#1Analyst & Investor Event Al in Drug Discovery & Interim Results for 6 months ended 30 June 2022 27 September 2022 Benevolent#2Disclaimer Forward-Looking Statements This document may contain forward-looking statements. Forward-looking statements are statements that are not historical facts and may be identified by words such as "plans", "targets", "aims", "believes", "expects", "anticipates", "intends", "estimates", "will", "may", "should" and similar expressions. Forward-looking statements include statements regarding objectives, goals, strategies, outlook and growth prospects; future plans, events or performance and potential for future growth; economic outlook and industry trends; developments in BenevolentAl's markets; the impact of regulatory initiatives; and/or the strength of BenevolentAl's competitors. These forward-looking statements reflect, at the time made, BenevolentAl's beliefs, intentions and current targets/aims. Forward-looking statements involve risks and uncertainties because they relate to events and depend on circumstances that may or may not occur in the future. The forward-looking statements in this release are based upon various assumptions based on, without limitation, management's examination of historical operating trends, data contained in BenevolentAl's records, and third-party data. Although BenevolentAl believes that these assumptions were reasonable when made, these assumptions are inherently subject to significant known and unknown risks, uncertainties, contingencies and other important factors which are difficult or impossible to predict and are beyond BenevolentAl's control. Forward-looking statements are not guarantees of future performance and such risks, uncertainties, contingencies and other important factors could cause the actual outcomes and the results of operations, financial condition and liquidity of BenevolentAl or the industry to differ materially from those results expressed or implied by such forward-looking statements. The forward-looking statements speak only as of the date of this release. No representation or warranty is made that any of these forward-looking statements or forecasts will come to pass or that any forecast result will be achieved. Benevolent 2#3Opening Remarks & Introduction Joanna Shields, CEO Benevolent#4ΑΙ Benevolent Because it matter Clinical-stage Al-enabled drug discovery company Uniting artificial intelligence with cutting-edge science to decipher complex disease biology and discover novel treatments#5The Benevolent Platform™ is scientifically and commercially validated and has already delivered: Named 13 Platform-generated drug programmes Identified a leading COVID-19 treatment that is now FDA approved 1 asset in Phase II 3 assets in pre-IND Successful multi-target collaboration with AstraZeneca further validates our approach with a total of 3 novel targets selected for AstraZeneca's portfolio +10 Exploratory stage programmes Well funded with key value inflection points in the near and medium term Benevolent 5#6Huge burden on society demands a new approach 96% overall failure rate in drug development $2.6bn in average R&D and to market cost per drug 10 to market years 30-50% efficacy for leading drugs Gaining a clear understanding of the underlying molecular mechanisms of disease based on the totality of available biomedical data is a vital step in the development of successful and efficacious treatments Benevolent 6#7Unprecedented opportunity to fundamentally rethink drug discovery 8.41 petabytes of data managed by healthcare institutions in 2018, an increase of almost ninefold from 2016 4.5 petabytes of data deposited to the US National Cancer Institute's Genomic Data Commons from 2016 to 2017 25 petabytes of genomic data estimated to be produced annually worldwide by 2030. The exponential growth in the production and availability of data, combined with advances in Al and machine learning, create the unprecedented opportunity to rethink the drug discovery and development process Benevolent 7#8The Benevolent Platform™: a versatile, scalable and proven Al-enabled R&D engine Experiments Molecular Literature Biological systems Regulatory Documents Omics Health Records Patient Clinical Trials 85+ diverse data sources Disease 00 TTT ИЛ ☀ | The Benevolent Platform™ Disease-agnostic Modality-agnostic Enables novel target ID Accelerates discovery Scalable and repeatable Potential to increase probability of success Benevolent 8#9About us $300m in platform investment Board with deep expertise across Al, drug discovery & development, pharmaceuticals Listed on EuroNext Amsterdam April 2022 Cash runway to Q4 2024 providing sufficient capital for key value inflection points TEAM as at June 2022 Full molecular biology, medicinal chemistry and in vivo pharmacology capabilities for in-house experimentation BOARD Baroness Joanna Shields CEO & Executive Director Jean Raby Non-Executive Director François Nader Chairman Jackie Hunter Non-Executive Director Science Susan Liautaud Non-Executive Director Nigel Shadbolt Non-Executive Director BizOps 350+ World Class Scientists & Technologists Tech Olivier Brandicourt Non-Executive Director John Orloff Non-Executive Director Benevolent 9#10Agenda Market Context - Al-enabled drug discovery Dr Ivan Griffin, COO The BenevolentAl Business Model Dr Ivan Griffin, COO Our Approach and Technology Dr Daniel Neil, CTO Olly Oechsle, whiteboard animation of the Benevolent Platform™ - Drug Discovery and Pipeline Review Dr Anne Phelan, CSO Professor Tom MacDonald - Immunology, Barts and the London School of Medicine and Dentistry, Queen Mary University of London Interim Results 2022 - H1 Review & Financials Nick Keher, CFO Closing remarks & Outlook Joanna Shields CEO Q&A Benevolent 10#11Market Context - Al-enabled drug discovery Dr Ivan Griffin, COO and Co-Founder Benevolent#12Al is becoming a validated approach in Pharma Significant investment fuels massive growth for the Al market in drug discovery & development ($bn Per Year) $5.0 $4.5 $4.0 $3.5 $3.0 $2.5 $2.0 $1.5 $1.0 $0.5 $0.0 $0.1 2013 $0.1 2014 Insight Engines Drug Design Clinical Trials Over $13bn Total Investment $0.5 $0.3 2015 $0.1 $0.1 $0.6 $0.2 $0.3 2016 50.1 >50% CAGR $1.1 $0.6 $0.4 2017 $0.1 $1.9 $0.2 $1.0 $0.7 2018 $1.8 50.3 $1.0 $0.5 2019 $3.2 $0.3 $2.0 $0.9 2020 $4.6 $0.7 $3.0 $0.9 2021 $1.2 $0.5 $0.2 $0.5 2022 YTD Number of clinical and preclinical assets 200 150 100 50 0 Al-drug discovery companies' internal pipelines 2010 Phase III Phase II Phase I Discovery/preclinical 2 2011 4 6 10 18 23 28 2012 Source: RBC Capital Markets; Emersion Insights. Capital includes funds from private investors, VC and corporate investment funds. Company Websites and press releases. Jayatunga et al. Nat Rev Drug Discov 2022: Number of annual R&D programmes and assets over time, showing the growth of Al-enabled drug discovery. Note: Categories are mutually exclusive. Investment includes equity, Partnerships/collaborations and acquisitions 2013 2014 2015 2016 2017 56 2018 121 158 119 2019 2020 This progress has been underpinned by three trends - advances in machine learning techniques, greater availability of biomedical data, increase in computational power 2021 Benevolent 12#13The Al value proposition for pharma R&D Direct R&D Cost Savings Discovery & Pre-Clinical "Faster and cost effective" INDUSTRY STANDARD $33m over 5.5 years AI-ENHANCED $15m over 3-3.5 years Based on industry benchmarks and internal programmes Reduce pre-clinical cost by >50% and time to market by 2-2.5 years Note Lab research and target identification costs and time not captured in industry data - likely to add significantly to the industry standard time and cost Notes and Sources: For illustrative purposes only; (1) Illustrative NPV for a theoretical $750m peak sales drug during initial 10Y on the market (assumes peak sales reached 5 years post-launch, (ii) 