• April 2017 • • •

• • • • • • • • April 2017 • • • • • • • • • • • • • • • • •• • • • • • • • . • • • • • • • • • • • • • • • • • . Dementia Discovery Fund 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 Financial Services 8 Markets Act 2000. Further disclosure at the end of the document. SV Life Sciences 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. 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All rights reserved. 2 • • • • • a a a a a EFTA00799223 Agenda .•.• . . . •• • Dementia Discovery : •• • 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 Dania Mochly-Rosen • DDF summary 3 • • • • ••• a A\ a a a EFTA00799224 Global burden of dementia •:•: . • Dementia Discovery : Fund • 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: Update • • . . :'•: • Dementia Discovery Fund • 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 Ittheimer's Research Department UK of Health Biogen A95tS2c.Tam de Olsuka 5 • • • • • • . a a •1 EFTA00799226 A roundabout, not a cascade :••: • Dementia • Discovery Fund • • 004.4•MMTLY Mort PIM FORMS OF SO HON -DOMINANT FORMS Of AD Mlomaso mulation• In •• u. F. oaff down* or pr••••••• I ow 2 gems 1•0••••0 tv•atsv• ADC pOduction IMdglqul ammlonSim lofty A OeMa01 eXI Ondoraft Site SC S.••• In Ile 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 MONIIO1 Ind lilloodint Iresomatry •••••••• * Mewl renal kat liam•S cod•O*FloY * MOW lismoS Otthitile Ns to Lif•Mm * Oic••••••1 folt•Orfel/loombeemfuceon DOI ••••••• ofoonsl im• SO •IWO•now000nollo *hots The amyloid cascade hypothesis at 25 years. Selkoe and Hardy. EMBO 2016 DDF perspective on dementia pathogenesis (The Magic Roundabout): 6 • • • • • • • • • a a la EFTA00799227 DDF scientific strategy Dementia Discovery :.: : Fund • 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 membrane biology Opportunistic Synaptic physiology & function 7 • • ▪ a • • EFTA00799228 DDF investments map on to scientific strategy Dementia Discovery : Fund • DDF investments range from DDF-led research projects to investments in established companies • Current and near future (---) investments are shown: Microglial biology & inflammation: ALECTOR Neuroinflammation Project ATIAK1 TIttRAPUITIES Trafficking and membrane biology: Membrane Contact Sites Project Opportunistic: DDF ChemCo Mitochondrial dynamics: Rheo stat Mitoconix Synaptic physiology & function: Scholar Rock TGFI3 Project \\X/X\\ q!-1:499Y cereVa nce Parkinson's Dementia g e ri Target Project 8 • • • • • • • EFTA00799229 DDF Investment Criteria Dementia Discovery : Fund 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 Agenda • • . . • • Dementia • : Discovery :.•: : 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 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 microglia • Surveillance, monitonng • Synaptic pruning. refinement • Synaptic plasticity 0 Protective I -Good" (-9 Aberrant / "Bad" Amyloid plaque Excessive synaptic pruning A13 clearance Debris clearance 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. C 1 q PSD95 C3 convertase it lk Phagocytosis Lysis &Membrane IBM ComplexAttack EFTA00799246 Microglial-Mediated Pruning Dependent on Complement Signaling Schafer et al., Neuron 2012 Stevens et al., Cell 2007 C2 C1q _JAcroglia Mic Al* • C3 C4 EFTA00799247 Are Developmental Mechanisms of Synapse Pruning Aberrantly Reactivated in AD? Immature astrocyte TG93‘ I C3b tQ C3 _,) Immature microglia Mature microglia Reactive astrocyte -1934, ‘1., Reactive 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 - APP/PS1 - Acute oAti Model 2. Human AD Brain - AD Brain - CSF Dennis Selkoe Cynthia Lemere Brad Hyman, Tara Spires Lee; John Trojanowsky C. Haass Soyon Hong EFTA00799250 Early, Region Specific Loss of Synapses in AD Models Hippocampus of 3 month J20 Mice Synaptophysin PSD95 Dentate Gyrus co 150— o_ + 100-.(% _c a_ 50-cr) 0 a_ 1* 0 ** CA1 CA3 DG WT El J20 N=3 per genotype "*P <0.01 for CA1 by Bonferroni post-test EFTA00799251 Early, Region-Specific Upregulation of Complement Cl q As early as 1 month in Regions Vulnerable to AP Deposition 150 u) a) > a) 100— ...• (7) C a) c 50- 0- Z3 0 * * * ; DG *** II ........„1 ORM% INT= STR CRB Ea VVT = J20 ***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) Synaptophysin + PSD95 Co-Localized Puncta in CM 150- NS WT APP,PS1APPIPS1 CAO ,C3k0 APP/PS1xC3 KO Synaptophysin PSD95 EFTA00799255 C3-deficiency resulted in improved spatial and contextual memory performance in AD mice Despite Enhanced Plaque Load C 0 et M ?.3 > • 100 cc .c u 50to cc -C %.