EFTA00799222.pdf

• • • • • • • • • • • • • • • • • • • • Dementia Discovery • • • • • • • • • . • • • • • • • • • • • • • • . • • • • Fund • • • April 2017 Dementia Discovery Fund Update and scientific deep-dive with Bill Gates Kate Bingham, Managing Partner +44 20 7421 7058, [email protected] Tetsuyuki Maruyama, Chief Scientific Officer, DDF +44 20 7421 7095, [email protected] Laurence Barker, Chief Business Officer, DDF +44 20 7421 7094, [email protected] This document has been issued in the UK by SV Life Sciences Managers LLP (authorised and regulated by the Financial Conduct Authority). and may only be distributed to persons falling within the definition of authorised persons. investment professionals or high net worth bodies as defined in the SV Life Sciences Financial Services 8 Markets Act 2000. Further disclosure at the end of the document. EFTA00799222  •••• •••• • Dementia • : Discovery •• • Fund Compliance disclaimer • • • • This document is issued for information purposes only by SV Life Sciences Managers LLP ('SV') who is authorised and regulated by the Financial Conduct Authority ("FCA"). It does not constitute an offer by SV to enter into any contract/agreement nor is it a solicitation to buy, sell, hold or subscribe for any investment. Nothing in this document should be deemed to constitute the provision of financial, investment or other professional advice in any way. The contents of this document are based upon sources of information believed to be reliable, however, save to the extent required by applicable law or regulations, no guarantee, warranty or representation (express of implied) is given as to its accuracy or completeness and SV, its members, officers and employees of the managing member do not accept any liability or responsibility in respect of the information or any views expressed herein. 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All rights reserved. • • 2 • • • a a a a a EFTA00799223  .•.• ... •• • Dementia Discovery :•:•: •• •• Fund Agenda • DDF update • Portfolio overview • Scientific deep dive into current prioritised areas of scientific focus for DDF 1) Microglia, the role of glia in synaptic health, lead by Professor Beth Stevens 2) Mitochondrial dynamics and their role in dementia, lead by Professor Dania Mochly-Rosen • DDF summary • • • • • • 3 • a A\ a a a EFTA00799224  •:•: . • Dementia Discovery : Fund Global burden of dementia • By 2030, there will be 75 million people with Alzheimer's disease globally, costing $2 trillion • No drugs that have any effect on the course of diseases of dementia have been developed yet • To discover disease-modifying new drugs, we need different approaches to those tried historically • The DDF is committed to investing in new biological approaches (outside amyloid to develop a range of safe, clinically effective drugs which can prevent or slow down the course of dementia o Taking a long-term approach to funding new approaches to treat dementia o Supporting start-ups considered too risky by regular venture capital firms The market for dementia drugs is massive and finding a way to open it up is an investment opportunity worth getting right • 4 • • • . a EFTA00799225  .• . • :'•: • Dementia Discovery Fund Dementia Discovery Fund: Update • Dementia represents a massive unmet medical need with huge associated costs of care • Launched in October 2015 as a result of the G8 Summit and World Dementia Council meetings, the DDF is the world's first dementia-focused venture capital fund - the first time charity, government and pharma have joined forces with a venture firm on this scale • Our vision is to demonstrate compelling disease-modifying clinical efficacy and safety data for 2-3 novel drugs in dementia patients by 2025, and expanded dramatically the range of treatment options in drug discovery and development • We have privileged access to global CNS pharma experts through our Scientific Advisory Board • Provide advice, share knowledge and offer insights on different approaches and historical