90% gross margin, (iii) 20% S&M expenses, (iv) 20% tax, (v) a 10% discount rate) and (vi) excludes any terminal value). (2) Based on Paul et al Nat Rev Drug Discov 2010. (3) Based on Harrison, Nat Rev Drug Discov 2016. (4) Based on Biomedtracker/Pharmalntelligence 2021. (5) Based on Odyssey Due Diligence report. PoS from Phase I to Market "Get it right more often" Highest attrition is at Phase II (current 34% success rate) (2) ~50% Phase II/III trial failures due to lack of efficacy (3) # Phase I Candidates Required for 1 Approved Drug Increasing Probability of Success Illustrative NPV(¹) Clinical Development INDUSTRY STANDARD 12% 9 c$60m AI-ENHANCED (ILLUSTRATIVE) 24% c$200m Illustrative 25% POS improvement at each clinical stage (Phase I-III) Context • Phase II trials with pre-selection biomarkers already >50% more likely to succeed(4) • Industry experts estimate that the use of Al can improve the PoS of each phase by up to 45% (5) Benevolent 13#14Categorisation of AI/ML companies in biotech, hit & target-ID Companies can be characterized across two key dimensions: Original technology focus and drug discovery approach Target-ID WHAT TARGET DO WE NEED TO HIT TO BE EFFECTIVE AND SAFE IN A SPECIFIC DISEASE (pathways, cellular processes)? HIGH COMPLEXITY THROUGH BIOLOGY Many layers of knowledge needed, and many areas where research is not yet complete Hit-ID HOW DO WE NEED TO HIT THE TARGET WE HAVE IDENTIFIED (specific drug characteristics)? HIGH COMPUTATIONAL COMPLEXITY Atom-to-atom interaction is relatively well known, but requires many calculations and simulations Company archetypes Target ID Original technology application focus Hit ID Benevolent SCHRÖDINGER. Hy othesis driven RECURSION Exscientia RELAY THERAPEUTICS B Drug Discovery approach C Non-Hypothesis driven Figure: Oliver Wyman Analysis (listed companies only) Source: Company Websites, Oliver Wyman Analysis Hypothesis driven Involves a data-driven hypothesis-led approach to therapeutic target identification Non hypothesis driven Leverages technology to identify solutions without specific conditions to target specified at the outset Pharma companies also active in the space, through internal development and/or collaborations Benevolent 14#15BenevolentAl technology approach Our data foundations integrate the world's relevant and available biomedical data to surface insights through our tools, improving how scientists discover and develop new therapies 'Omics Molecules Experimental Data Literature Pathology Biological Systems 85+ Data Sources 46% information proprietary 1. Creating Data Foundations Integrated knowledge platform built to ingest, represent, and surface insights from large volumes of diverse data types Predictive algorithms Triage Evaluation Boi Hypothesis- Driven Target ID *<<<<<< Progressibility Assessment <<<< Experimental validation 2. Al Tools for Scientists Suite of Al-driven tools and workflows allow scientists to explore data and discover novel, high-quality targets Portfolio Programmes Benevolent 15#16Principles and benefits of our technology approach ! Industry R&D CHALLENGES Half of clinical failures due to poor understanding of disease biology/mechanisms • Siloed disease-specific approach - scientists can't connect or infer shared mechanisms across diseases Single modality data - each with limitations and biases • Often limited understanding of what drives lab phenotypic effects • Much of target discovery is serendipitous, not a scalable or repeatable process BenevolentAl's APPROACH 1 Biology first 2 Comprehensive data approach 3 Hypothesis driven 4 Software based iii 000 Benevolent Platform T BenevolentAl BENEFITS DISEASE-AGNOSTIC MODALITY-AGNOSTIC ENABLES NOVEL TARGET ID ACCELERATES DISCOVERY SCALABLE & REPEATABLE POTENTIAL TO INCREASE PROBABILITY OF SUCCESS Benevolent 16#17How BenevolentAl's approach compares to industry benchmarks Deployment run for chosen disease Typical proportion of targets identified validated by lab assay 23% Time from target to candidate 2 - 2.5 yrs Cost from target to IND $15m Industry benchmarks based on Paul et al Nat Rev Drug Discov 2010. Potential increase in chance of a drug reaching the market vs industry benchmark >2x (based on 25% increase in PoS at each clinical stage) Potential time saved relative to industry benchmarks At least 2 yrs Potential cost benefit per IND relative to industry benchmarks $18m saving >50% ACCURACY AND EFFICIENCY TIME COST Higher ROCE per $ spent on R&D Benevolent 17#18What that equates to: higher productivity Number of new INDs filed by year by pharma and biotech companies Median number of Phase I starts over five years (2015-2020)* Companies with >20 commercialised products Companies with 3+ commercialised products Companies with <3 commercialised products AstraZeneca Pfizer MERCK Roche sanofi AMGEN GILEAD Creating Possible Benevolent Incyte) VERTEX REGENERON Alnylam ● sosel IONIS nektar Benevolent moderna DENALI Sangame aclaris EFFECTOR 0 2 2 2 N N 2 3 3 3 4 4 5 1-2 7 7 8 2-4 9 10 11 2027-31 AIM 2023-26 AIM 12 Market cap¹ $188bn $257bn $219bn $273bn $101bn $130bn $79bn $1bn $15bn $72bn $62bn $24bn $1bn $6bn $1bn $1bn $51bn $3bn $1bn $1bn $0bn Note *IND filing rate is based on Phase I trial starts with the company as the lead sponsor. Average adjusted for companies which started clinical development during time period; ¹ Market cap as of 06 September 2022 Source: clinicaltrials.gov; Company websites: L.E.K. research & analysis BenevolentAl potential productivity is in line with medium and large companies, but at a fraction of the total cost. BenevolentAl will aim to increase the number of INDs from its Platform with incremental cost largely from development through to the clinic only Benevolent 18#19The BenevolentAl Business Model Dr Ivan Griffin, COO and Co-Founder Benevolent#20The BenevolentAl business model - leveraging our technology platform to generate new drug IP at scale Al-Discovery Tools Target Identification C поо D Precision Medicine Knowledge Graph Molecular Design allon 100% owned in-house pipeline of novel discovery-stage assets taken to IND Pharma Collaborations: Selective platform collaborations which can leverage the Platform in areas outside our core competencies Non-commercial collaborations (DNDI, COVID-19) Economic benefits ESG A B Platform validation Platform validation BenevolentAl develop in-house Out-license at IND, end Phase I or end Phase II (upfront, milestones, royalties) Data generated enriches the Benevolent Platform™ Data generated enriches the Benevolent Platform™ Benevolent 20#21Therapy area and business model rationale SCIENTIFIC COMMERCIAL CLINICAL DEVELOPMENT DATA SCIENTIFIC & BD STRATEGY CORE THERAPEUTIC AREAS IMMUNOLOGY NEUROLOGY ONCOLOGY OTHER CURRENT PIPELINE PROGRAMMES Clinical development & ANY INDICATIONS commercialisation Development & out-license at IND, Phase I or Phase II Out-license prior to Phase I NON CORE THERAPEUTIC AREAS Pharma collaborations Non-commercial collaborations Benevolent 21#22Benevolent Platform TM: a validated approach INTERNAL PIPELINE VALIDATION Pipeline generated from the Benevolent Platform™ ✓ One asset in Phase II, 3 assets in pre-IND and 13 Named Platform- generated drug programmes +10 Exploratory stage programmes Discovery Preclinical BEN-2293 - Atopic Dermatitis BEN-8744 - Ulcerative Colitis BEN-9160 - ALS BEN- 28010 - Glioblastoma ✔Disease-agnostic Clinical Olumiant Image source: olumiant.com/hcp/rheumatoid-arthritis/dosing STRATEGIC VALIDATION Successful delivery on multi-target long-term collaboration AstraZeneca Chronic kidney disease (CKD) Idiopathic pulmonary fibrosis (IPF) Heart failure Systemic lupus erythematosus CLINICAL & REGULATORY VALIDATION US FDA DRUG APPROVED The Benevolent Platform™ successfully discovered an FDA approved treatment for COVID-19 Lilly N= O=S=O ALWAYS DISPENSE W MEDICATION QUIDE NDC 0002-4180-30 Olumiant (baricitinib) tablets 2 mg 30 tablets Lilly Benevolent 22#23Internal validation: pipeline generated from the Benevolent Platform™ BEN-2293 | Atopic Dermatitis BEN-8744 | Ulcerative Colitis BEN-9160 | Amyotrophic Lateral Sclerosis BEN-28010 | Glioblastoma Multiforme Inflammatory Bowel Disease Amyotrophic Lateral Sclerosis Antiviral Oncology Oncology Nonalcoholic Steatohepatitis Oncology Parkinson's Disease Parkinson's Disease Chronic Kidney Disease Idiopathic Pulmonary Fibrosis Idiopathic Pulmonary Fibrosis +10 Exploratory stage programmes Target ID Hit to Lead Lead Opt Preclinical Phase I AstraZeneca 27.01.2021 AstraZeneca 15.12.2021 AstraZeneca 17.05.2022 Phase II Phase III BEN-2293 - Phase lb complete, Phase Ila ongoing BEN-8744 Novel target - zero prior linkage to UC 2 years from target validation to candidate selection Broad disease coverage given platform Balance of risk between "best in class" and "first in class" drug candidates Benevolent 23#24Strategic validation: successful collaboration with AstraZeneca Multi-year Target-ID collaboration is delivering multiple, novel targets for complex diseases with high unmet need Separate data environment established to integrate AstraZeneca's data into a bespoke Knowledge Graph BenevolentAl and AstraZeneca teams working in close collaboration to explore, identify and validate targets Deal structure of upfront license fee, milestone payments and downstream royalties Collaboration enables BenevolentAl to enrich its platform via the data generated as part of the collaboration but also further validate the use of our Al platform AstraZeneca B THERAPEUTIC AREAS INITIAL DEAL (APRIL 2019) Chronic kidney disease (CKD) GO EXPANSION (DEC 2021) Heart failure KEY MILESTONES CKD: Jan 2021 IPF: Dec 2021 do To date, three novel targets have been validated & selected for AstraZeneca's portfolio IPF: May 2022 Idiopathic pulmonary fibrosis (IPF) Systemic lupus erythematosus#25Regulatory validation: identified a COVID-19 treatment now fully approved for use by the FDA ✓ NOVEL ✔ RAPID EFFECTIVE FDA U.S. FOOD & DRUG ADMINISTRATION Our technology and Al workflows identified a previously unknown antiviral mechanism (¹) The Benevolent PlatformTM empowered scientists to rapidly formulate a hypothesis in just 48 hours Baricitinib shown to reduce mortality from COVID-19 in randomised controlled trials: COV-BARRIER trial showed baricitinib reduces mortality by 38% in hospitalised patients(2), and by 46% in ventilated or ECMO patients (3) FDA approved the use of baricitinib to treat COVID-19 in May 2022 (4) after first granting emergency use authorisation for baricitinib in combination with remdesivir in Nov 2020 (5) Sources: (1) Richardson et al. Lancet 2020; (2) Marconi et al. Lancet Respiratory Medicine 2021; (3) Ely et al. Lancet Respiratory Medicine 2022; (4) Lilly press release 11 May 2022; (5) Lilly press release 19 Nov 2020 BenevolentAl published research in Feb 2020(¹) THE LANCET Led to equity investment from Eli Lilly Lilly Benevolent 25#26Animated Benevolent Platform™ Video Dr Olly Oechsle, Director of Engineering Benevolent#27The BenevolentAl Approach & our Technology Dr Daniel Neil, CTO Benevolent#28The Benevolent PlatformTM: Data Foundations and Al Tools Our data foundations integrate the world's relevant and available biomedical data to surface insights through our tools, improving how scientists discover and develop new therapies 'Omics Molecules Experimental Data Literature Pathology Biological Systems 1. Data Foundations Integrated knowledge platform built to ingest, represent, and surface insights from large volumes of diverse data types Predictive algorithms Triage Evaluation Hypothesis- Driven Target ID *<<<<<< Experimental validation Progressibility Assessment >>>>>> 2. Al Tools for Scientists Suite of Al-driven tools and workflows allow scientists to explore data and discover novel, high-quality targets Portfolio Programmes Benevolent 28#29Data Foundations integrate diverse data types Experiments Assay Data (Binding, Omics Comparison, CRISPR Screens) Clinical Trial OMICS Genes Proteins Isoforms Transcripts & Variants Molecules Organic Compounds Preclinical Candidates Approved Drugs Antibodies Other Biologics Pharmacology Pharmacokinetics Literature Scientific Literature Patent Literature Regulatory Documents Aetiology Diseases Symptoms Biological Systems Cellular Component Molecular Function Biological Process Mechanism Pathways Integrates 85+ disparate data sources A data foundation that is proprietary, and scalable DATA PROCESSING PIPELINES CLINICAL DATA TRANSCRIPTOMICS CLINICAL DATABASES LITERATURE EXTRACTED & INFERRED DATA Natural Language Processing: Named Entity Recognition & Relationship extraction SOD1 mutation causes ALS phenotype in human MNs SOD 1 ALS 1. Data Foundations ....... THE DATA FOUNDATION OF OUR PLATFORM Benevolent 29#30The BenevolentAl Data Foundations, in numbers 85+ Relationships (millions) 500 400 300 200 100 O Data Modalities Data Volume Jun 2021 Dec 2021 Aug 2022 Ontology and Dictionary Genetics and Clinical Experimental Literature Structured Databases Omics-derived Total Proprietary Data sources 1. Data Foundations 409m Biomedical relationships 33 Entity types 46% Proprietary information Benevolent 30#31Data modalities paired with processing pipelines Literature processing pipeline DBs APIs Files Genetic Summary Stats Genetic Cohorts Annotation Features (eQTL/pQTL, chromatin, locus features, etc.) Automated Download and Ingestion Reliably bring in fresh, up-to-date scientific literature Document Normaliser Standardize and remap the text for further processing GWAS Pipeline Spark-enabled, scalable pipeline to link traits to variants Named Entity Recognition WES/WGS Pipeline Spark-enabled, scalable pipeline to link traits to variants Identify the key concepts in the text Identifier Builder Relation Extraction Methods Rule-based Methods ML-based Methods Extract relationships between identified biomedical concepts Precision Medicine genetics processing pipeline Ensure consistent entities across the platform Variant-to-Gene Annotation Match variants to an associated gene Representation Harmonisation Ensure consistent genetic linkage 1. Data Foundations EXTRACTED & INFERRED DATA Benevolent 31#32The Benevolent PlatformTM: Data Foundations and Al Tools Our data foundations integrate the world's relevant and available biomedical data to surface insights through our tools, improving how scientists discover and develop new therapies 'Omics Molecules Experimental Data Literature Pathology Biological Systems 1. Data Foundations Integrated knowledge platform built to ingest, represent, and surface insights from large volumes of diverse data types Predictive algorithms Triage Evaluation Rii Hypothesis- Driven Target ID *<<<<<< Progressibility Assessment <<<< Experimental validation 2. Target ID 2. Al Tools for Scientists Suite of Al-driven tools and workflows allow scientists to explore data and discover novel, high-quality targets Portfolio Programmes Benevolent 32#33BenevolentAl's Target ID workflow and tools Disease Selection Target Identification Prep Phase: Define disease of interest and scope potential assays. Hyp Gen & Hyp Val Assay Definition Define the Tech Approach Predictions Hit ID & Expansion BenevolentAI TID Tool Portfolio Triage Define the Tech Approach, Prediction, and Assessment Iteratively formulate a hypothesis for the tools to predict against, alongside the context used to define the disease state, then generate predictions to triage. During triage, scientists review evidence for each target and determine progressibility based on relevance to biology. Discovery Lead Op ΤΡΑ Candidate Seeking Assay Preclinical Development Phase I ΤΡΑ Assay: Targets sent to a series of mechanistic and disease-relevant assays to assess a target's potential. Target Progressibility Ass sment (TPA) Assessment on the