ADVANCING THERAPEUTICS FOR NEUROINFLAMMATION IN ALZHEIMER'S DISEASE: CLINICAL DEVELOPMENT CONSIDERATIONS

Abstract

Substantial epidemiologic evidence associates chronic anti-inflammatory drug use with reduced AD risk; equally substantial biomarker and neuropathology evidence implicates neuroinflammation in AD pathophysiology. However, clinical trials of various anti-inflammatory drugs conducted from 1993-2008 were neutral or negative, reducing interest in inflammation-targeting therapeutics thereafter. Recently though, intriguing genetic findings of both risk and protective alleles associated with CNS innate immune system (IIS) components, particularly microglia, have dramatically galvanized interest in neuroinflammation as a therapeutic focus. Accordingly, the early trials were reviewed to appreciate reasons for lack of clinical benefit and to identify lessons that might promote success of forthcoming trials of novel agents. Relevant findings from recent molecular biology, genomic, and biomarker research, and data from clinical use of anti-inflammatory treatments for systemic disorders were also considered. Published reports of trials testing anti-inflammatory drugs or drug combinations were reviewed, supplemented by interactions with study leaders when possible. Factors investigated included drug class (steroid, NSAID, other), population (age, disease stage, APOE4 status), sample size, clinical entry criteria, concomitant medications, clinical/biomarker endpoints, and treatment duration. Performance characteristics of established neuroinflammatory biomarkers (cytokines, e.g., Ifn-γ, IL-6) and emerging measures (YKL-40, sCD40L, exosomes, PET tracers) were also reviewed to assess readout utility. The potential that systemic factors (inflammatory disorders and/or treatments) might influence outcome of brain IIS-targeting treatment trials was considered. Seventeen trials testing 13 drugs were identified; 16 were conducted in MCI or AD, 1 in at-risk elderly. Treatments included a glucocorticoid, several NSAIDs (both nonselective COX inhibitors and COX-2-selective antagonists), and a PPAR-γ agonist. Sample sizes ranged from 20-2981; treatment duration was 3 mos-3.5 y. Biomarkers use was fairly limited. Temporal variability of classical cytokines is high; properties of newer markers are incompletely established but show promise. Systemic inflammatory disorders and even non-BBB-penetrant treatments might influence CNS IIS biology. The reasons for failure of early trials remain uncertain, but evaluating their design can significantly inform trial strategies for novel agents targeting brain innate immunity. Future trials must address the potential influence of peripheral immune factors. Promising biomarkers need early, translational evaluation, and development plans should include robust bioinformatics/pharmacogenomic strategies.