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20-F
AC IMMUNE SA filed this Form 20-F on 03/21/2019
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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.

 

Lead characterization

 

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Ref: AC Immune unpublished data

 

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