• ■ ■ ■ WT APP/PS1 APP/PS1;C3 KO C3 KO Using Water T-Maze Reversal Learning Paradigm C. cr) CC v. tte: ' 44- • • II% APP/PS I A P P/PS I ;C:3 1(0 * E. ct, 0.4 C Ts 5 cL. 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 I Synapsin + PSD95 Colocalized Puncta 200-i Also see similar protection using Cl blocking antibody EFTA00799259 A13 Oligomers Induce Microglia to Engulf Synaptic Elements xz i Homer-GFP lbal Homer-GFP EFTA00799260 Blocking Microglial Engulfment Protects Synapses cV,S Microglia CR3 Synaptotagmin + Homer Colocalized Puncta 150- 150- l= PBS ns oAs X100- 100- ch 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 . .' T til Super-resouon Array Tomography and SIM ......• . . • * . . . . • .,. • • . •I•, . • • . 0 . •' - • • •• 2. Biomarker Potential? " * • • It. . • • • . • .. . , : . e .' , . . • • . . b a 1. Synapse-Associated Complement in Human AD 4 s.t .• Tissue? •• . 4 O. • - MCl/AD CSF (sporadic) with Christian Hvss (DZNE Germany •• • * .16 • • • .• • : „ 1 • • • "41.4 . -.C1q FIA,vrinr lb 1 ft* IP • • qt. • . • • •••• q4 Cure Alzheimer', FUND EFTA00799265 Microglia as Potential Biomarkers of Neuroinflammation and Dementia TSPO Ligands (PK- 11195) Huntington's Disease Healthy adult Development of Novel Microglia PET ligands • Specific for Microglia • Increased Early in Disease • Biomarker of Synaptic and Cognitive Dysfunction EFTA00799266 Stevens Lab J. • • e *AA er• a Victoria Beja-Glasser 441F.Ni Unwana Abasi d • • Collaborators • 41t EFTA00799267 THANK YOU! to/A 4fr(4kcoo.tCure Alzheimer' FUND ••• * 4,1 C.A.R.T.oins for Alzheimer's Research Tru vvoini eine !Very CI* in %Ana 14 '4, National Institute of / Neurological Disorders and Stroke iDSZ,Z;:,::S of Hc-,a;:r, )MID National Institute on Aging 41. 1.'141 Cure AD Fund Merck Scholars Program Ellison Foundation Dana Foundation Smith Family Foundation as EFTA00799268 Agenda Dementia Discovery :.•• : 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? ROS . 0 r ATP C (Fp./ http://www.immortalhumans.com/wp- content/uploads/feat_mitochondria_diag_zoom.jpg • Power producers, ATP • Polluters; free radicals (ROS) • Detoxifiers (aldehydes) • Building blocks producers (neurotransmitters) • Coordinators of apoptosis (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 billion ATP molecules per second • Richest in mitochondria — highest ROS producer.. Healthy mitochondria = healthier neurons EFTA00799273 Mitochondria are dynamic organelles Fison Fusion Chen et al (2003) J Cell Biol 160, 189-200. EFTA00799274 Excessive mitochondrial fragmentation is observed in several neurodegenerative diseases e.g., Huntington's disease (HD) models and in patients derived cells: mouse neurons Control HD a X.. JCI. 2013 r' HD mouse brain WT HD Song W, et al., Nature Medicine 2011 EFTA00799275 Excessive mitochondrial fragmentation also in fibroblasts from patients with AD, ALS and PD APOE mut AD Sporadic AD Joshi, in preparation LRRK G2019S PD .44% ef.:Vcs" .4e 7 EFTA00799276 What regulates mitochondrial fragmentation? Dynamin-related protein 1 (Drp1) and its partner, Fis1 M itochonciria or gib Fisl Mitochondria' fission Neurodegeneration Mitochondria' fragmentation and damage f. • AVAIL'. Mitochondria] dynamics tGTPase EFTA00799277 Can excessive mitochondrial fission be inhibited? Mitochondria % Fisl Mitochondrial fission tGTPase Neurodegeneration Mitochondrial fragmentation and damage " ....... ..... ........ T , ........ Rational design identifies a specific protein-protein (PPI) interaction inhibitor of Fisl/Drpl interaction P110 Peptide PPI P110 DLLPRGT 7 amino acids TAT47.57 P110 DRP1 Qi et al., JCS, 126, 789-802, 2013 9 EFTA00799278 P110 reduces mitochondrial fragmentation in neurons derived from HD patients HD patient 4693 Tom20 Enlarge. HD patient 4693 + P110 Drp1 P110: 1 uM/per day for 3 days treatment Guo et al., .1 Clin Invest. 2013; 123:5371-5388 EFTA00799279 P110 treatment corrected mitochondrial dysfunction in neurons derived from HD patients Mitochondrial integrity 0 120 100. 0 880 - Mcc 60 -2 e. 40- c 20-m 0 Con Mitochondrial ROS 13 2500 a> 2000 o 1500 O g E 1000 ae ▪ 500 O P110 110 100 • 90 ae r, • 80 <I— 70 a ;ral 60 Con ATP 1 1 P11.0 HD iPS cell-derived neurons P110: 1µM/per day for 5 days Guo et al., J Clin Invest. 