failures • The pharma companies have no commercial or decision making rights though they will be well positioned to acquire/license DDF-developed drugs/companies in due course • DDF has raised -£100M to date from strategic investors, and Woodford Investment Management (to close in April). DDF is now seeking an additional £130M to reach its target I ttheimer's Research UK Department of Health Biogen Tam A95tS2c. de Olsuka • • • • • • 5 . a a •1 EFTA00799226  :••: • Dementia • Discovery • Fund A roundabout, not a cascade • 004.4•MMTLY MortPIM HON -DOMINANT DDF perspective on dementia pathogenesis (The Magic Roundabout): FORMS OF SO FORMS Of AD Mlomaso mulation•In •• u. F . oaff down* or pr••••••• I ow 2 gems ammlonSim lofty A OeMa01 eXI 1•0••••0 tv•atsv• Ondoraft Site ADC pOduction IMdglqul SC S.•••InIle braes * * Pafonflehon OM 4_.._ M. Cl 542 of Into and ancoaloo coMOM * WS ~is a AD *PM" Fa FM.M•C Mof•Of 4. Gadd dapMilon of /042 *cows atlas plaSS * (I\ MbOgMl OW IMMCMIC MONIIO1Ind lilloodint Iresomatry •••••••• * Mewlrenal kat liam•S cod•O*FloY * MOW lismoS Otthitile Ns to Lif•Mm * Oic••••••1folt•Orfel/loombeemfuceon DOI ••••••• ofoonsl im• SO •IWO•now000nollo *hots The amyloid cascade hypothesis at 25 years. • Selkoe and Hardy. EMBO 2016 • • • • • • • 6 • a a la EFTA00799227  Dementia Discovery :. : : Fund DDF scientific strategy • We have prioritized four key scientific areas initially, supported by human genetic and pathological data for near term, proactive investment, whilst remaining open to compelling opportunities outside of these key areas: Microglial Mitochondrial biology & dynamics inflammation Trafficking and Synaptic membrane physiology & biology function Opportunistic • 7 • • • ▪ a EFTA00799228  Dementia Discovery : Fund DDF investments map on to scientific strategy • DDF investments range from DDF-led research projects to investments in established companies • Current and near future (---) investments are shown: Microglial biology & inflammation: Mitochondrial dynamics: Neuroinflammation Rheo ALECTOR Project stat Mitoconix ATIAK1TIttRAPUITIES Synaptic physiology & function: Trafficking and Scholar Rock \\X/X\\ TGFI3 Project membrane biology: q!-1:499Y Membrane Contact Sites Project cereVance Opportunistic: Parkinson's Dementia DDF ChemCo geri Target Project • • 8 • • • • • EFTA00799229  Dementia Discovery : Fund DDF Investment Criteria Disease modifying impact • We invest in drug discovery opportunities that have the potential to prevent or slow the course of dementia Scientific opportunity • We invest in biological mechanisms that have already demonstrated clinical impact in diseases outside dementia, as well as new mechanisms which can be proven in stratified patient groups Filling the gaps • We invest in targets and mechanisms too early for pharma and too high risk for most venture funds • We deploy long-term and flexible capital to fund key scientific milestones that overcome critical hurdles in the development of dementia therapies by working with our world-class, global network of experts Leveraging DDF investments • We invest in projects and companies with potential to attract funds from sources beyond the DDF and its investors • • • • • • • 9 a da a a Ilk EFTA00799230  . •. • • • Dementia • : Discovery :.•: : Fund Agenda • DDF update • Portfolio overview • Scientific deep dive into current prioritised areas of scientific focus for DDF 1) Microglia, the role of glia in synaptic health, lead by Professor Beth Stevens 2) Mitochondrial dynamics and their role in dementia, lead by Professor Daria Mochly-Rosen • DDF summary • 10 • • • • . . • . EFTA00799231 Microglia Contribute to Cognitive Function and Dysfunction • A-40, iv7 New Insighti Into Novel • Biomarkers and Therapies Beth Stevens EFTA00799232  Established Roles of Microglia: Both Harm and Protect the Brain 1. Neuroinflammation 2. Clear pathogens and debris 3. Remove toxic proteins EFTA00799233 Activated Microglia Surround Plaques in Alzheimer's Disease Brain EFTA00799234 Microglia Have Many Roles