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UNITED STATES

SECURITIES AND EXCHANGE COMMISSION

Washington, D.C. 20549

 

FORM 6-K

 

REPORT OF FOREIGN PRIVATE ISSUER PURSUANT TO RULE 13a-16

OR 15d-16 UNDER THE SECURITIES EXCHANGE ACT OF 1934

 

For the month of November, 2019

 

Commission File Number: 001-37891

 

AC IMMUNE SA

(Exact name of registrant as specified in its charter)

 

EPFL Innovation Park

Building B

1015 Lausanne, Switzerland 

(Address of principal executive office)

 

Indicate by check mark whether the registrant files or will file annual reports under cover of Form 20-F or Form 40-F:

 

Form 20-F

X

   Form 40-F

 

 

Indicate by check mark if the registrant is submitting the Form 6-K in paper as permitted by Regulation S-T Rule 101(b)(1):

 

Yes   No

X 

 

Indicate by check mark if the registrant is submitting the Form 6-K in paper as permitted by Regulation S-T Rule 101(b)(7):

 

Yes   No

X 

 

 

 

 

 

AC IMMUNE SA

 

On November 6, 2019, representatives from AC Immune will present at its Key Opinion Leader (“KOL”) meeting held in New York City, using the presentation slides attached as Exhibits 99.1 and 99.2 hereto.

 

This report on Form 6-K (including Exhibits 99.1 and 99.2 hereto) shall be deemed to be incorporated by reference into the registration on Form F-3 (Registration Number: 333-224694), the registration statement on Form F-3 (Registration Number: 333-227016) and the registration statement on Form S-8 (Registration Number: 333-216539) of AC Immune and to be a part thereof from the date on which this report is filed, to the extent not superseded by documents or reports subsequently filed or furnished.

 

 

 

SIGNATURE

 

Pursuant to the requirements of the Securities Exchange Act of 1934, the registrant has duly caused this report to be signed on its behalf by the undersigned, thereunto duly authorized.

 

    AC IMMUNE SA
     
      By: /s/ Andrea Pfeifer
        Name: Andrea Pfeifer
        Title: Chief Executive Officer

 

     
      By: /s/ Joerg Hornstein
        Name: Joerg Hornstein
        Title: Chief Financial Officer

 

Date: November 6, 2019

 

 

 

EXHIBIT INDEX

 

Exhibit Number Description
99.1 Presentation dated November 6, 2019
99.2 Presentation dated November 6, 2019

 

 

Exhibit 99.1

 

www.acimmune.com © 2019 AC Immune. Not to be used or reproduced without permission. Novel Therapeutics and Diagnostics for Neurodegenerative Diseases Andrea Pfeifer, Ph.D., CEO AC Immune Version November 4

 

 

© 2019 AC Immune. Not to be used or reproduced without permission. 2 NASDAQ: ACIU | KOL Lunch | November 2019 Disclaimer 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. Forward - looking statements are statements other than historical fact and may include statements that address future operating, financial or business performance or AC Immune’s strategies or expectations. In some cases, you can identify these statements by forward - looking words such as “may,” “might,” “will,” “should,” “expects,” “plans,” “anticipates,” “believes,” “estimates,” “predicts ,” “projects,” “potential,” “outlook” or “continue,” and other comparable terminology. Forward - looking statements are based on management’s current expectations and beliefs and involve significant risks and uncertainties that could cause actual results, developments and business decisions to differ materially from those contemplated by these statements. These risks and uncertainties include those described under the captions “Item 3. Key Information ‒ Risk Factors” and “Item 5. Operating and Financial Review and Prospects” in AC Immune’s Annual Report on Form 20 - F and other filings with the Securities and Exchange Commission. Forward - looking statements speak only as of the date they are made, and AC Immune does not undertake any obligation to update them in light of new information, future developments or otherwise, except as may be required under applicable law. All forward - looking statements are qualified in their entirety by this cautionary statement.

 

 

© 2019 AC Immune. Not to be used or reproduced without permission. 3 NASDAQ: ACIU | KOL Lunch | November 2019 ▪ Pioneering new ways to treat neurodegenerative diseases associated with misfolded proteins ▪ Listed on Nasdaq since September 2016 (ticker: ACIU) ▪ 71.1 million shares outstanding 1 (free float approximately 50%) ▪ Cash position of CHF 286 million as of Q2 2019 ▪ Based at the EPFL campus in Lausanne, Switzerland ▪ 123 full - time employees About AC Immune (1) As of April 25, 2019

 

 

© 2019 AC Immune. Not to be used or reproduced without permission. 4 NASDAQ: ACIU | KOL Lunch | November 2019 ▪ Addressing largest market opportunity in healthcare ▪ Pioneering precision medicine in neurodegenerative diseases ▪ CHF 286 million in cash, supports operations through Q3 2023 1 ▪ Increasing investment into key areas of NeuroOrphan and neuroinflammation Investment highlights AC Immune: a leader in neurodegenerative diseases ( 1) As of Q2 2019. Expected cash runway, excluding potential incoming milestones. ▪ Broad pipeline with four therapeutic candidates in Phase 2 ▪ Multiple near - term value inflection points ▪ Partnerships with Roche, Janssen and Eli Lilly ▪ Complementary diagnostics in clinical development ▪ Highly - valued preclinical assets in Tau, a - syn and TDP - 43 ▪ Highly productive validated discovery platforms for sustained growth to address misfolded proteins applicable across multiple diseases ▪ SupraAntigen TM : vaccines and antibodies specific to disease causing conformations ▪ Morphomer TM : conformation - sensitive small molecules 1 2 3 4 5