progressibility potential of the target, chemistry or biologic opportunity, opportunity to differentiate in the field, and safety. Can occur before, during, or after targets are sent to assay. Phase II Validation Package 2. Target ID Phase III Portfolio Entry Portfolio Entry Preparation: Evidence from assays, surfaced insights, and analysis combined to form a validation package to evaluate for portfolio entry. Benevolent 33#34BenevolentAl's target discovery tools and process identifies promising, novel therapeutic targets TECH APPROACH PREDICT TRIAGE ΤΡΑ ASSAY 1. Define the Tech Approach Using our in-house tools and algorithms we explore the data and define the input to our predictive models 3. Triage and Assess Progressibility Can we treat ALS by reversing Autophagy impairment in microglia by reducing oxidative stress? Our tools aggregate and present the necessary data for scientific decision- making, progressing only the most promising hypotheses. Sign 120 Disease Target 120 C Mechanism CARMI PDK1 ULK1 Endpoint: What we are measuring in the assay NR1H3 Cell type P 1 G * 2. Target Prediction Our Al algorithms, data queries, and endotype-driven workflows identify targets that are likely to address the tech approach. Graph Models Transcriptomics Models Precision Medicine Genetics 2. Target ID Precision Medicine 'Omics Data queries Large Language Model Aggregation Prioritization Targets 4. Validate Experimentally Targets sent to a series of mechanistic and disease-relevant assays to assess a target's potential. Benevolent 34#35Define the tech approach by exploring the data TECH APPROACH PREDICT TRIAGE ΤΡΑ ASSAY Visualise Saved Shortlists amyotrophic lateral sclerosis [N Disease Venn diagram Upset diagram Display geneset genes Related entities Mechanisms Cluster mechanisms amyotrophic lateral sclerosis 525 genes Mechanism name astrocyte activation 135 genes Entity information Ontology tree There are Mechanisms related to amyotrophic lateral sclerosis Recommended entities are listed in ascending order of Rank by default. Diseases related to amyotrophic lateral sclerosis RNA localization to nucleus cellular response to oxidative stress 226 genes + Filter by: Related tissues: All Rating ✓ 100% V Data relevance score . 0.98 Related cell: All Entity definition 205 Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease motor neurons in the primary motor cortex, corticospinal tracts, bra Benchmark Genes Geneset Genes There are 525 benchmark genes in your selection: SLC8A3, NUP42, MFN2, SYNCRIP, SLC30A3, CLP1, SMN2, LGALS4 SNRPN, TNPO1, SACMIL Show all 525 benchmark genes + Add as new custom list (525) Number of benchmark genes Mechanism ontology: All Number of geneset genes 247 v Benchmark gene overlap → 52 Perc flier 6.5% ed Shortlists MK2A PEA15 C5AR1 PRDX3 O SNADIN HTRA2 O LRRK2 CFA 40 LANGA SYNCH TTBK1 PINK1 DPYSL3 MAPT MFN2 RHON $0: FO PRKN HNRNPA2B1 ● CDK5R1 CSNKID DPYSL2 O SNCA O GJA1 CDK5 RAD52 O AATK OSBP ABL1 BDNF PRKD1 PDGFRB PIK3CA LYN 2. Target ID NTF4 TRPV1 FYN GRIN 28 O KIT SMO TYROBP O EFNAS SRC IGF HNRNP O PRNP SCN5A Benevolent 35#36TECH APPROACH Triage targets to select only the most promising hypotheses PREDICT TRIAGE TPA ASSAY A Programs / ALS Demo / ALS / ALS Search Q Target Symbol Filter Triage status Triaged (0) Assessment decision Match (0) Uncertain (220) Context Mechanism On other lists Present 1 Ligandability Triage criteria Biological Rationale 1 Safety Not triaged (250) 1 Not match (30) Clear all Absent Sort by: Target Rank ↑ ALS Prediction MAPKAPK2 MAPK activated protein kinase 2 Biological Rationale-class 1 (out of 4) MAPK7 Not Match Your comment (can be edited when changing target decision) Biological Rationale-class 2 (out of 4) DYRK1A mitogen-activated protein kinase 7 Not Match Ligandability-class 4 (out of 4) Biological Rationale - class 2 (out of 4) LDHA Uncertain Your comment (can be edited when changing target decision) Ligandability-class 4 (out of 4) Biological Rationale-class 3 (out of 4) 2 Target Rank? 1 Target Rank? dual specificity tyrosine phosphorylation regulated kinase 1A Ligandability-class 4 (out of 4) lactate dehydrogenase A Safety-class 1 (out of 4) 4 Target Rank ? Safety-class 3 (out of 4) Your comment (can be edited when changing target decision) Ligandability-class 4 (out of 4) Safety-class 1 (out of 4) Safety-class 3 (out of 4) Uncertain Your comment (can be edited when changing target decision) Therapeutic Evidence-class 3 (out of 3) 3 Target Rank ? Therapeutic Evidence-class 3 (out of 3) Therapeutic Evidence- class 3 (out of 3) Therapeutic Evidence-class 3 (out of 3) View from the Triage Tool Visualise Show criteria Chemical Opportunity-class 1 (out of 4) Chemical Opportunity-class 1 (out of 4) Chemical Opportunity-class 1 (out of 4) Chemical Opportunity-class 1 (out of 4) Copy UUIDS Showing 250 of 250 targets □ 2. Target ID G Benevolent 36#372. Target ID Target Progressibility Assessment (TPA): Identify the hypotheses most likely to succeed TECH APPROACH PREDICT TRIAGE ΤΡΑ ASSAY ✰ Programs / ALS Demo: Target progressability assessment list / ACKR3 (atypical chemokine receptor 3) Back to the list. ACKR3 TAntagonist Biology triage Opportunity to differentiate Patent landscape Selectivity Druggability Tractability Previous assessment (0) Selectivity Q Search for off-targets Symbol AVPR1A AGTR2 AVPR2 GALR1 GPR15 OPRD1 OPRK1 OPRL1 OPRM1 SSTR2 Off targets (59) Pocket Select ACKR3's pocket to compare it with pockets of off-targets Detected Pocket 1 Sequence similarity score ↓ Show multiple sequence alignment 94% 89%. 89% 89% 89%. 89% Y 89%. 89% 89% 89% Protein similarity Rows per page: View from Target Assessment Tool Feedback feedback ⠀ Protein O 10 ▼ 1-10 of 59 60%. >>> Your assessment Notes Selectivity 1 Off-targets (based on target homology and/or existing tools) for which selectivity is required, but is considered be likely unachievable. Off-targets (based on target homology and/or existing tools), for which selectivity is required, is considered possible, but has not been demonstrated with existing tools. x Chemical Space Plot for Druggability Activity DOI MW TPSA MW vs M Druggability evidence ligand data for ACKR3 (Click to link to publication) ISNEY W pActivity value 0+*&USOR Benevolent 37#38Benefits from our technology approach DISEASE-AGNOSTIC go Enabled by: a focus on breadth of biomedical information and the integration of diverse, wide-ranging data types. ACCELERATES DISCOVERY Enabled by: supporting scientists with aggregated, summarised information and tools to support efficient decisions MODALITY-AGNOSTIC S Enabled by: early Target ID tools supporting both small molecule and biologics approaches. SCALABLE & REPEATABLE 2 Enabled by: workflows and software foundations designed for scale, run repeatedly for internal deployment and external collaborators. NOVEL TARGET Enabled by: large volumes of integrated data can surface novel targets never considered before and spark creativity in scientists. POTENTIAL TO INCREASE PROBABILITY OF SUCCESS ஊ Enabled by: tools enabling early data-driven decisions to progress only the most promising hypotheses. Benevolent 38#39Drug Discovery & Pipeline Review Dr Anne Phelan, CSO Benevolent#40Advanced laboratory capabilities help move programmes faster, and generate data at scale for continuous innovation Advanced capabilities and technologies • Fully equipped laboratory facilities; Biology, Chemistry, CMC, DMPK. • Highly experienced scientists across all drug discovery disciplines • In-house investment in CRISPR, RNA seq and human IPSC capabilities • Robust and secure data storage capacity . Access to the Babraham Institute Research facility, with state of the art High Content Imaging and FACS capabilities. • CROS and academic collaborations complement and extend internal capabilities Cambridge, The Babraham Institute Campus Experimental capabilities enhance entire drug