2013; 123:5371-5388 11 EFTA00799280 And in vivo — does P110 treatment improve behavioral deficit in HD mouse model? R6/2 HD Tg mice 41120 1Motor and cognitive activities 5 weeks P110 or TAT 12 weeks EFTA00799281 P110 treatment increases mitochondrial function in HD mice Oxygen consumption n=7 I HD mice control mice More functional mitochondria = more ATP Guo et al, I Clin Invest 2013 EFTA00799282 Sustained treatment with P110 increases number of dopaminergic neurons in HD mice HD mice Control P110 -5, 120 100 gz. 8° E e ("4 td cL 40 CC 20 i 1P110 C P110 contro HD More functional mitochondria = more ATP = more repair = more neurons Guo. J Clin Invest 123:5371,2013 EFTA00799283 P110 improves motor activity of HD mice Inactivity period Rearing activity 150 n=12 0 C P110 C P110 HD control mice 100_n=12 80 re 60 rn40 20 C P110 C P110 HO control mice More functional mitochondria = more ATP = more repair = more neurons = better behavior Observer was blinded to the experimental conditions http://info.noldus.com/topic/rats Guo et al., J Clin Invest. 2013; 123:5371-5388 15 EFTA00799284 Sustained treatment with P110 increases survival of HD mice (data from four independent studies) More functional mitochondria = more ATP = more repair = more neurons = better behavior = longer life EFTA00799285 Benefit of P110 in other neurodegenerative diseases Parkinson's disease control Control Parkinson's diseases P110 EFTA00799286 And in sporadic & familial AD patient fibroblasts; P11( corrects excessive mitochondrial fission in Healthy Subject Control Control APOE mut AD Patient „. .f.,4:•40)1g Sporadic AD Patient • 4. Control Amit Joshi, in preparation 1,311O • -.9c • P110 7‘". • 1"0" .14,1LL 0 '110 P110 110 72 4, Endpoint n=3 in duplicate 120 cells per condition EFTA00799287 And in ALS patient fibroblasts corrects excessive mitochondrial fission ALS Fl ALS F2 ALS F3 7, • n=3 in duplicate 120 cells/ condition Amit Joshi, in preparation EFTA00799288 P110 inhibits neuroinflammation, in vivo e.g., Huntington's disease GFAP -3 vehicle GFAP .......,,_ ......... ..."."-\\- ... \ • • P110 CD1lb vehicle CD1lb P110 IL- 6 Levels „3000- *** ** 12000- 31000. iftri 1"7" - P110 - P110 WT HD mice 20 EFTA00799289 Marie-Helene Amit Joshi Disatnik P110 may benefit patients with a number of neurodegenerative and ischemic diseases including Parkinson's and Huntington's Disease •:-7 --__- -----: 4.ril Xin Qi (Case Western) VI conix EFTA00799290 Sustained treatment with P110 for 5 month is safe; it may reduce aging-induced dysfunctions in normal mice Moving (seconds) 00:9 600, 0.01 400 5 o o '2200 Cont p110 Cont p110 009 164 days 178 days 10000 -g 8000 0 E -- 6000 4000 A 2000 0 Distance moved 0 02 Cont P110 Cont P110 164 days 178 days 22 Amit Joshi, in preparation EFTA00799291 Agenda Dementia Discovery 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 71 • • • • • • . • . EFTA00799292 .•.• . . • . • Dementia • : Discovery First year DDF performance ::•: : Fund Investments • 12 investments to date exploring novel mechanisms across all key themes • 14% of current capital committed (invested, committed and reserved is £47m (48%) • DDF investments leveraged with other investors' and grant funding Deal flow • Proactive translation of novel biology using targeted project-based funding in addition to investments in emerging companies • Sourcing science and academic relationships in UK, US and Israel to date DDF team • Core DDF team supported by EIRs and world-class consultants in London and Boston • Streamlined, rapid communication and decision making processes in place Fundraising: • -40% of fund raised (£97.4m) • Broadening investors beyond strategics to include financial investors, family offices, sovereign wealth, impact investors and pension funds . • • 72 • • • • • • . . . EFTA00799293 Scope to increase DDF's impact Dementia Discovery Fund Raising further capital will enable DDF to: 1. Expand the landscape of novel targets and mechanisms to develop into new dementia drugs (no shortage of opportunities) • Including mechanisms proven in oncology, inflammation, metabolism etc • Share learnings (successes and failures) • Broader geographic sourcing of science/academics 2. Build more robust preclinical and clinical translational data packages to increase the success of new drug development • Human tissue preclinical models • Biomarker development • Broader clinical evaluation in stratified patient groups 3. Leverage DDF's investments in novel translational biology to build momentum and confidence in the field, bringing more R&D funding into dementia drug discovery 4. Invest further in catalytic infrastructure to support dementia drug discovery beyond ChemCo, e.g. blood-brain-barrier technologies, iPSC banks, diagnostic technologies, novel clinical end points -* Larger DDF fund will enable discovery and development of many more than 2-3 novel drugs for dementia patients (both through the DDF and beyond) 73 • • ▪ • • EFTA00799294