 

 

© 2019 AC Immune. Not to be used or reproduced without permission. 5 NASDAQ: ACIU | KOL Lunch | November 2019 “Firsts” reflect ACIU’s leadership in NDD 1 (1) Neurodegenerative diseases; (2) Alzheimer's disease; (3) Progressive supranuclear palsy; (4) First - in - Man; (5) Small molecule Tau - specific aggregation inhibitor 2013 Prevention trial in AD 2 ( crenezumab ) 1 st 2014 A nti - pTau vaccine clinical trial in AD 1 st 2015 1 st Clinical vaccine trial in Down syndrome ( Abeta vaccine ) 2018 1 st FiM 4 clinical data for a - syn PET - imaging tracer 2019 1 st Morphomer TM Tau 5 clinical trial (ACI - 3024)

 

 

AC Immune’s Roadmap to successful therapies for neurodegenerative diseases

 

 

© 2019 AC Immune. Not to be used or reproduced without permission. 7 NASDAQ: ACIU | KOL Lunch | November 2019 (1) Reardon S, Nature 2018 ; (2) Pontecorvo MJ, et al ., Brain 2019 ; (3) Gordon BA, et al., Brain 2019 ; (4) Strydom A, et al ., Alzheimers Dement (N Y) 2018 ; (5) Lott IT and Head E., Nat Rev Neurol . 2019 ; (6) Robinson JL, et al., Brain 2018 ; (7) Heneka MT et al ., Nat Rev Neurosci . 2018 ; (8) Wang S et al ., Int Immunopharmacol . 2019 ; (9) NOD - like receptor protein 3; (10) Apoptosis - associated speck protein containing a CARD Precision medicine is a key driver for effective treatments Target neuroinflammation 7,8 ▪ Develop monoclonal antibodies and small molecules for microglial balance targeting the inflammasome NLRP3 9 - ASC 10 pathway ▪ Diagnose co - pathologies with selective diagnostics ▪ Select study population based on specific proteinopathies Precision medicine 6 ▪ Familial Alzheimer’s disease, Down syndrome ▪ NeuroOrphan indications More homogeneous populations 4,5 Target Tau 2,3 ▪ Develop therapies and use Tau PET tracers to diagnose/select patients Treat earlier 1 ▪ Prioritize primary and secondary prevention trials ▪ Access diagnostic tools for patient identification Roadmap to successful therapies for neurodegenerative diseases

 

 

AC Immune’s business strategy

 

 

© 2019 AC Immune. Not to be used or reproduced without permission. 9 NASDAQ: ACIU | KOL Lunch | November 2019 Vision SupraAntigen TM Vaccines and antibodies specific to disease causing conformations Morphomer TM Conformation - sensitive small molecules To become a global leader in precision medicine 1 for neurodegenerative diseases leveraging dual proprietary technology platforms to develop breakthrough mono - and combination therapies (1) The goal of precision medicine is to deliver optimally targeted and timed interventions tailored to the individual disease drivers Dual Proprietary Technology Platforms Images: Hickman et a l, JBC 2011; Kroth et al , JBC 2012

 

 

© 2019 AC Immune. Not to be used or reproduced without permission. 10 NASDAQ: ACIU | KOL Lunch | November 2019 Precision medicine ultimately creates differentiation Business strategy: 3 - pillar approach Vision Alzheimer’s disease (AD) Non - AD NeuroOrphans Diagnostics Technology platforms Values ▪ Develop best - in - class late stage assets in partnership ▪ Develop preventive/therapeutic vaccines as fully owned assets (ACI - 24) ▪ Establish a pipeline of disease modifying small molecules Alzheimer’s disease (AD) ▪ Discover therapeutics in Parkinson’s disease ▪ Leverage AD therapeutics in Down syndrome, PSP 1 and other NeuroOrphan diseases ▪ Target neuroinflammation for NDDs 2 as mono - and combination therapy Non - AD, NeuroOrphans ▪ Accelerate diagnostic pipeline to late stage development ▪ Use diagnostics for improved clinical trials and external partnerships Diagnostics (1) Progressive supranuclear palsy; (2) Neurodegenerative diseases

 

 

© 2019 AC Immune. Not to be used or reproduced without permission. 11 NASDAQ: ACIU | KOL Lunch | November 2019 Investors and funds from partnerships Highly committed institutional investors 1 Five private financing rounds IPO NASDAQ September 2016 Share capital offering of 10 million common shares July 2018 Corporate funding to date 2 (in CHF millions) Upfront payments Milestone payments 1 ) Based on latest schedule 13G and 13F filings; (2) Converted to CHF based on exchange rates at times of receipt; (3) Milestone payments as of 30 September, 2019; (4) With Lilly convertible loan Partner equity investments ▪ CHF 313 million from investor funds ▪ CHF 322 million in partnering related funds 3,4 ▪ CHF 3 billion in total potential payments plus potential royalties outstanding

 

 

Pipeline and catalysts

 

 

