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Table 2 Tau therapeutics in clinical trials

From: The informed road map to prevention of Alzheimer Disease: A call to arms

Class Compound Current status Disease Stage Trial # Sample Size Preclinical models used Trial Outcome measures Opportunity for preventiona Evidence from clinical studies
(active vaccine and passive antibodies)
AADvac1—active vaccine against truncated
N-terminal tau
Phase 2 (mild AD) Mild AD NCT02579252 208 Human truncated tau cDNA-rat Safety; Yes Slowing of NfL rise; possible slowing of MRI atrophy and CSF p-tau
N-terminal of aggregated tau
Phase 2 Mild AD
NCT02880956 453 P301S AD-ongoing
PSP-clinical progression
Possible Phase 2 study in PSP demonstrated no clinical/imaging benefit at interim
N-terminal mid-domain tau
Phase 1 AD NCT03056729 46 P301L Safety Possible Phase 1 completed-results pending
N-terminal extracellular tau
Phase 2 AD
NCT03352557 654 ADAD iPSC; P301L Safety; Yes Phase 2 study in PSP demonstrated no clinical
JNJ-63733657—passive; mid-domain (tau seeds) Phase 1 Mild AD NCT03375697 72 P301L Safety possible Safety study in mild AD completed; results pending
Semorinemab—passive; n-terminal (monomeric/oligomeric) Phase 2 Mild AD NCT03828747
P301L Clinical/Cognition possible Phase 2 study reported no effect on cognitive decline
Microtubule stabilizer epothilone D—microtubule stabilizer (taxane derivative) [70] Discontinued Mild AD NCT01492374 40 P301L
Safety/CSF biomarkers Unknown Phase 1b study completed but no results provided
TPI287-tubulin-binding and microtubule-stabilizing (taxane derivative) Phase 1 AD
NCT01966666 29 NA Saftey/CSF PK Unknown Lack of clear clinical benefit for all tauopathies tested; increased anaphylactoid reaction in AD [71]
Tau Aggregation inhibitor Anle138b—general inhibitor of protein aggregation [72] Phase 1 Healthy adults NCT04208152 68 P301S [73]
hTau [72]
Safety Possible Good safety in phase 1 healthy adults
LMTM-second-generation tau protein aggregation inhibitor (Aminothienopyridazines) [74] Phase 3 AD
NCT03446001 588 Recombinant Tau/cellular models Clinical/cognitive decline Possible Multiple phase 2/3 studies with multiple formulations/doses have failed to identify a clear clinical benefit
Phosphorylation/protein kinase inhibitors/dephosphorylation enhancers Lithium—multiple but some glycogen synthase kinase 3 (GSK3-β) inhibition Phase 2 Mild AD NCT01055392 80b NA Clinical/cognition Unknown Possible stabilization of cognition in mild AD [75]
Tideglusib-inhibitor of glycogen synthase kinase 3 (GSK3-β) Phase 2 AD
306 Double transgenic APP/Tau Safety/Clinical improvement Unknown No clinical benefit
Non-specific Davunetide—activity-dependent neurotrophic protein; decreased tau phosphorylation Discontinued AD
NCT00422981 144 ADNP transgenic mice Safety/clinical No No clear cognitive benefit
MAPT lowering (Antisense Oligonucleotide) BIIB080 Phase 2 AD NCT03186989 46 P301S Safety/Clinical Yes TBD
  1. The table represents the recent approaches to tau therapeutics highlighting the focus on mechanisms based primarily from preclinical models
  2. AD Alzheimer disease, CBS corticobasal syndrome, PSP progressive supranuclear palsy
  3. aProposed potential as a prevention therapy is based on how likely the known mechanism of action aligns with the earliest stages of tau-pathology (soluble extracellular tau, reversibility of initial aggregated pathology), the known side effect profile (long term treatments likely required) and the available data on clinical efficacy
  4. bEstimated enrollment