discovery process • Mechanism selection, Target identification, target triage and experimental validation • Refined, model-enabled Design-Make-Test cycle Closing the data loop • Experimental data from hypothesis validation workflows, portfolio projects and disease relevant expression data are integrated back to further enrich the knowledge graph and our representation of human biology Work progresses rapidly from in-silico to in-vitro experimental test Dynamic experimental feedback loop between scientists & technologists Benevolent 40#41Internal validation: pipeline generated from the Benevolent Platform™ BEN-2293 | Atopic Dermatitis BEN-8744 | Ulcerative Colitis BEN-9160 | Amyotrophic Lateral Sclerosis BEN-28010 | Glioblastoma Multiforme Inflammatory Bowel Disease Amyotrophic Lateral Sclerosis Antiviral Oncology Oncology Nonalcoholic Steatohepatitis Oncology Parkinson's Disease Parkinson's Disease Chronic Kidney Disease Idiopathic Pulmonary Fibrosis Idiopathic Pulmonary Fibrosis +10 Exploratory stage programmes Target ID Hit to Lead Lead Opt AstraZeneca AstraZeneca AstraZeneca Preclinical Phase I Phase II Phase III Highlights • All Pipeline programmes generated from the Benevolent Platform™ • Broad therapy area coverage given disease-agnostic approach to date, with future investment to focus on three Therapeutic Indications ● 50/50 mix of Best in class and novel / First in Class indications • Potential for rapid scaling and expansion into new modalities Benevolent 41#42BEN-2293 - Atopic Dermatitis (AD) • Atopic dermatitis is the most common chronic inflammatory skin disease, characterized by intensely itchy, red, and swollen skin(¹) o Affects 10-20% of children and up to 3% of adults(2) o Approximately 60-70% of all cases present with mild-moderate disease severity(3) o Prevalence is rising (3), with market value in 7MM forecast to exceed $14 billion (2,4) Skin inflammation and chronic pruritus associated with atopic dermatitis negatively impact quality of life and psychosocial well-being(¹) • Clear unmet need in mild to moderate patient segment for treatment addressing itch and inflammation, without side effects of steroids Photo Source:https://www.bmj.c Sources: (1) Weidinger et al. Nat Rev Dis Primers 2018; (2) Global Data Report 2018: Atopic Dermatitis: Global Drug Forecast and Market Analysis to 2027; (3) Global Data Report 2018: Atopic Dermatitis: Epidemiology Forecast to 2027; (4) Evaluate Pharma Benevolent 42#43BEN-2293 - A potent PanTrk antagonist developed to relieve inflammation and provide rapid itch resolution Atopic Dermatitis · ● BEN-2293 is a PanTrk inhibitor targeting TrkA, B and C receptors. The Trk receptors were identified as part of an effort to find mediators of both itch and inflammation in AD. Using our Molecular Design expertise we were able to design a PanTrk inhibitor, equipotent against the 3 receptors BEN-2293 is expected to treat atopic dermatitis by: inhibiting itch signaling and blocking nerve sensitization (TrkA) in addition to inhibiting Th1 and Th2-mediated dermal inflammation (TrkB, TrkC) BEN-2293 will target Mild, Moderate and Severe Atopic Dermatitis patients, addressing unmet need in the treatment of mild to moderate Atopic Dermatitis as a steroid sparing alternative and in more severe patients undergoing treatment with biologics (e.g. dupilumab) that require add-on treatment NGF Y TrkA PIP2 PLC BDNF TrkB NTF-3 4 TrkC GAB1 Neurotrophins bind to high affinity receptors (TrkA, B and C), directly activating both inflammation and itch signalling which propagates a cycle of itching and scratching. Key: Tropomyosin-related kinase (Trk) receptor tyrosine kinase family, namely TrkA, TrkB, and TrkC; Nerve Growth Factor (NGF); Brain Derived Neurotrophic Factor (BDNF); Neurotrophin-3 (NTF-3)/NT3 Benevolent 43 Image source: Amatu et al. ESMO Open 2016#44TrkC ● ● Atopic Dermatitis - BEN-2293, PanTrk rationale ● NT3/TrkC potentiates stimulated Th2 T-cell inflammatory responses and synergistically enhances T-cell receptor induced IL-4 production by Th2 cells TrkB ● Mast cells within AD skin lesions express high levels of NT3 compared to normal controls AD skin-resident eosinophils express elevated levels of TrkB (together with TrkA and C) and functionally respond to BDNF BDNF/TrkB inhibit eosinophil apoptosis and increase chemotactic index Source: Weidinger et al. Nat Rev Dis Primers 2018 Healthy skin Stratum Skin microbiota corneum Staphylococcus aureus. Stratum granulosum Stum spino um Stratum basa Dermis Blood vessel B cell T cell Non-lesional skin IL-18 IL-33 TARC IL-25 MDC TSLP w ILC2 cell CLA CCR4 IL-5 IL-13 Lichenification Barrier dysfunction, innate immune system activation and T 2-driven inflammation and/or T, 22-driven inflammation Keratinocyte Variable T1 and T 17 activation CCR10 CRTH2 x T₁2 cell T 22 cell Allergen IL-4 IL-13 T₁1 cell Acute lesional stage FceR1 Eosinophil OX40L H4R T 17 cell IL-4 IL-13. IgE IL-31 Trm cell IL-33 TSLP -Cutaneous sensory neuron Chronic lesional stage Langerhans cell Me Dermal dendritic cell Osums IDEC TrkA ● • NGF produced by AD keratinocytes is a major mediator of cutaneous hyperinnervation ● TrkA levels in skin dramatically increase in response to inflammatory stimuli ● Increased NGF in the skin sensitizes primary afferents contributing to peripheral itch sensitization and chronic pruritus Involved in the inflammatory activation of mast cells and basophils Benevolent 44#45We expect BEN-2293 to provide both symptomatic relief and to reverse disease progression in atopic dermatitis • BEN-2293 is highly selective for Trk receptors, with IC50 potencies in the low nM range for TrkA, B, and C • BEN-2293 dose dependently inhibits release of inflammatory Thl and Th2 cytokines TNFa, IFNY, IL-13, and IL-4 in human peripheral blood mononuclear cells (PBMCs) stimulated with an inflammatory T-cell stimulus (anti-CD3/CD28) • BEN-2293 inhibits the release of Calcitonin Gene-Related Peptide (CGRP), a mediator of itch, sensory nerve hypersensitisation and neurogenic inflammation, in dorsal root ganglion (DRG) isolated from adult rats and stimulated with NGF • BEN-2293 series significantly (p<0.05) reduced mouse ear inflammation following administration of PMA, significantly reducing expression of cytokines IL-1B, IL-4, IL-6, CXCL1, MCP-1, and Tarc • BEN-2293 demonstrates excellent tolerability and safety margins in IND/CTA-enabling toxicology studies Key: Tropomyosin-related kinase (Trk) receptor tyrosine kinase family, namely TrkA, TrkB, and TrkC; Nerve Growth Factor (NGF); Brain Derived Neurotrophic Factor (BDNF); Neurotrophin-3 (NTF-3)/NT3 BEN-2293 Inhibition of human primary T-cell activation Luminescence 25000- 20000- 15000- 10000- 5000- 0.1 100- 75- 50- 25- 0- -25- -50- TNFa Inhibition of sensory neuron activation -3 Timmy Timą, 100 1000 10000 -2 Hillslope IC50 -1 0 Log BEN-2293 (μm) -Donor 1 Donor 2 10 10 BEN-2293 nM 100 1000 10000 BEN-2293 nM Human PBMCs from 2 donors. Anti-CD3/CD28 stimulus +/- BEN-2293 2.827 0.03033 1 Luminescence 1500 1000- 13500 Net ear thickness (x 0.01 mm) 500- 15- IL-4 0.1 Vehicle THE TIT Reduction in mouse ear inflammation H... Crisabarole (Img) Tacrolimus (0.05mg) - -Donor 1 -Donor 2 PanTrk (0.5mg) Dexamethasone (0.1mg)- Benevolent 45#46BEN-2293 - Phase Ib safety and tolerability study successfully completed Phase Ib/Ila double-blind, placebo-controlled, first-in-patient, two-part clinical study Phase Ib 3 First-in-human dose escalation 2 Phase Ib completed Dec 2021 8 Mild-Moderate AD patients (18-65 years) per cohort, randomised 3:1 BEN-2293:Placebo Safety, Tolerability, PK • Adaptive multiple ascending dose cohort design Includes efficacy endpoints • MALDI imaging To evaluate human skin PK Phase Ib: ✔ Successfully completed Safety and Tolerability arm BSA= Body surface area. QD = once per day dosing BID= twice per day dosing Cohort 1 0.25% QD 7 Days 10% BSA Not tolerated/ Inadequate