© 2019 AC Immune. Not to be used or reproduced without permission. 13 NASDAQ: ACIU | KOL Lunch | November 2019 Driven by proprietary technology platforms for sustained growth TARGETS PRODUCT CANDIDATE INDICATION DISCOVERY PRECLIN PHASE 1 PHASE 2 PHASE 3 PARTNERS Tau semorinemab (anti - Tau antibody) AD 1 trt 2 – prodromal mild AD trt - moderate ACI - 35 (anti - pTau vaccine ) AD treatment Abeta c renezumab (anti - Abeta antibody) 3 AD prevention ACI - 24 (anti - Abeta vaccine) AD treatment AD trt in Down syndrome 4 a - synuclein Anti - a - syn antibody PD 5 , NeuroOrphan TDP - 43 Anti - TDP - 43 antibody NeuroOrphan Tau Morphomer Tau (Tau inhibitor, small molecule) AD treatment Tau - PET 6 tracer AD and PSP 7 diagnostic Abeta Morphomer Abeta (Abeta inhibitor, small molecule) Glaucoma a - synuclein Morphomer a - syn (a - synuclein inhibitor, small molecule) PD, NeuroOrphan a - syn - PET tracer PD, a - synuclein pathologies TDP - 43 TDP - 43 - PET tracer diagnostic Broad and robust pipeline in neurodegenerative diseases (1) Alzheimer’s disease; (2) Treatment (3) Prevention trial API - ADAD in Colombia; (4) AD - like and cognitive impairment associated with Down syndrome; (5) Parkinson’s disease (6) Positron emission tomography; (7) Progressive supranuclear palsy SupraAntigen TM Morphomer TM b iologics small molecules diagnostics

 

 

© 2019 AC Immune. Not to be used or reproduced without permission. 14 NASDAQ: ACIU | KOL Lunch | November 2019 Key milestones for 2019 Successful delivery of strategy with multiple near - term catalysts ACI - 24 ACI - 35 a - synuclein TDP - 43 a - synuclein PET tracer Morphomer Tau Phase 1b in DS 2 Start Phase 1b/2a Preclinical POC 2 nd generation molecule starts FiM 6 Start Phase 1 SupraAntigen TM Morphomer TM b iologics small molecules diagnostics Preclinical POC semorinemab anti - Tau antibody Start Phase 2 in moderate AD 1 ( 1) Alzheimer’s disease; (2 ) P reliminary interim data look (high dose cohort ) (3) T reatment ; (4) AD - like and cognitive impairment associated with Down syndrome; (5) Parkinson’s disease; (6) First - in - Man Preclinical POM AD treatment AD trt 3 in Down syndrome 4 AD treatment PD 5 and NeuroOrphan NeuroOrphan NeuroOrphan PD, a - synuclein pathologies AD treatment Tau PET tracer Start Phase 2 longitudinal study AD treatment neuroinflammation Morphomer Q2 2019 Q1 2019 Q3 2019 Q4 2019 Q3 2019 Q2 2019 Q1 2019

 

 

Focus on Tau

 

 

© 2019 AC Immune. Not to be used or reproduced without permission. 16 NASDAQ: ACIU | KOL Lunch | November 2019 Affected cell Healthy cell Recipient cell AC Immune’s molecules target pathological Tau at key points in the disease pathway Nucleus Misfolded proteins Normally folded proteins Reverse misfolding Promote disaggregation Inhibit spreading Prevent seeding Morphomer TM target Immunotherapy target ( mAbs , vaccines) Nucleus Nucleus ▪ Targeting both intracellular seeds and extracellular spreading by combination therapy of Morphomers and immunotherapy enables full control of Tau pathology progression ▪ Highly selective Tau imaging diagnostic enables more precise patient characterization and potentially more precise prediction of AD 1 progression (1) Alzheimer’s disease

 

 

© 2019 AC Immune. Not to be used or reproduced without permission. 17 NASDAQ: ACIU | KOL Lunch | November 2019 2019 Tau pipeline news 30m € Milestone payment in connection with initiation of a Phase 2 trial CHF milestone payment clinical trial started to evaluate ACI - 35.030 vaccine Tau PET substudy initiated 2 nd anti - Tau monoclonal antibody trial in moderate AD Ph2 Ph1b/2a

 

 

© 2019 AC Immune. Not to be used or reproduced without permission. 18 NASDAQ: ACIU | KOL Lunch | November 2019 Diagnostics and therapies: AC Immune: broadest anti - Tau pipeline with key clinical newsflow funds generated from Tau assets clinical trials diagnostic vaccine antibody small molecule Phase 2 1,2 Phase 1b/2a 3 Phase 1 Phase 2 (1) Prodromal/mild trial primary completion estimated; (2) Moderate trial primary completion estimated; (3) I n Alzheimer's disease; (4) Trial of anti - pTau vaccine (safety and immunogenicity); (5) Trial in progressive supranuclear palsy patients (test/ retest) results f Q2 2020 1 f ollowed by Q3 2021 2 Q2 2020 interim analysis 4 Q1 2020 with interim in Q4 2019 Q4 2020 PET tracer 5 Next milestone Product candidates Status Partner

 

 