in AD and Other NDDs Disease When Do Microglia Become Dysfunctional? Do Microglia Contribute to Synaptic and Cognitive Impairment? How? EFTA00799235 Microglia Have Many Roles in Neurodegenerative Disease Understanding Microglia Biology and Specific Mechanism is Critical Inflammation Healthy neuron Homeostatic Excessive microglia synaptic pruning • Surveillance, monitonng • Synaptic pruning. refinement • Synaptic plasticity A13 clearance Debris clearance 0 Protective I -Good" Amyloid (-9 Aberrant / "Bad" plaque EFTA00799236 EFTA00799237 Microglia: CX3CR1-EGFP Mouse EFTA00799238  In Vivo Imaging: Mouse Cerebellum Microglia: CX3CR1-EGFP 1,,,,,,11,../1A EFTA00799239  IF S+4P -;r Davalos et al., Nature Neurosci. 200-5) EFTA00799240 EFTA00799241 Schafer et al. Neuron 2012 EFTA00799242 Synapse Loss: The Strongest Correlate of Cognitive Decline Clinical Disease Stage Sperling et al., 2011 EFTA00799243  How are CNS Synapses Eliminated ? oiigodenerocyte Neuron EFTA00799244 Immune System: Complement Proteins are 'Eat me' signals that Tag Apoptotic cells and Bacteria for Rapid Elimination The Classical Complement Cascade EFTA00799245  Brain: Complement Proteins Tag Synapses for Elimination by Microglia The Classical Complement Cascade microbe, debris, etc. C1q PSD95 C3 convertase it lk Phagocytosis Lysis &Membrane Attack Complex IB M EFTA00799246  Microglial-Mediated Pruning Dependent on Complement Signaling Schafer et al., Neuron 2012 Stevens et al., Cell 2007 _JAcroglia Mic Al* • C3 C4 C2 C1q EFTA00799247  Are Developmental Mechanisms of Synapse Pruning Aberrantly Reactivated in AD? Immature astrocyte Reactive astrocyte I -1934, TG93‘ ‘ 1 ., C3b tQ C3 _,) Immature microglia Reactive microglia Mature microglia EFTA00799248 Development/Plasticity/Repair J J Neuroscience (2013) A Dramatic Increase of Clq Protein in the CNS during Normal Aging Alexander H. Stephan,' Daniel V. Madison,2 Jose Maria Mateos,3 Deborah A. Fraser,' Emilie A. Lovelett,' Laurence Coutellier,5 Leo Kim,5 Hui-Hsin Tsai,6.2,8 Eric J. Huang,9 David H. Rowitch,6.2)3 Dominic S. Berns,' Andrea J. Termer,' Mehrdad Shamloo,5 and Ben A. Barres' EFTA00799249  Do Microglia Contribute to Synapse Loss and Cognitive Dysfunction in AD ? 1. AD Models: - J20 APP Dennis Selkoe - APP/PS1 Cynthia Lemere - Acute oAti Model Soyon Hong 2. Human AD Brain - AD Brain Brad Hyman, Tara Spires - CSF Lee; John Trojanowsky C. Haass EFTA00799250 Early, Region Specific Loss of Synapses in AD Models Hippocampus of 3 month J20 Mice Synaptophysin PSD95 co 150— Dentate Gyrus WT ** o_ El J20 + 100- .(% _c a_ 50- cr) 0 a_ N=3 per genotype 1* 0 "*P <0.01 for CA1 by Bonferroni CA1 CA3 DG post-test EFTA00799251 Early, Region-Specific Upregulation of Complement Cl q As early as 1 month in Regions Vulnerable to AP Deposition *** 150 Ea VVT u) ; a) = J20 > a) * * * II 100— .. .• (7) C a) c 50- 0- Z3 0 DG ........„1 STR ORM% CRB INT= ***P<0.0001 by 2-way ANOVA for genotype and region "P<0.001 by Bonferroni posttest EFTA00799252  Early Increased Deposition to PSD95+ Synapse in Hippocampus of AD Mice 400 S, 300 200 (,?, 100 EFTA00799253 Does Inhibition of Microglia- Synaptic Pruning Rescue Synapse Loss and Cognitive Decline? Measure: 1) Synapse Loss 2) Microglia Activation and Synaptic Eating 3) Memory and Cognitive tests EFTA00799254  C3 Deficiency Protects Against Synapse Loss in APP/PS1 Mice (4 m and 16 m) APP/PS1xC3 KO Synaptophysin + PSD95 Co-Localized Puncta in CM 150- NS Synaptophysin PSD95 WT APP,PS1APPIPS1 CAO ,C3k0 EFTA00799255 C3-deficiency resulted in improved spatial and contextual memory performance in AD mice Despite Enhanced Plaque Load APP/PS I A P P/PS I ;C:3 1(0 C. C WT 0 APP/PS1 * et ■ M ■ APP/PS1;C3 KO ?.3 ■ C3 KO •II% v. tte: ' 44- • •> 100 cc .c u 50 C cr) to C cc -C E. ct, 0.4 %.