Ac Immune Sa · NASDAQ:ACIU
Ac Immune Sa — CTAD 2018 late breaking session
18 slides from Ac Immune Sa's conference presentation, Oct 26, 2018
Slide 1: Targeting neurodegenerative diseases with novel therapeutics and diagnostics
www.acimmune.com © 2018 AC Immune. Not to be used or reproduced without permission. Targeting neurodegenerative diseases with novel therapeutics and diagnostics CTAD late breaking session l O ctober, 2018
Slide 2: Disclaimer
© 2018 AC Immune. Not to be used or reproduced without permission. CTAD | October 2018 2 This presentation may contain statements that constitute “forward - looking statements” within the meaning of Section 27A of the Securities Act of 1933 and Section 21E of the Securities Exchange Act of 1934. For
Slide 3: Identification and characterisation of small molecule clinical candidates targeting intracellular Tau pathology
© 2018 AC Immune. Not to be used or reproduced without permission. CTAD | October 2018 3 IDENTIFICATION AND CHARACTERISATION OF SMALL MOLECULE CLINICAL CANDIDATES TARGETING INTRACELLULAR TAU PATHOLOGY Dr. S. Poli Head of Translational Science October 27 th , 2018
Slide 4: Rationale for targeting Tau
© 2018 AC Immune. Not to be used or reproduced without permission. CTAD | October 2018 4 ▪ Tau pathology correlates well with disease severity AD patients brain Pet Imaging: Excellent inverse correlation of Pet signal and MME score AD patients brain histology: Inverse correlation of NFT with MMSE sc
Slide 5: Discovery of Generation of conformation-specific small molecules
© 2018 AC Immune. Not to be used or reproduced without permission. CTAD | October 2018 5 ▪ Conformation - specific, non - peptidic , small molecules with drug like properties ▪ Protein propagation inhibitors ( Kroth et al . , 2012 ) ▪ Validated for selective binding to Abeta , Tau and alpha - Synucl
Slide 6: Mechanism of action of Morphomers
© 2018 AC Immune. Not to be used or reproduced without permission. CTAD | October 2018 6 ▪ Morphomer binding induced conformational changes in Tau aggregates ▪ Most of the conformational changes in Tau are located between amino acids 231 - 281 Limited proteolysis in absence (A) o r presence (B) of M
Slide 7: Summary of in vitro results - Lead characterization
© 2018 AC Immune. Not to be used or reproduced without permission. CTAD | October 2018 7 Summary of in vitro results ACI - 3024 - L ead characterization Tau aggregation inhibition ▪ Potent reduction of Tau aggregation ▪ Effect independent of Tau and FTDP - 17 isoform mutants Target engagement ▪ Sele
Slide 8: In vitro Pharmacology
© 2018 AC Immune. Not to be used or reproduced without permission. CTAD | October 2018 8 ACI - 3024 – I n vitro Pharmacology Ref.: AC Immune unpublished data Intracellular Tau misfolding in in vitro differentiated neuroblastoma cells expressing Tau P301L Undifferentiated cells Retinoic acid differen
Slide 9: Target engagement and functional selectivity
© 2018 AC Immune. Not to be used or reproduced without permission. CTAD | October 2018 9 ▪ ACI - 3024 specifically binds Tau NFTs and is able to disaggregate Tau NFTs from human AD brain sections even in presence of amyloid plaques. [3H] - ACI - 3024 [3H] - ACI - 3024 Cold ACI - 3024 High resolution
Slide 10: In vivo Evaluation in rTg4510 mice
© 2018 AC Immune. Not to be used or reproduced without permission. CTAD | October 2018 10 ACI - 3024 - In vivo E valuation in rTg4510 mice Treatment study in aged transgenic mice ▪ rTg4510 tauopathy model expresses repressible (Tet promotor Tau on/off) human 4R0N Tau carrying the P301L mutation ( Sa
Slide 11: Biochemistry: Analysis of pathological Tau in Tau ON/OFF rTg4510 mice
© 2018 AC Immune. Not to be used or reproduced without permission. CTAD | October 2018 11 ▪ Treatment with ACI - 3024 significantly reduced aggregated and insoluble pS202/pT205 hyper - phoshorylated Tau in cortical homogenates. The decrease was proportional to the plasma exposure to ACI - 3024 Aggre
Slide 12: Immunohistochemistry: Analysis of misfolded Tau (MC1) in rTg4510 brain section
© 2018 AC Immune. Not to be used or reproduced without permission. CTAD | October 2018 12 Immunohistochemistry: Analysis of misfolded Tau (MC1) in rTg4510 brain section MC1 in brain sections ▪ Treatment with ACI - 3024 significantly reduced misfolded Tau. ▪ The decrease was proportional to the plasm
Slide 13: Effect on neuro-inflammation
© 2018 AC Immune. Not to be used or reproduced without permission. CTAD | October 2018 13 ▪ In rTg4510 mice, treatment with ACI - 3024 reduced microgliosis . T his was likely due to a detoxification of Tau aggregates that consequently decreases pathological Tau induced - microglial activation Total
Slide 14: Evaluation of a potential biomarker for efficacy
© 2018 AC Immune. Not to be used or reproduced without permission. CTAD | October 2018 14 ▪ The significant inverse correlation between CSF Tau and ACI - 3024 exposure in plasma might indicate an increase of Tau clearance from the brain ▪ CSF Tau concentrations will be explored as a biomarker for ef
Slide 15: AC Immune's therapies intervene at key points in the disease pathway
© 2018 AC Immune. Not to be used or reproduced without permission. CTAD | October 2018 15 Nucleus Nucleus Affected cell Healthy cell Recipient cell ▪ Targeting both intracellular seeds and extracellular spreading by combination therapy of Morphomers and immunotherapy enables to fully control Tau pat
Slide 16: Lead candidate profile: selectivity, ADME and toxicology
© 2018 AC Immune. Not to be used or reproduced without permission. CTAD | October 2018 16 • ACI - 3024 is active and selective in multiple in vitro pharmacology assays • Binding assessed on 138 targets ( Cerep Bioprint profile) shows good selectivity In vitro on - and off - target activity • ACI - 3
Slide 17: Conclusions
© 2018 AC Immune. Not to be used or reproduced without permission. CTAD | October 2018 17 ▪ The Morphomer platform has enabled identification of a new class of low molecular weight compounds, which specifically target misfolded and aggregated Tau 1 2 3 ▪ ACI - 3024 has shown excellent preclinical sa
Slide 18: Acknowledgements
© 2018 AC Immune. Not to be used or reproduced without permission. CTAD | October 2018 18 AC Immune F. Capotosti N. Sreenivasachary A. Lamontanara E. Gabellieri P. Rodriguez Y. Varisco T. Jürgens AC Immune team Acknowledgements Prof. P. Davies H. Kroth D. Hickman S. Poli D. Lowe A. Muhs A. Pfeifer C