© 2019 AC Immune. Not to be used or reproduced without permission. 19 NASDAQ: ACIU | KOL Lunch | November 2019 Anti - Tau antibody Semorinemab – Phase 2 in AD 1 (1) Alzheimer’s disease; (2) Healthy volunteers; (3) Mini - mental state exam; (4) Clinical Dementia Rating - Global Score; (5) Clin ical Dementia Rating - Sum of the Boxes; (6) Repeatable Battery for Assessment of Neuropsychological Status; (7) Alzheimer’s Disease Assessment Scale - cognitive subscale Target Designed to intercept the cell - to - cell spread of pathological Tau in extracellular space of brain Licensee Key differentiator ▪ Tau pathological spread is dose dependently reduced independent of effector function ▪ Proven target engagement through dose - dependent rise of plasma Tau (mice, cynos , humans) Development status Phase 2 design (prodromal to mild AD; Tauriel ): primary completion estimated in Q2 2020 ▪ 360 prodromal - to - mild AD patients (MMSE 3 20 - 30, CDR - GS 4 = 0.5 or 1) ▪ 3 active doses or placebo for 72 weeks, followed by 96 week open label study ▪ Primary endpoints: safety measures and CDR - SB 5 ; secondary endpoints: RBANS 6 and ADAS - cog13 7 Phase 2 design ( moderate; Lauriet ): primary completion estimated in Q3 2021 ▪ 260 patients ( MMSE 16 - 21; CDR - GS = 1 or 2) ▪ 1 dose or placebo for 49 weeks, followed by open - label study ▪ Primary endpoints: ADAS - cog11 and ADCS - ADL; secondary endpoints: CDR - SB, MMSE, safety AD/PD conference, Vienna, April 2017 Control Anti - gp120, 30mg/kg Anti - Tau DANG 30mg/kg Kerchner et al , CTAD 2017 ▪ Compared to HV, AD patients exhibited two - fold greater levels of plasma Tau following RO7105705 administration, despite identical RO7105705 exposures in the two populations Dose dependent reduction of Tau pathology (preclinical) Phase 1 results: Pharmacodynamic response: Plasma Tau concentration 2x higher in AD than in HV 2 ▪ Median half - life of 32.3 days ▪ No dose - limiting toxicities at high doses

 

 

Preclinical programs with newsflow in Q3

 

 

© 2019 AC Immune. Not to be used or reproduced without permission. 21 NASDAQ: ACIU | KOL Lunch | November 2019 Target Misfolded, aggregated a - synuclein (a - syn) Target characteristics ▪ Pathological a - syn aggregates and forms oligomers and fibrils ▪ Aggregation and spreading of misfolded a - syn are linked to synucleinopathies as shown in patients and animal models Key results ▪ Antibodies with specificity and high affinity for pathological human a - syn (KD 2 down to 3pM ) ▪ Target binding shown for PD, DLB 3 and MSA 4 in human brains from multiple patients ▪ A - syn antibodies, ACI - 5755 and ACI - 5756, show aggregation inhibition in vitro ▪ In vivo , ACI - 5755 and ACI - 5756 significantly decrease pathological a - syn spreading ▪ IND 8 enabling studies start in Q1 2020 Anti - a - synuclein (a - syn) antibody – Discovery in PD 1 Next steps (1) Parkinson’s disease; (2) Equilibrium dissociation constant; (3) Dementia with Lewy bodies; (4) Multiple system atrophy; ( 5) C ortex ; (6) p - syn antibody (pSer129; Abcam , UK); (7) Immunohistochemistry; (8) Investigational new drug SupraAntigen platform is ideally positioned to generate antibodies with selectivity to: ▪ Misfolded, aggregated a - syn Lewy bodies AC Immune unpublished data Target engagement on Lewy bodies of PD amygdala PD patient Binding preference Phosphorylated S129 a - syn (p - Syn 6 ) IHC 7 Reduction of pathological a - syn in vivo 5 Recombinant a - syn aggregation assay Delay of a - syn aggregation in vitro SupraAntigen TM platform Key differentiation ▪ High affinity for pathological a - syn ; significant decrease of a - syn spreading

 

 

 

 

 

 

© 2019 AC Immune. Not to be used or reproduced without permission. 22 NASDAQ: ACIU | KOL Lunch | November 2019 Target Aggregated TDP - 43 1 Target characteristics ▪ TDP - 43 is a RNA/DNA binding protein involved in RNA metabolism ▪ Aggregated TDP - 43 loses its physiological function and the extracellular pathological protein is involved in spreading of the pathology ▪ TDP - 43 pathology is found in multiple neurodegenerative diseases such as FTD 2 , AD 3 , HD 4 , ALS 5 and CTE 6 Key results ▪ ACI - 5891 antibody binds to all forms of pathological human TDP - 43 with high affinity ▪ In vivo , ACI - 5891 significantly decreases aggregated TDP - 43 Anti - TDP - 43 antibodies – Discovery Phase ▪ IND enabling studies start in Q2 2020 (1) TAR DNA - binding protein 43; (2) Frontotemporal dementia; (3) Alzheimer's disease; (4) Huntington’s disease; (5) Amyotrophic lateral sclerosis; (6) Chronic traumatic encephalopathy ; ( 7 ) Walker et al Acta Neuropathol 2015; (8) Immunohistochemistry Ref: AC Immune unpublished data SupraAntigen platform is ideally positioned to generate antibodies with selectivity to: ▪ Misfolded, aggregated TDP - 43 SupraAntigen TM platform Target engagement on FTD frontal cortex (IHC 8 ) FTD patient Binding preference pTDP - 43 (IHC 8 ) Insoluble TDP - 43 ( biochemistry ) Reduction of pathological TDP - 43 in vivo 7 V e h i c l e A C I - 5 8 9 1 0 5000 10000 15000 RIPA insoluble fraction I n s o l u b l e T D P - 4 3 ( R e l a t i v e u n i t s ) Vehicle ACI-5891 ✱✱✱✱ T g ( r N L S 8 ) V e h i c l e T g ( r N L S 8 ) A C I - 5 8 9 1 0 25 50 75 100 125 pTDP-43 in Cortex p T D P - 4 3 d e n s i t y ( n u m b e r / m m 2 ) Tg(rNLS8) Vehicle Tg(rNLS8) ACI-5891 ✱✱ Next steps Key differentiation ▪ Only antibody reported with demonstrated in vivo activity

