Figure 23: Morphomers
derived of proprietary Morphomer platform
Approximately 1,000 Morphomers were screened
so far for the Anti-Tau Morphomer program. This approach has enabled the identification of several chemical series of orally bioavailable
small molecules with CNS properties which can specifically and potently bind to pathological Tau to prevent misfolding and promote
disaggregation. Further optimization using multiple orthogonal in vitro, ex-vivo and in vivo tests addressing pharmacology, but
also ADME and early safety properties has led to the identification of the lead candidate ACI-3024.
ACI-3024 was shown to be a potent inhibitor
of Tau aggregation, not only on the Tau native form, but also on synthetic fibers derived from the six human Tau isoforms or from
the four mutants containing common point mutation associated with human Tauopathies, such as FrontoTemporal Dementia-17 and Pick’s
disease. ACI-3024 selectively binds to aggregated Tau but does not bind to the monomeric forms of Tau; moreover the binding to
Tau is selective, with no cross-reactivity to Abeta and α-Synuclein.
ACI-3024 showed a potent and dose-dependent
reduction in spontaneous intracellular Tau aggregation and misfolding as measured by immunocytochemistry in human neuronal-like
cells over-expressing Tau. Furthermore ACI-3024 promoted ex-vivo disaggregation of Tau neurofibrillary tangles on human
AD brain sections.
The in vivo efficacy of ACI-3024
was evaluated in the rTg4510 mouse model (Ramsden et al., 2005). In vivo treatment of Tg4510 transgenic mice with ACI-3024
significantly reduced aggregated and insoluble hyper-phosphorylated Tau. Immunohistochemistry analysis of misfolded Tau (MC1) in
the Tg4510 brain section of the same mice treated with ACI-3024 showed a significant reduction of misfolded Tau (MC1). These effects
were proportional to the plasma concentration of ACI-3024 (Figure 24 below).
Total Tau concentration in CSF was significantly
correlated with ACI-3024 exposure in plasma and indicates an increase of Tau clearance from the brain, opening the possibility
of exploring CSF Tau concentrations as a biomarker.
Figure 24: Assessment
of ACI-3024 treatment effects on misfolded Tau
Ref: AC Immune unpublished data