Tau therapeutics: Clinical development status and future directions

Abstract

AbstractBackgroundAccumulation of insoluble, misfolded tau protein is a hallmark of AD, chronic traumatic encephalopathy and approximately half of frontotemporal lobar degeneration (FTLD), including progressive supranuclear palsy (PSP) and individuals with autosomal dominant mutations in the tau gene (MAPT), collectively termed tauopathies. While the protein structure and isoform composition differ among diseases, a general principle is that disease severity and clinical phenotype are strongly related to the amount and anatomical distribution of tau protein throughout the brain. In preclinical models generated from human MAPT mutations, strong evidence suggests that disease progression could be explained by transcellular spread of misfolded tau protein, and that reduction of misfolded tau protein levels or prevention of transcellular spread may be viable therapeutic strategies.MethodReview of tau therapeutics currently in clinical development and the tauopathies in which clinical trials may be most feasible at different stages of development.ResultThree classes of tau therapeutics are currently in clinical development: 1) small molecules designed to alter post‐translational modification, aggregation or clearance, 2) immunological therapies (anti‐tau monoclonal antibodies and vaccines) and 3) genetically‐targeted approaches (antisense oligonucleotides, siRNA, AAV‐mediated gene therapies). A few small molecules have completed phase 2 or 3 clinical trials in AD, FTLD or PSP, and two anti‐tau monoclonal antibodies have completed phase 2 studies in PSP. To date, there has been no evidence of clinical efficacy, although a few compounds have demonstrated target engagement.ConclusionThe availability of blood, CSF and PET biomarkers of AD tau pathology suggests that, early stage clinical trials focused on proof of biological concept are likely to be most informative in AD‐spectrum diseases, whereas there are potential advantages to conducting later stage clinical trials focused on clinical efficacy in primary tauopathies such as PSP. Regardless of clinical indication, genetically targeted therapies may have development advantages because of the potential responsiveness of biomarkers to these interventions. Questions to be addressed include: Which diseases are most likely to respond to tau therapeutics given that most were developed in preclinical models that overexpress human MAPT mutations? Do we have adequate biomarkers to demonstrate biological proof of concept and determine appropriate dose?