 

 

Strategic outlook

 

 

© 2019 AC Immune. Not to be used or reproduced without permission. 24 NASDAQ: ACIU | KOL Lunch | November 2019 Strategy for value creation 3. INVEST to further build leadership in neurodegenerative diseases ▪ Execute in line with our “Roadmap” ▪ Focus on Tau and new targets in neuroinflammation 1 . ENFORCE focus on early treatment and prevention trials in homogeneous patient populations 4. DIVERSIFY into other neurodegenerative and NeuroOrphan diseases ▪ Potential for streamlined regulatory pathway ▪ Favorable pricing and reimbursement 2. EVOLVE strategy to add precision medicine and combination therapy approaches based on patients’ specific proteinopathies ▪ Leverage diagnostics portfolio to identify and track patients 5. CAPTURE maximum u pside by partnering assets at optimal point in development

 

 

© 2019 AC Immune. Not to be used or reproduced without permission. 25 NASDAQ: ACIU | KOL Lunch | November 2019 Milestone highlights H1 2020 Identification of first NLPR3 - ASC inflammasome inhibitor with in vivo activity Semorinemab anti - Tau antibody Phase 2 primary completion estimated in prodromal/mild AD 1 ACI - 24 - DS 2 Phase 1b full study results and Phase 2 initiation ACI - 35.030 Phase 1b/2a in AD interim analysis of anti - pTau vaccine ( safety and immunogenicity) Mor - Tau Phase 1 MAD 3 readout Mor - a - syn PET tracer FiM 4 start (3rd gen) (1) Alzheimer’s disease; (2); Down syndrome; ( 3) Multiple Ascending Dose; (4) First - in - Man

 

 

© 2019 AC Immune. Not to be used or reproduced without permission. 26 NASDAQ: ACIU | KOL Lunch | November 2019 We continue to shape the future of neurodegeneration by discovering and developing breakthrough therapies through pioneering science and precision medicine AC Immune

 

 

Exhibit 99.2

 

 

© 2019 AC Immune. Not to be used or reproduced without permission. Tau Morphomer TM Therapeutics and ACI - 35 A nti - pTau Therapeutic V accine Marie Kosco - Vilbois, Ph.D , CSO AC Immune Version Nov 4

 

 

© 2019 AC Immune. Not to be used or reproduced without permission. NASDAQ: ACIU | KOL Lunch | November 2019 2 Disclaimer 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. Forward - looking statements are statements other than historical fact and may include statements that address future operating, financial or business performance or AC Immune’s strategies or expectations. In some cases, you can identify these statements by forward - looking words such as “may,” “might,” “will,” “should,” “expects,” “plans,” “anticipates,” “believes,” “estimates,” “predicts ,” “projects,” “potential,” “outlook” or “continue,” and other comparable terminology. Forward - looking statements are based on management’s current expectations and beliefs and involve significant risks and uncertainties that could cause actual results, developments and business decisions to differ materially from those contemplated by these statements. These risks and uncertainties include those described under the captions “Item 3. Key Information ‒ Risk Factors” and “Item 5. Operating and Financial Review and Prospects” in AC Immune’s Annual Report on Form 20 - F and other filings with the Securities and Exchange Commission. Forward - looking statements speak only as of the date they are made, and AC Immune does not undertake any obligation to update them in light of new information, future developments or otherwise, except as may be required under applicable law. All forward - looking statements are qualified in their entirety by this cautionary statement.

 

 

 

 

 

www.acimmune.com © 2019 AC Immune. Not to be used or reproduced without permission. ACI - 3024: Potential First in Class Small Molecule Tau Aggregation Inhibitor

 

 

© 2019 AC Immune. Not to be used or reproduced without permission. NASDAQ: ACIU | KOL Lunch | November 2019 4 Nucleus Nucleus Affected cell Healthy cell Recipient cell Misfolded proteins Normally folded proteins Reverse misfolding Promote disaggregation Prevent seeding Morphomer target Nucleus Morphomers TM address spreading hypothesis of misfolded Tau in neurodegenerative diseases Multiple points of potential intervention in the disease pathway Inhibit spreading ▪ Targeting both intracellular seeds and extracellular spreading would lead to control of Tau pathology progression ▪ Combined with our highly selective Tau imaging diagnostic, enables more precise patient characterization and potentially more precise prediction of AD 1 progression and successful clinical outcome ( 1) Alzheimer’s disease

 

 

© 2019 AC Immune. Not to be used or reproduced without permission. NASDAQ: ACIU | KOL Lunch | November 2019 5 ▪ Conformation - specific, non - peptidic , small molecules with drug like properties ▪ Protein propagation inhibitors ( Kroth et al . , 2012 ) ▪ Robust library contains > 7000 compounds with desirable properties including brain penetration ▪ Validated for selective binding to Abeta , Tau, alpha - synuclein and TDP - 43 ▪ Combination of library and medicinal chemistry program led to the discovery of ACI - 3024 Morphomer TM platform: discovery of ACI - 3024 Generation of conformation - specific small molecules

 

 