SM Adaptive design for Phase Ib of the clinical study Cohort 3a 1% Cohort 2 1% QD 7 Days 10% BSA Terminate Study Tolerated/PK Supports SM Not tolerated/ Inadequate SM Tolerated/PK Supports SM QD 14 Days 30% BSA Not tolerated/ Inadequate SM Cohort 3b 0.25% QD 14 Days 30% BSA Not tolerated/ Inadequate SM Terminate Study Tolerated/PK Supports SM Tolerated/PK Supports SM Cohort 4a 1% BID 14 Days 30% BSA Cohort 4b 0.25% BID 14 Days 30% BSA Benevolent 46#47BEN-2293 - Phase Ib safety and tolerability study successfully completed Phase Ib/Ila double-blind, placebo-controlled, first-in-patient, two-part clinical study Phase Ib 3 First-in-human dose escalation 2 Phase Ib completed Dec 2021 8 Mild-Moderate AD patients (18-65 years) per cohort, randomised 3:1 BEN-2293:Placebo Safety, Tolerability, PK • Adaptive multiple ascending dose cohort design Includes efficacy endpoints • MALDI imaging To evaluate human skin PK Phase Ib: ✔ Successfully completed Safety and Tolerability arm BSA= Body surface area. QD = once per day dosing BID= twice per day dosing Cohort 1 0.25% QD 7 Days 10% BSA Not tolerated/ Inadequate SM Adaptive design for Phase Ib of the clinical study Cohort 3a 1% Cohort 2 1% QD 7 Days 10% BSA Terminate Study Tolerated/PK Supports SM Not tolerated/ Inadequate SM Tolerated/PK Supports SM QD 14 Days 30% BSA Not tolerated/ Inadequate SM Cohort 3b 0.25% QD 14 Days 30% BSA Not tolerated/ Inadequate SM Terminate Study Tolerated/PK Supports SM Tolerated/PK Supports SM Cohort 4a 1% BID 14 Days 30% BSA Cohort 4b 0.25% BID 14 Days 30% BSA Benevolent 47#48BEN-2293 - indicative data from Phase Ib Eczema Area and Severity Index (EASI) Caveats: • Phase lb was NOT powered to meaningfully assess efficacy - only 6 patients dosed with active per group • Maximum duration of dosing 14 days (EASI score changes typically measured at 28 days) Mean change from baseline -3 EASI: Eczema Area and Severity Index 4 Cohort 3: Patients dosed 1% ointment, 30% BSA, once per day -6 5 Mean Change from Baseline %BSA affected in treated areas 6 7 Days 9 10 11 12 13 Cohort 4: Patients dosed 1% ointment, 30% BSA, twice per day 14 14 day placebo treatment 15 0.25% ointment, once per day, 10% BSA 1% ointment, once per day, 10% BSA 1% ointment, once per day, 30% BSA 1% ointment, twice per day, 30% BSA Placebo 7d Placebo 14d Benevolent 48#49BEN-2293-Phase Ila progressing Phase Ib/Ila double-blind, placebo-controlled, first-in-patient, two-part clinical study Screening Baseline assessments itch and AD score Wash out 7 day Wash out from any existing medication Re-baseline or exclude Run in 3 day Placebo run in Phase Ila clinical study design Continuous safety monitoring 28d BID dosing over affected skin area 28 day BID dosing on affected skin upto a maximum of 30% BSA Placebo:Active (1:1), Moderate: Mild patient ratio 70:30, Total of 90 patients (45 active:45 placebo) Study endpoints - itch and AD rating scales 11 active recruiting sites, 7 in the UK, 4 in Europe. A further 17 sites under final approval Recruitment completion anticipated 4Q22 Follow up 14 day Final safety assessment Our intention is to to partner this asset with a pharmaceutical company that has a focus in dermatology for continued clinical development and, if approved, commercialisation Benevolent 49#50BEN-2293 is being developed to address key unmet needs in the treatment of Atopic Dermatitis TREATMENT FLOW Atopic Dermatitis Treatment Paradigm Mild Steroid Treatment Current Moderate Calcineurin inhibitors Future Eucrisa/PDE4 inhibitors Topical JAKS BEN-2293 (Pan Trk) Other topicals (tapinarof) L1_ PanTrk positioning Severe Immuno- suppressants Dupilumab Other anti-IL13/IL4 mAbs Oral JAKS BEN-2293 development is targeting: Efficacy against both itch and inflammation, with potential disease modifying effects Improved safety profile, suitable for chronic use with no irritancy on application ● ● Positioning: Potential to displace ineffective and poorly tolerated second line treatment for chronic use in ● ● adults and paediatrics Potential use in a subset of first line patients where rapid itch resolution is key and In the severe patient population as an adjunct treatment option Benevolent 50#51Thomas T MacDonald PhD FMedSci Professor of Immunology Barts and the London School of Medicine and Dentistry, QMUL INTERESTS Mucosal immunology and inflammation in man Principles of MUCOSAL IMMUNOLOGY Edited by Philp D. Smith Richard S. Blumberg Thomas T. MacDonald SOCIETY FOR MUCOSAL MINOLOGY CRC SECOND EDITION Benevolent 51#52Ulcerative Colitis (UC) Affects 0.4% US population (¹), 1.7 million patients in 7MM(¹), forecast $7.8bn market by 2026(²) • A chronic, lifelong disease that causes inflammation and ulceration of the inner lining of the colon and rectum • Efficacy - 20-40% of Moderate-severe patients do not respond to anti-TNF (main treatment paradigm) (3) • Safety - Treatments have many side effects from steroids to anti-TNF and JAK inhibitors (black box warnings)(4) • High unmet need for an alternative oral small molecule treatment option with improved safety profile and efficacy in treatment of refractory patients 64% Mild- moderate Ulcerative Colitis 31% Moderate- severe 5% Severe- fulminant Sources: (1) GlobalData: Ulcerative Colitis, Global Drug Forecast and Market Analysis to 2026; (2) Evaluate Pharma: Gastro-intestinal, Inflammatory bowel disease (IBD), Ulcerative colitis, Worldwide Overview (report 17th Sep 2021); (3) Roda et al. Clin Transl Gastroenterol 2016; (4) Kobayashi et al Nat Rev Dis Primers 2020 and US FDA Drug Safety Communication 2021 Experimental Model System: Inflamed colonic mucosa biopsies from UC patients • Disease phenotype retained with high basal cytokine release • Readouts: IL6 and IL8 - key mediators of UC pathology • Efficacy demonstrated with standard of care therapies Culture 24 hrs Cytokines in sups Store biopsies Single cell work Western blots PCR Biopsies NO: SEX: AGE: D.O.BIRTH: SCU-47 NAME: Resections Lamina propria mononuclear cells for in vitro activation • Short term organ culture of human intestinal mucosa . Gut is a tissue that is sampled a lot • Inflamed biopsies do not know that they are not in the gut Benevolent 52#53Experimental Model System: Inflamed colonic mucosa biopsies from UC patients ● Cytokine production (ng/ml) Therapeutic anti-TNF monoclonal antibodies inhibit the spontaneous release of inflammatory cytokines and chemokines in ex vivo cultures of inflamed CD and UC tissue. 50 3 2 - O IL-6 ID2A V565 V565 V565 IgG IFX 300nM 30nM 100nM 300nM 67nM 67nM Source: Crowe et al 2018 Cytokine production (ng/ml) 40 35 30 25 20 15 IL-8 Mihali ID2A V565 V565 V565 IgG IFX 300nM 30nM 100nM 300nM 67nM 67nM Cytokine production (pg/ml) 100 90 80 70 60 50 40 30 20 10 0 TNFa ID2A V565 V565 V565 lgG IFX 300nM 30nM 100nM 300nM 67nM 67nM Benevolent 53#54Colon biopsy signatures pixel intensity (AU) pixel intensity (AU) Phosphorylation pattern in... 2000 1800 1600 1400 1200 1000 800 600 400 200 0 20 SENER EGFRIEDB1 2000 1800 1600 1400 1200 1000 800 600 400 200 0 BR2/E82 EGFRBt81 ER2/ErbB2 FGFR1 FGFR1 FGFR3 FGFR3 FGFR4 FGFR4 InsR IGF-IR TrkA/NTRK1 TKB/NTRK2 MetHGFR Ron MSTIR InsR IGF-IR Tik A/NTRK1 MetHGFR TikB/NTRK2 Ron/MSTIR Ret ALOGFR ALK CKISCER Healthy colon biopsies PDGFR kitSCFR の SAHIT M-CSFRICSF-1R EphA1 EphA2 PLT3/FK2 M-CSFRICSF-IR del EphA1 Inflamed Crohn's biopsies Eph43 Tyro3/Dik EphB1 VEGFR2 Aki/PKB/Rac Th308 e2/TEK Tyro3/Dek 42 MAK Tie2/TEK Akt/PKB/R PKB/Rac T RK1 S6bos. Protein 0 AktPKB/Rac Ser473 D44/42 MAPK (ERK1/2) 96 dbos. Protein IRS-1 Zap-70 d healthy- healthy Stat3 Stat1 Lck Src -Zap-70 IAS-1 c-Abl S6 ribos. Protein p44/42 MAPK (EAK 1/2) Akt/PKB/Rac Ser473 Akt/PKB/Rac Thr308 -VEGFR2/KDA Tie2/TEK HeaTE Axl -Tyro3/Dtk -EphB4 EphB3 -EphB1 Spro EphA3 EphA2 Pu -EphA1 MCSE M-CSFR/CSF-1A FLT3/FIK2 c-kit/SCFA PDGFR ALK 2 Rot Ron/MSTIR MovHGFA TrkB/NTAK2 -TrkA/NTRK1 IGE-IR INSH InsA LEGFR4 FGFR3 