifying treatments. Their experiential rather than theoretical origins may better equip potentially successful drug-development strategies.

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Section: Inadequate Understanding Of the Complex Pathophysiology Of Amentioning

confidence: 99%

Section: Inadequate Understanding Of the Complex Pathophysiology Of Amentioning

confidence: 99%

Reasons for Failed Trials of Disease-Modifying Treatments for Alzheimer Disease and Their Contribution in Recent Research

et al. 2019

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“…9 Similarly, naturally occurring antiβ-amyloid autoantibodies with neuroprotective effects were reported in mice, but did not meet primary cognitive endpoints when tested in a phase III clinical trial. 44 Nonetheless, our work does not rule out the possibility of protective anti-PrP autoantibodies in the general population or in PRNP mutation carriers specifically. Our study was restricted to the assessment of autoantibody levels against fulllength, wild-type, recombinant human PrP C .…”

Section: Discussionmentioning

confidence: 72%

Autoantibodies against the prion protein in individuals with PRNP mutations

Frontzek

Carta

Losa³

et al. 2020

Neurology

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ObjectiveTo determine whether naturally occurring autoantibodies against the prion protein are present in individuals with genetic prion disease mutations and controls, and if so, whether they are protective against prion disease.MethodsIn this case–control study, we collected 124 blood samples from individuals with a variety of pathogenic PRNP mutations and 78 control individuals with a positive family history of genetic prion disease but lacking disease-associated PRNP mutations. Antibody reactivity was measured using an indirect ELISA for the detection of human immunoglobulin G1–4 antibodies against wild-type human prion protein. Multivariate linear regression models were constructed to analyze differences in autoantibody reactivity between (1) PRNP mutation carriers vs controls and (2) asymptomatic vs symptomatic PRNP mutation carriers. Robustness of results was examined in matched cohorts.ResultsWe found that antibody reactivity was present in a subset of both PRNP mutation carriers and controls. Autoantibody levels were not influenced by PRNP mutation status or clinical manifestation of prion disease. Post hoc analyses showed anti-PrPC autoantibody titers to be independent of personal history of autoimmune disease and other immunologic disorders, as well as PRNP codon 129 polymorphism.ConclusionsPathogenic PRNP variants do not notably stimulate antibody-mediated anti-PrPC immunity. Anti-PrPC immunoglobulin G autoantibodies are not associated with the onset of prion disease. The presence of anti-PrPC autoantibodies in the general population without any disease-specific association suggests that relatively high titers of naturally occurring antibodies are well-tolerated.Clinicaltrials.gov identifierNCT02837705.

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“…Recent RCTs on the elimination of the accumulated Aβ or tau proteins could not provide solid evidence for improvement of the symptoms of LOAD 47–49 . While clinical trials with small sample sizes have shown that eliminating the Aβ elements led to symptomatic improvement 50 , larger studies have failed to establish consistent results 47, 51, 52 . The agents reducing tau phosphorylation represented promising benefits in pilot clinical studies 53, 54 , but failed to show significant improvements in a cohort study 54 ; tau aggregation inhibitors showed a similar pattern 55 .…”

Section: Discussionmentioning

confidence: 99%

“…Our results suggested that the etiology of LOAD involves multiple biological processes, including the amyloid and tau proteins in the AD pathophysiology. This complex nature of LOAD could partly explain the recent multiple failures of clinical trials of anti-amyloid monotherapy 47, 51, 52, 74, 75 . Further MR studies for multiple candidate biomarkers could be helpful to find appropriate drug targets for LOAD and larger GWAS data with sufficient numbers of IVs are necessary to validate the causality of CSF Aβ and p-tau on the risk for LOAD.…”

Section: Discussionmentioning

confidence: 99%

Causal relationship of cerebrospinal fluid biomarkers with the risk of Alzheimer’s disease: A two-sample Mendelian randomization study

Kim

Nho

et al. 2019

Preprint

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Whether the epidemiological association of amyloid beta (Aβ) and tau pathology with Alzheimer's disease (AD) is causal remains unclear. The recent failures to demonstrate the efficacy of several amyloid beta-modifying drugs may indicate the possibility that the observed association is not causal. These failures also led to efforts to develop tau-directed treatments whose efficacy is still tentative. Herein, we conducted a two-sample Mendelian randomization analysis to determine whether the relationship between the cerebrospinal fluid (CSF) biomarkers for amyloid and tau pathology and the risk of AD is causal. We used the summary statistics of a genome-wide association study (GWAS) for CSF biomarkers (Aβ 1-42 , phosphorylated tau 181 [p-tau], and total tau [t-tau]) in 3,146 individuals and for late-onset AD (LOAD) in 21,982 LOAD cases and 41,944 cognitively normal controls. We tested the association between the change in the genetically predicted CSF biomarkers and LOAD risk.We found a modest decrease in the LOAD risk per one standard deviation (SD) increase in the genetically predicted CSF Aβ (odds ratio [OR], 0.63 for AD; 95% confidence interval[CI], 0.38-0.87; P = 0.02). In contrast, we observed a significant increase in the LOAD risk per one SD increase in the genetically predicted CSF p-tau (OR, 2.37; 95% CI, 1.46-3.28; P = 1.09×10 -5 ). However, no causal association was observed of the CSF t-tau with the LOAD risk (OR, 1.15; 95% CI, 0.85-1.45; P = 0.29). Our findings need to be validated in future studies with more genetic variants identified in larger GWASs for CSF biomarkers.Alzheimer's disease (AD), a leading cause of dementia, is the largest burden source of morbidity and mortality in older adults. One in every 85 individuals is expected to develop AD, which means that delaying the onset by one year can reduce the number of patients with AD worldwide up to 9 million by 2020 1 . Given that eightfold as many individuals have preclinical AD at risk of progression 2 , the development of disease-modifying therapies is urgently required. Amyloid beta (Aβ) peptides are transmembrane amyloid precursor proteins 3 and tau is a microtubule-associated protein 4 . Decades of research have accumulated the evidence on the pathophysiology of Aβ and tau proteins that independently form plaques and tangles and lead normal functional neurons into a disabled state, AD 5 . Understanding AD as the result of abnormal proteins, extracellular amyloid plaques, and intraneuronal neurofibrillary tau tangles, two-thirds of the novel treatment pipelines aim at diseasemodifying therapies, 90% of which are anti-amyloid and anti-tau protein agents 6 .However, numerous trials to develop novel therapies targeting the amyloid plaques to modify the disease progress recently turned out failures. These failures could bring a reasonable doubt about the role of Aβ in the pathophysiology of AD with delicate elaboration 7 . One possible explanation of the failure of clinical trials targeting the amyloid plaques is that the intervention is perfor...

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A phase 3 trial of IV immunoglobulin for Alzheimer disease

Cited by 137 publications

References 29 publications

Reasons for Failed Trials of Disease-Modifying Treatments for Alzheimer Disease and Their Contribution in Recent Research

Reasons for Failed Trials of Disease-Modifying Treatments for Alzheimer Disease and Their Contribution in Recent Research

Autoantibodies against the prion protein in individuals with PRNP mutations

Causal relationship of cerebrospinal fluid biomarkers with the risk of Alzheimer’s disease: A two-sample Mendelian randomization study

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