© 2019 AC Immune. Not to be used or reproduced without permission. NASDAQ: ACIU | KOL Lunch | November 2019 6 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 1 isoform mutants Target engagement ▪ Selective binding to aggregated Tau (25.1 nM ) ▪ No binding to monomeric forms of Tau ▪ Selective binding to AD 2 brain - derived pathological Tau (Ki 11.7nM) Cross - reactivity to Abeta and alpha - synuclein ▪ No binding to human brain - derived Abeta ▪ No binding to human brain - derived alpha - synuclein ▪ No binding to healthy brain tissue ( 1) Frontotemporal dementia with parkinsonism - 17; (2) Alzheimer’s disease

 

 

© 2019 AC Immune. Not to be used or reproduced without permission. NASDAQ: ACIU | KOL Lunch | November 2019 7 ACI - 3024: i n vitro pharmacology Ref.: Poli S, et al., CTAD 2018 Intracellular Tau misfolding in in vitro differentiated neuroblastoma cells expressing Tau P301L Undifferentiated cells Retinoic acid differentiated cells Bright field Misfolded Tau (MC - 1) Mean + SEM Dose - dependent reduction of misfolded Tau Dose - dependent reduction of intracellular pathological Tau ▪ In vitro treatment with ACI - 3024 led to a dose - dependent decrease of misfolded Tau at low nM concentrations

 

 

© 2019 AC Immune. Not to be used or reproduced without permission. NASDAQ: ACIU | KOL Lunch | November 2019 8 [3H] - ACI - 3024 [3H] - ACI - 3024 Cold ACI - 3024 High resolution autoradiography on human AD 1 brain sections Ex vivo disaggregation on Tau NFT 2 on human AD brain sections A CI - 3024: target engagement and functional selectivity Ref.: Poli S, et al., ADPD 2019 Mean + SEM ▪ ACI - 3024 specifically binds Tau NFTs and is able to disaggregate Tau NFTs from human AD brain sections even in presence of amyloid plaques (1) Alzheimer’s disease; (2) Neurofibrillary tangles; (3) Thioflavin S 3

 

 

© 2019 AC Immune. Not to be used or reproduced without permission. NASDAQ: ACIU | KOL Lunch | November 2019 9 ACI - 3024: in vivo evaluation in rTg4510 mice Treatment study in aged transgenic mice ▪ rTg4510 T auopathy mouse model expressing repressible (Tet promotor Tau on/off) human 4R0N Tau carrying the P301L mutation ( SantaCruz , 2005 ) Tauopathy model ▪ Independent experiments with different sources of rT g 4510 mouse colony ▪ 30mg/kg bi - daily (BID) dose randomized to vehicle starting at 5 months of age ▪ 10, 30 or 100 mg/kg BID dose randomized to vehicle starting at 5 months of age Protocol design ▪ Significant reduction in misfolded, hyper - phosphorylated and aggregated Tau at 30mg/kg; Proof of mechanism confirmed at 100 mg/kg BID in a follow up dose - response experiment Treatment results

 

 

© 2019 AC Immune. Not to be used or reproduced without permission. NASDAQ: ACIU | KOL Lunch | November 2019 10 Immunohistochemistry: analysis of misfolded Tau (MC1) in rTg4510 brain section Misfolded Tau levels in brain sections Representative staining (MC1 in red , DAPI in blue ) 50 µm Mean + SEM ANOVA * p< 0.05 ACI - 3024: decrease in misfolded Tau MC1 area fraction 0.00 0.01 0.02 0.03 0.04 Ref.: Poli S, et al., CTAD 2018 ▪ Treatment with ACI - 3024 significantly reduced misfolded Tau ▪ The decrease was proportional to the plasma exposure to ACI - 3024 Vehicle Vehicle - tTa ACI - 3024 50 µm 50 µm

 

 

© 2019 AC Immune. Not to be used or reproduced without permission. NASDAQ: ACIU | KOL Lunch | November 2019 11 Activation of microglial cells Inflammatory marker release from microglial cells Human AD - brain derived Tau activation of rat primary microglial cells ACI - 3024: e ffect on neuroinflammation Assessment of compound effect on Tau - induced microglial activation A D - b r a i n P H F P H F + A C I - 3 0 2 4 5 µ M M o n o m e r i c T a u M o n o m e r i c T a u + A C I - 3 0 2 4 5 µ M 0.00 0.05 0.10 0.15 0.20 0.25 C 1 q - O D 4 5 0 n m * A D - b r a i n P H F P H F + 3 0 2 4 2 . 5 µ M P H F + 3 0 2 4 5 µ M M o n o m e r i c T a u 0.00 0.02 0.04 0.06 C D 6 8 / I b a 1 ( % c o n f l u e n c e ) *** **** 0.00 0.02 0.04 0.06 CD68/lba1 (% confluence) 0.00 0.05 0.10 0.15 0.25 C1q – OD450nm 0.20 Ref.: Poli S, et a l., CTAD 2018 ▪ Treatment with ACI - 3024 significantly decreases microglial activation induced by human - derived Tau aggregates Mean + SEM ANOVA **** p< 0.0001 *** p< 0.001 * p< 0.05

 

 