FGFA1 HER3/ErbB3 HER2/ErbB2 -EGFA/ErbB 1 56 Benevolent 54#55UC and CD biopsies responsive to pharmacological intervention % RIPK2 (of DMSO control) c) % RIPK2 (of DMSO control) % cytokine (of DMSO control) 150- 100- 50- -12 1501 O 100- 50- -12 150-₁ 100- 50- [PROTAC 6] log (M) PROTAC 6 PROTAC 7 -10 -6 [compound] log (M) CD Patient Biopsies 暅 6 hours 24 hours -8 0.05 IL-1B IL-6 TNFa PROTAC 6 (nM) b) % cytokines (of DMSO control) d) % TNFa (of DMSO control) % cytokine (of DMSO control) 150 100- 50- 0- -50- -12 150 100- 50- -50- -12 200₁ 150- 100- 50- HOH O -6 [PROTAC 6] log (M) -10 PROTAC 6 PROTAC 7 -10 -6 [compound] log (M) UC Patient Biopsies 0.05 0.5 TNFa IL-6 IL-8 IL-10 IL-18 IL-1B IL-6 TNFa PROTAC 6 (nM) Benevolent 55#56UC Target Identification workflow Mechanism 1 4 Biological Question Disease Can we treat UC by reversing chronic inflammation of the colonic mucosa by targeting pathways in colon epithelial cells and tissue resident immune cells? Endpoint: What we will measure Sign Experimental validation Cell type Endoscopic Biopsy from UC patients 2 Target Identification Predictive algorithms ran over the curated knowledge graph to identify potential targets, aggregate findings and present the most relevant ones to DD scientists 200 Colonic mucosa tissue culture and compound treatment 3 Target assessment and validation tools presented scientific evidence allowing scientists to evaluate the rational and opportunity for progressibility ✔PDE10 has zero linkage to UC in all available biomedical literature PDE10 inhibition promoted an anti-inflammatory effect Inflammatory cytokine measurement Benevolent 56#57BEN-8744 - Phosphodiesterase 10 (PDE10) - a novel target for UC Transcriptomics data support the rationale for PDE10 as a novel target for UC ● PDE10 regulates signal transduction by hydrolysing cGMP PDE10 is significantly upregulated in UC-derived colon and colonic mucosa samples, whilst guanylyl cyclase, which makes CGMP, is down-regulated Reduced levels of guanylyl cyclase correlate with increased TNF-a in UC colonic mucosa (¹) CGMP is downregulated in UC and its expression inversely correlates to disease severity ● PDE10 is well-studied in CNS disorders but not in inflammation with zero linkage to UC PDE10 demonstrates restricted expression in peripheral tissue Reduces the safety liability of targeted inhibition nitric oxide synthase arginine soluble guanylyl cyclase NOS NO readily diffuses across plasma membranes NO activates GC GTP CGMP activates protein kinases and other proteins breaks down phosphodiesterase e.g. PDE10 PDE10 degrades cGMP Source: (1) Brenna et al. Scand J Gastroenterol 2015 Image (left): Rashed, Second Messenger System 2018 GUCY2C • LogFC PDE 10A LogFC Differential RNA expression of PDE10A and GUCY2C: normal vs UC colonic mucosa colon log FPKM Adipose ww pose Tissue Adrenal Gland Bladder Blood Blood Vessel Brain Breast Cervix Uteri Colon Esophagus Fallopian Tube Heart RNAseq Lun Liver Tissue Nerve M Ovary Pancreas Pituitary Prostate Salivary Gland Skin Intest Small Spleen Stomach Testis Low basal PDE10 expression, highest levels in brain. Low basal soluble guanylate cyclase (GUCY2C) levels except in colon and sm intestine Gene 8 MI PDEGA PDE10A GUCY2C Benevolent 57#58Target validation in colon tissue from ulcerative colitis patients Inflamed colonic mucosa biopsies from UC patients • Disease phenotype retained with high basal cytokine release • Readouts: IL6 and IL8 - key mediators of UC pathology Tissue samples treated with: • Target-selective tool compound (BEN-3218) • Positive controls - prednisolone and tofacitinib Selective target inhibition showed comparable reduction of IL-6 and IL-8 to the positive controls Validated as a target with a novel mechanism of action for ulcerative colitis Endoscopic Biopsy from UC patients Colonic mucosa organ culture and compound treatment IL-6(pg/ml) 20000 15000- 10000- 5000- 0 ✓ DMSO Prednisolone Tofacitinib BEN-3218 IL-8(pg/ml) 30000 20000- 10000- 0 Inflammatory cytokine measurement L L DMSO Prednisolone Tofacitinib BEN-3218 Benevolent 58#59PDE10 inhibition: potential to normalise dysregulated mechanisms in IBD ● Macrophage M1 M2. Dendritic Cell INF-KB PGE₂ IL-12 IL-6 IL-18 IL-18 IL-23 TNF Th1 IFNY TNFO IL-2 ILC3 TIL-17A IL-22 Th17 IL-17A IL-17F IL-21 IL-22 IL-23 • Reduced inflammatory cytokine release from intestinal epithelia via NFkB(¹) Reduced tissue-resident macrophage activation (¹) Reduced intestinal inflammation PDE10 inhibition ↑ CGMP ↑ CAMP Sources: (1) Harmel-Laws et al PLoS One 2013: (2) Han et al PLoS One 2011; (3) Brenna et al Scand J Gastroenterol 2015 Images: Nettleford and Prabhu, Antioxidants 2018 (left); He et al. Int J Mol Sci 2020 (right) fluid Na* Nutrients action as pena claudins PAMR agent occludin MLCK Nutrients MLCK TNF • Improved TJ assembly via PKG/PKA-mediated pMLC(2) • Improved fluid/mucus homeostasis via PKG phosphorylation of intestinal CFTR (3) Improved barrier integrity Benevolent 59#60BEN-8744 results and progress to date 2020 Target validation 2019 Novel, potent advanced lead molecule developed within 2 years TARGET IDENTIFICATION Novel target for UC ✓ Discovered using Benevolent TargetID tools PDE10 has zero linkage to UC in all available biomedical literature ✓ Experimentally validated in ex-vivo UC colon samples from patients refractory to SoC treatment 2021 Candidate nomination Preclinical CHEMISTRY Rapid and efficient lead optimisation ✓ Molecular Design tools enabled rapid and efficient lead optimisation ✔ Candidate nominated in Sep '21 Novel, potent, selective, peripherally restricted PDE10. Inhibitor, with low dose prediction ✓ Only 2 years from programme initiation 2022 2023 Phase I clinical study CLINICAL DEVELOPMENT Developing responder and progression endotypes We will develop responder and progression endotypes, adding molecular descriptors These will inform our trial design, patient selection and further target identification in UC Augmenting a further loop of iteration on an enriched graph Benevolent 60#61BEN-8744 - Best-in-class, oral, peripherally restricted potent and selective drug for the treatment of Moderate-Severe UC • Phosphodiesterase 10 (PDE10) was identified by our TargetID platform as an entirely novel target for the treatment of UC/IBD • Using our Molecular Design expertise we optimally designed a best in class peripherally restricted PDE10 inhibitor: BEN-8744 • BEN-8744 is expected to provide an efficacious disease modifying oral treatment for UC/IBD • BEN-8744 will target Moderate and Severe UC/IBD patients, meeting the unmet need left by existing therapies including: o Patients refractory to anti-TNFS or other biologics o Improved safety and tolerability profile compared to competitors o A Precision Medicine approach to target key responder patient cohorts, avoiding the safety risks associated with ineffective therapies An opportunity to differentiate on safety, efficacy and a precision medicine approaches Drug Zeposia (Ozanimod) Etrasimod Jyseleca (Filgotinib) Rinvoq (Upadacitinib) TD-1473 Company BMS Arena Galapagos & Gilead Abbvie Theravance & Janssen MOA SIP1 receptor agonist SIP1 receptor agonist JAK1 inhibitor JAKI inhibitor Pan-JAK inhibitor (gut-selective) Safety • S1P1 agonists are associated with immunosuppression and anaemia JAK inhibitors carry a black box health. warning Benevolent 61#62Internal Pipeline - continued progress BEN-2293 | Atopic Dermatitis BEN-8744 | Ulcerative Colitis BEN-9160 | Amyotrophic Lateral Sclerosis BEN-28010 | Glioblastoma Multiforme Inflammatory Bowel Disease Amyotrophic Lateral Sclerosis Antiviral Oncology Oncology Nonalcoholic Steatohepatitis Oncology Parkinson's Disease Parkinson's Disease Chronic Kidney Disease Idiopathic Pulmonary Fibrosis Idiopathic Pulmonary Fibrosis 10+ Exploratory stage programmes Target ID Hit to Lead Lead Opt AstraZeneca AstraZeneca AstraZeneca Preclinical Phase