• Using Water T-Maze C Reversal Learning Paradigm cL. 5 Ts E•0.2 0- 0.1 0.0 APP/PSI A PP/PSI ;(13 KO EFTA00799256 Do Microglia Aberrantly Prune Synapses in AD Models ? EFTA00799257  In Vivo Model of Acute Synapse Loss WT mice Is Synapse Loss Rescued in the Absence of Complement? EFTA00799258 C1q : Necessary for Al3-Induced Synapse Loss In Vivo Model of Acute Synapse Loss WT mic Synapsin + PSD95 Colocalized Puncta I 200-i Also see similar protection using Cl blocking antibody EFTA00799259  A13 Oligomers Induce Microglia to Engulf Synaptic Elements Homer-GFP xz lbal i Homer-GFP EFTA00799260 Blocking Microglial Engulfment Protects Synapses Synaptotagmin + Homer Colocalized Puncta 150- 150- l= PBS cV,S ns oAs Microglia X ch 100- 100- CR3 50- 50- 0 0 CR3 VVT CR3 KO EFTA00799261 New Role of Microglia in Synaptic Pathology EFTA00799262  Complement- Synapse Elimination Pathways as Novel Therapeutics ? • Complement inhibitors and blocking antibodies • Microglial phagocytic receptors • Early Biomarkers? Broader Relevance for Other CNS Disorders? EFTA00799263  A Common Mechanism of Synapse Loss and Cognitive Dysfunction? Reactive astrocyte Alzheimer's Disease Glaucoma Howell et al JCI 2011; Stevens et al.,2007) FTD West Nile Virus Models Huntington's Disease (DAN WILTON; UNPUBLISHED) EFTA00799264  How to Translate to Human Disease? :. . e .' , . . • •. b a t 1. Synapse-Associated Complement in Human AD 4 s. .• Tissue? •• . 4 O. e. • - .'.. Super-resouon l ti Array T Tomography and SIM .• . . ... • * . . . . • • . • .,. • • 0 . . •I• , . ' • • - • • • 2. Biomarker Potential? " * • MCl/AD CSF (sporadic) . • • • • .It.• .. with Christian Hvss (DZNE Germany . , •• • * .16 • • • .• • : „ 1• • • "41.4 . Cure • qt. • Alzheimer', IP • - . C1q FIA,vrinr lb 1 ft * . • FUND • •••• q4 EFTA00799265  Microglia as Potential Biomarkers of Neuroinflammation and Dementia TSPO Ligands (PK- 11195) Development of Novel Huntington's Disease Healthy adult Microglia PET ligands • Specific for Microglia • Increased Early in Disease • Biomarker of Synaptic and Cognitive Dysfunction EFTA00799266  Stevens Lab • e Collaborators *AA er• • a 41t • Victoria Beja-Glasser J. • 441F.Ni Unwana Abasi d • EFTA00799267  THANK YOU! Cure '4, National Institute of / Neurological Disorders and Stroke Alzheimer' iDSZ,Z;:,::S of Hc-,a;:r, FUND MID ) National Institute t o/A ••• * 4,1 on Aging C.A.R.T. 4fr(4kcoo.t oins for Alzheimer's Research Tru vvoini eine !Very CI* in %Ana 14 41. 1.'141 as Cure AD Fund Merck Scholars Program Ellison Foundation Dana Foundation Smith Family Foundation EFTA00799268  Dementia Discovery Agenda •.•: : Fund :.•• • DDF update • Portfolio overview • Scientific deep dive into current prioritised areas of scientific focus for DDF 1) Microglia, the role of glia in synaptic health, lead by Professor Beth Stevens 2) Mitochondrial dynamics and their role in dementia, lead by Professor Daria Mochly-Rosen • DDF summary • 48 • • • • • EFTA00799269 Treating Neurodegeneration and Dementia by Improving Mitochondrial HCaILII Nerve cell mitochondrion Darla Mochly-Rosen Professor, Chemical and Systems Biology Stanford University, School of Medicine Founder and Director of SPARK at Stanford President of SPARK Global [email protected] SPARKmed.Stanford.edu Conflict of interest: Inventor of patents related to the talk Founder of Mitoconix, September 2016 STANFORD UNIVERSIT1Y EFTA00799270  Treating Neurodegeneration and Dementia by Improving Mitochondrial Health Inactivity period 150 n=12 • 100 , 50 0 C drug C drug HD control mice More functional mitochondria = more ATP = more repair = more neurons = better behavior http://info.noldus.comitopic/rats Observer was blinded to the experimental conditions Guo et al., J Clin Invest. 2013; 123:5371-5388 EFTA00799271 What are mitochondria? What do they do? • Power producers, ATP ROS • Polluters; free radicals (ROS) . 0 r ATP • Detoxifiers (aldehydes) C (Fp./ • Building blocks producers (neurotransmitters) • Coordinators of apoptosis http://www.immortalhumans.com/wp- content/uploads/feat_mitochondria_diag_zoom.jpg (program cell death) EFTA00799272 Why focus on mitochondria health for dementia treatment? The brain: • 2% of the body mass (1.5kG) • Consumes of - 20% of the oxygen • Uses 25% of the body's glucose to generate ATP • Uses —4.7