© 2019 AC Immune. Not to be used or reproduced without permission. NASDAQ: ACIU | KOL Lunch | November 2019 12 • Active and selective in multiple in vitro pharmacology assays • Good selectivity as assessed on 138 targets ( Cerep Bioprint profile) In vitro on - and off - target activity • Good in vitro and in vivo ADME properties, including low clearance, long half - life and good CNS 3 disposition as assessed by brain and CSF concentrations ADME 2 • Low potential for drug - drug interaction in vitro (EC 50 on CYP > 25 uM) • No P - glycoprotein 4 interaction • Negative in in vitro genotoxicity assays (AMES 5 and MNT 6 ) and in the in vivo MLY 7 In vitro tox and drug - drug interaction • In vivo study showed compound related treatment effects by biochemistry and immunohistochemistry (brain, CSF 1 and microglia) In vivo studies • In 4 - week oral repeated - dose toxicity studies, NOAEL 8 established at 300 mg/kg in rodents and 450 mg/kg in non - rodents T oxicology in rodents and non rodents • ICH S 7 safety pharmacology battery successfully completed : cardiovascular telemetry study in non rodent ; respiratory and Irwin study in rodents Safety pharmacology • First - in - Human study initiated Q 3 2019 Clinical trial (1) Cerebral spinal fluid; (2) Absorption , distribution, metabolism, and elimination; (3) Central nervous system; (4) Permeability - glycoprotein; (5) Bacterial mutagenesis and carcinogenesis test; (6) Micronucleus test in human cell lines; (7) I n vivo mouse lymphoma; (8) No observed adverse event level ACI - 3024: summary of preclinical evaluation Nonclinical safety package for regulatory submission for first in human study

 

 

ACI - 3024: First in Human study

 

 

© 2019 AC Immune. Not to be used or reproduced without permission. NASDAQ: ACIU | KOL Lunch | November 2019 14 Escalation scheme SAD 1 (ongoing) Cohort 2 Dose 2 Cohort 3 Dose 3 Cohort 4 Dose 4 Cohort 5 Dose 5 Cohort 1 Dose 1 Dosing Dose Escalation Meeting: evaluate safety, tolerability, pharmakinetic data (up to 48 hours post - dose) Q3 - Q4 2019 (1) Single ascending dose

 

 

© 2019 AC Immune. Not to be used or reproduced without permission. NASDAQ: ACIU | KOL Lunch | November 2019 15 Escalation scheme MAD 1 (next) MAD - HV1 2 Dose 1 MAD - HV2 Dose 2 MAD - HV3 Dose 3 MAD - HV4 Dose 4 Dosing Dose Escalation Meeting: evaluate safety, tolerability, pharmacokinetics data (steady state) Q1 2020 (1) Multiple ascending dose; (2) Healthy volunteer

 

 

© 2019 AC Immune. Not to be used or reproduced without permission. NASDAQ: ACIU | KOL Lunch | November 2019 16 ▪ The Morphomer TM 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 safety and tolerability profile and has entered clinical development as a first in class, Tau - specific disease - modifying small molecular weight compound for the treatment of neurodegenerative diseases characterized by misfolded Tau 4 ▪ ACI - 3024 has shown effects on Tau pathology and downstream neuroinflammation and neurodegeneration in an aggressive animal model of Tau pathology ▪ Through a thorough medicinal chemistry program, ACI - 3024 was identified as lead candidate with optimal drug like properties suitable for clinical development ACI - 3024: selective Tau aggregation inhibitor Summary

 

 

© 2019 AC Immune. Not to be used or reproduced without permission. ACI - 35 1st and 2nd Generation Anti - pTau Vaccines

 

 

© 2019 AC Immune. Not to be used or reproduced without permission. NASDAQ: ACIU | KOL Lunch | November 2019 18 1 st generation vaccine: ACI - 35 structure Anti - pTau therapeutic vaccine Liposomal anchor (Palmitic chains) Liposomal bilayer (Cholesterol and phospholipids) Adjuvant ( MPLA) ACI - 35 is an active immunotherapeutic based on AC Immune’s proprietary SupraAntigen TM technology ▪ Peptide: Epitope Binding ▪ Human phospho - Tau synthetic peptide T3 as antigen (Tau 393 - 408 (pS396/pS404)) ▪ Linker : Conformation ▪ Palmitic chains anchor peptides to generate desired conformation ▪ Adjuvant : Immunogenicity ▪ Synthetic Monophosphoryl Lipid A (MPLA) Peptide ▪ Aim : to generate a T - cell independent anti - Tau antibody response

 

 

© 2019 AC Immune. Not to be used or reproduced without permission. NASDAQ: ACIU | KOL Lunch | November 2019 19 Key preclinical results ACI - 35: proof - of - concept **** p<0.0001; ANOVA Improvement of behavior (hTauP301S mice) Immune response specific to phosphorylated Tau ( pTau ) ACI - 35 vaccinated mice – anti - p Tau vs.Tau response after 5 immunizations 15 rpm ACI - R - 40 Rotarod 5M vehicle vs. ACI - 35 (1 ) tg , transgenic ; (2) wt , wild type; (3) PBS, phosphate - buffered saline ▪ Specific antibody response to phosphorylated Tau; improvement of behavior observed

 

 

© 2019 AC Immune. Not to be used or reproduced without permission. NASDAQ: ACIU | KOL Lunch | November 2019 20 ACI - 35: proof - of - concept * * PBS ACI - 35 AT - 100 Anti - pS396 * p <0.05 AC Immune, unpublished data Key preclinical results ▪ Specific antibody response to pathogenic Tau; Decrease of pT212/pS214 and pS396 Tau in the cortex

 

 

ACI - 35 Phase 1b study - overview of clinical d ata

 

 