I Phase II Phase III Progress in 1H22 - several programmes have progressed through key DD stage gates GBM - Candidate nominated, IND-enabling studies to begin 2nd ALS asset - transitioned through to Candidate Seeking 2 oncology programmes - transitioned into Lead Optimisation New portfolio entrant for Parkinson's Disease Benevolent 62#63Our Precision Medicine approaches are applied to multiple stages of our pipeline and can support repurposing activities Precision Medicine enabled Target ID Target Identification Hyp Gen & Hyp Val Hit ID & Expansion Discovery Lead Op Candidate Seeking Indication mapping Preclinical Repurposing a target or drug (approved or in development) through the identification of additional disease indications Address additional unmet need Maximise the value of a target or drug programme Identifying key patient cohorts and responders for drugs Optimise clinical development Increase probability of success Improve outcomes for patients Development Phase I Phase II Phase III Approval & Launch Identification of patient cohorts & responders Phase IV Additional indications Commercial & Lifecycle Optimised trial design & patient outcomes for each indication Benevolent 63#64Portfolio key inflection points BEN-2293 Atopic Dermatitis BEN-8744 Ulcerative Colitis H2 2022 BEN-28010 Glioblastoma multiforme Pipeline depth and progression Complete Phase lla clinical study File Clinical Trial Application (CTA) late 2022 Commence iND enabling studies Move at least 1 project into lead opt & Initiate 2 - 4 new drug discovery programmes 2023 Full data package available Q1 2023 Begin Phase I study early 2023 Submit Clinical Trial Application (CTA) Expect to add 4-6 names drug programmes 2024 Phase I data package early 2024, with Phase II to follow shortly after Initiate Phase I study Aim to progress 1-2 CTA/IND stage drug candidates every year Benevolent 64#65Interim Results - H1 Operational & Financial Review 6 months ended 30 June 2022 Nick Keher, CFO Benevolent#66H1 2022 Highlights 1 Continued progress across in-house pipeline 2 3 4 5 6 7 Consistent delivery in collaboration with AstraZeneca - non-commercial collaborations progressing Full FDA approval of COVID-19 treatment first identified by BenevolentAl Continuous enhancement of the Benevolent Platform™ Completed Business Combination/listed Amsterdam EuroNext - raised gross proceeds of €225m Strengthened Board of Directors and Leadership Building Business Operations capability for long term success Benevolent 66#671H 2022 Financial highlights Revenue R&D - Drug discovery ["DD"]¹ R&D - Product & technology ["P&T"]¹ G&A - Business operations ["Bus Ops"]¹ Underlying expenses related to share-based payments Other income Normalised operating loss Normalised EPS (in pence)² Weighted average ordinary shares outstanding (in millions) Six months ended 30 June 2022 £'000 4,843 (19,292) (10,684) (8,074) (22,145) 72 (55,280) (44.7) 100.5 2021 £'000 1,664 (12,957) (9,940) (7,000) (18,343) 74 (46,502) (45.8) 89.8 1) Excludes exceptional costs related to the Business Combination 2) Normalised EPS also excludes taxation impact from exceptional items and finance income related to the Business Combination Revenue increase across AstraZeneca collaboration, with a milestone reached related to the second novel target for idiopathic pulmonary fibrosis. DD spend increase driven by portfolio advancing into later stages of development, in particular BEN-2293 entering adaptive Phase I/II clinical study. P&T spend increase reflecting increased headcount, which is set to plateau. Bus Ops spend +15%, driven predominantly by listing status but expected to maintain at this level. Benevolent 67#68Walk from Reported to Normalised¹ Reported operating loss Adjustments for: G&A- Exceptional share-based payment ("SBP") expenses G&A Direct Transaction costs G&A - Non-cash listing service expense Normalised¹ group operating loss 1) Excludes exceptional costs related to the Business Combination Six months ended 30 June 2022 £'000 (134,547) 2,611 11,255 65,401 (55,280) 2021 £'000 (46,502) (46,502) Reported loss significantly driven by non-recurring costs of Business Combination. Non-cash exceptional costs related to acceleration of share based payments also incurred from Business Combination, and set to reduce beyond 2022. Non-cash listing service expenses reflects cost of share issuance to Odyssey SPAC as part of Business Combination net of assets acquired (before PIPE and backstop) Benevolent 68#69Cashflows focused upon drug and platform development Normalised¹ operating loss Depreciation & amortisation Foreign exchange Equity share-based payment Cash flows from changes in working capital Cash expended from underlying operating activities Opening cash balance Closing cash balance 1) Excludes exceptional costs related to the Business Combination Six months ended 30 June 2022 £'000 (55,280) 1,506 (1,589) 21,913 (12,312) (45,762) 40,553 165,338 £0.3m lab equipment; £0.1m computer; £1.1m property-related leases £3m charge from Euro holdings, £1.8m gain from operational Non-Transaction-related equity awards removed from the P&L (no cash impact) Largely driven by outstanding R&D tax credit receivable (£12m) expected in 2H and other payable decreases End-June cash position of £165.3m provides ample liquidity to meet multiple key value inflection points Benevolent 69#70Cash runway to Q4-2024 providing sufficient capital for key value inflection points Cash Runway Cash at 30th June 2022 H2 2022 cash spend £165m £36m-£40m BEN-2293 trial costs (c.£15m) fall away in 2023 Cash runway guidance assumes no future capital from licensing or collaboration agreements Multiple assets at or close to key value inflection points and ready for out-licensing Benevolent 2 Capital allocation Fund Phase I/II trial for BEN-2293 in Atopic Dermatitis (before subsequent out-license) Fund Phase I trial for BEN-8744 in Ulcerative Colitis and commencement of Phase II trial in 2024 Prioritisation of clinical spend on target Therapeutic Indications, with 2 Phase I trial starts by 2025 Continuous enhancement of the Benevolent Platform™ Investment to support listing status and further collaborations Benevolent 70#71Closing Remarks and Outlook Joanna Shields, CEO Benevolent#72Benevolent • Investment Highlights Market leader in Al drug discovery with scientifically and technologically differentiated approach Significant platform scale and internal capability Rich portfolio of drug programmes all generated from the Benevolent Platform™ High-value and successful commercial partnership proving strategic validation Robust IP with patents on drug pipeline and copyright and trade secrets on our technology platform Flexible business model with revenue opportunities to extend cash runway Near and medium-term key value inflection points World-renowned Board and experienced leadership team Benevolent 72#73Poised for growth and success Strengthened financial position enhances our leadership position in Al-enabled drug discovery and enable us to: ✓ Independently pursue the clinical development of certain in-house pipeline assets in core therapeutic areas ✓ Out-license multiple assets over the next 1-3 years to strengthen our balance sheet and drive long term value creation ✓ Increase the size of our pipeline with a healthy balance of new first-in-class and best-in-class assets with 1-2 CTA / IND-stage drug candidates every year ✓ Sign new collaboration agreements with pharma companies to to leverage our disease agnostic capabilities into therapeutic indications outside our focus areas, to generate incremental revenue ✔ Maintain our leading position in Target ID through increased investment in our technology capabilities ✓ Build out our technology metrics to exemplify the differentiation of our approach Benevolent 73#74# Because benevolent.com @benevolent_ai A matters in benevolentai [email protected]