© 2019 AC Immune. Not to be used or reproduced without permission. NASDAQ: ACIU | KOL Lunch | November 2019 22 Clinical study design ACI - 35 Phase 1 study in AD 1 Cohort 1 (Dose 1: ACI - 35 or placebo) Cohort 2 (Dose 2: ACI - 35 or placebo) Cohort 3 (Dose 2: ACI - 35 or placebo) Cohort 4 (Dose 3: ACI - 35 or placebo) Immunization with ACI - 35 ( n=4) (n=8) (n=4) (n=4) Cohort 5 (Dose 3: ACI - 35 or placebo) (n=4) ▪ Ratio of 3:1 active (ACI - 35) versus placebo per cohort ▪ Primary readouts: Safety , tolerability and induction of IgG titers against pTau in serum (1 ) Alzheimer’s disease

 

 

© 2019 AC Immune. Not to be used or reproduced without permission. NASDAQ: ACIU | KOL Lunch | November 2019 23 Responder analysis ( MSD 1 assay in serum) Immunogenicity results ▪ Essentially all actively treated patients were anti - pTau responders ▪ No anti - pTau response observed with placebo ▪ Early target - specific antibody response against pTau observed after the first injection in the vast majority of patients (1 ) Meso Scale Discovery technology

 

 

© 2019 AC Immune. Not to be used or reproduced without permission. NASDAQ: ACIU | KOL Lunch | November 2019 24 Safety results ▪ Injection site reactions and fatigue were the most common study adverse events ▪ Except for injection site reactions, no pattern of adverse events (AE) compared to placebo suggested a relationship to study medication ▪ Injection site reactions were generally mild and self - limiting, and more frequent at higher doses

 

 

© 2019 AC Immune. Not to be used or reproduced without permission. NASDAQ: ACIU | KOL Lunch | November 2019 25 ACI - 35: Phase 1b study in AD patients Key clinical observations ▪ Safe at all doses tested ▪ Early target - specific antibody response against pTau after the first injection in the vast majority of patients ▪ Study not powered to assess changes in clinical or cognitive parameters

 

 

© 2019 AC Immune. Not to be used or reproduced without permission. NASDAQ: ACIU | KOL Lunch | November 2019 26 2 nd generation vaccine: ACI - 35.030 structure Anti - pTau optimized therapeutic vaccine and ▪ Aim: An optimized liposomal vaccine comprising a tau peptide and a T cell epitope capable of binding to HLA - DR 1 molecules Adjuvant 1 Adjuvant 2 pTau peptide T cell epitope (1 ) Human leukocyte antigen - major histocompatibility complex, class II

 

 

© 2019 AC Immune. Not to be used or reproduced without permission. NASDAQ: ACIU | KOL Lunch | November 2019 27 pTau-specific IgG titers -14 8 22 36 50 64 78 92106120134148162176190 10 100 1000 10000 100000 1000000 Time (days) E n d p o i n t t i t e r ACI-35.030 ACI-35 ACI - 35.030: r ationale pTau - specific IgG titers in immunized rhesus monkeys Geometric mean of n=4 (ACI - 35) or n=6 (ACI - 35.030) monkeys ▪ Increased level of pTau - specific IgG titers induced by ACI - 35.030 as compared to ACI - 35 Vaccine administration

 

 

© 2019 AC Immune. Not to be used or reproduced without permission. NASDAQ: ACIU | KOL Lunch | November 2019 28 ACI - 35.030: r esults from rhesus immunization B inding to Tau from human AD 1 brain Healthy brain tissue AD Braak Stage V/VI ▪ Sera from rhesus monkeys immunized with ACI - 35.030 binds to pathological Tau in brain sections with AD as compared to healthy human brain tissue (1 ) Alzheimer’s disease

 

 

© 2019 AC Immune. Not to be used or reproduced without permission. NASDAQ: ACIU | KOL Lunch | November 2019 29 ACI - 35.030 non - clinical studies Key learnings ▪ Demonstrates an excellent nonclinical safety profile ▪ Produces an enhanced homogeneous antibody response with boosting effect ▪ No Tau - specific T - cell response observed

 

 

ACI - 35.030: Phase 1b/2a study

 

 

© 2019 AC Immune. Not to be used or reproduced without permission. NASDAQ: ACIU | KOL Lunch | November 2019 31 ACI - 35.030 Phase 1b/2a study in AD 1 ▪ A randomized, multicenter, double - blind, placebo - controlled clinical study ▪ Ratio of 3:1 active (ACI - 35.030) versus placebo per cohort ▪ Primary readouts: safety, tolerability and immunogenicity of different doses of ACI - 35.030 in treated AD patients ▪ First patient in: Q3 2019 (1 ) Alzheimer’s disease

 

 

© 2019 AC Immune. Not to be used or reproduced without permission. NASDAQ: ACIU | KOL Lunch | November 2019 32 AC Immune: pioneers in anti - Abeta 1 and anti - Tau vaccines 2008 ACI - 24 - 0701 study Dose escalation in mild to moderate AD 2 2013 ACI - 35 - 1201 study Dose escalation and exploration of dose regimen in mild to moderate AD 2016 ACI - 24 - 1301 study Dose escalation in Down syndrome Phase 1/2 Phase 1 Phase 1b 2018 ACI - 24 - 1801 study Single dose, adaptive study design in mild AD 2019 ACI - 35 - 1802 study Evaluate different doses, regimens of Tau targeted vaccines Phase 2 Phase 1b/2a ACI - 35.030 clinical trial: first patient dosed Q3 2019 (1 ) ACI - 24; (2) Alzheimer’s disease