Slide 1: Decoding Biology To Radically Improve Lives
9g Recursion. Decoding Biology To Radically Improve Lives January 2024
Slide 2: Forward-looking statements
This presentation and any accompanying discussion and documents contain information that includes or is based upon "forward-looking statements" within the meaning of the Securities Litigation Reform Act of 1995. These forward-looking statements are based on our current expectations, estimates and pr
Slide 3: Digital data, profile systems and algorithms
Digital (bits) Data Aggregate and organize data to create digital maps of reality 2 2 Real (atoms) 1 Profile Systems Capture high-dimensional data to create a digital record of reality (things, places, preferences, etc.) 1 Algorithms Navigate digital maps to predict novel relationships, then try the
Slide 4: Reproducibility crisis, analog standard, siloed data
Reproducibility Crisis Multiple studies have shown that the vast majority of published academic literature cannot be recapitulated Analog Standard The fax machine is alive and well in medicine, while in biopharma, study results from CROs are still often reported as PDFs or scanned printouts Siloed D
Slide 5: Algorithms, profile systems and data
Algorithms We own and operate one of the fastest supercomputers on earth, allowing us to train LLMs & FMs fit for the purpose of drug discovery Profile Systems We have built and continue to scale among the world’s most prolific automated wet labs Data Each week we digitize millions of our own experi
Slide 6: The Recursion OS combines many tools to industrialize drug discovery
The Recursion OS combines many tools to industrialize drug discovery amare, wile ra -_ ecsbaeididiali oo Yan trained ead ' Invivomie Prortization automated nt writing LLMs query global 2M physical compounds & knowledge for program ~368 compounds with ideation & evaluation, target predictions ‘Curren
Slide 7: In Brief: The Recursion Value Proposition
In Brief: The Recursion Value Proposition 7
Slide 8: Failing faster and earlier to explore biology at scale
Screen — Hit ID — Validated Lead — Advanced Candidate — Development Candidate — Industry Recursion Failing faster and earlier to › 100 80 60 51 80% 75% 85% 100 55 18 55% 33% 62% 7 37% St ag e 40 — 30 — 20 — 10 — 0 — › explore biology at scale efficiently Ti m e to V al id at ed L ea d (m o) Industry
Slide 9: Pipeline, partnership and data strategy
Pipeline Build internal pipeline in indications with potential for accelerated path to approval Pipeline Strategy Precision Oncology Rare Disease Partnerships Data Partnership Strategy Partner in complex therapeutic areas requiring large financial commitment or competitive arbitrage Leverage partner
Slide 10: Build internal pipeline in indications with accelerated path
Build internal pipeline in indications with potential for accelerated path to approval Pipeline Strategy Precision Oncology Rare Disease Pipeline Partnerships Data *Includes a single oncology indication from our Roche and Genentech collaboration.10
Slide 11: Pipeline by therapeutic area and indication
PreclinicalLate DiscoveryTherapeutic Area Indication Rare & Other CEREBRAL CAVERNOUS MALFORMATION (CCM; est. 360K1) NEUROFIBROMATOSIS TYPE 2 (NF2; est. 33K2) CLOSTRIDIOIDES DIFFICILE INFECTION (est. 730K) Phase 1 Phase 2 Phase 3 11 More than a dozen additional early discovery and research programs i
Slide 12: Partnership Strategy
Partnership Strategy Partner in complex therapeutic areas requiring large financial commitment or competitive arbitrage Leverage partner knowledge and clinical development capabilities Undruggable Oncology Other large, intractable areas of biology (e.g. CV/Met) Neuroscience* Pipeline Partnerships Da
Slide 13: Partnership terms: Roche, Bayer, NVIDIA, Tempus
Undruggable oncology targets • $30M upfront and $50M equity investment • Increased per program milestones which may be up to $1.5B for up to 7 oncology programs • Mid single-digit royalties on net sales • Recursion owns all algorithmic improvements Neuroscience and a single oncology indication • $15
Slide 14: Data strategy and licensing
Pipeline Partnerships License subsets of data and key tools Direct generation of new data internally to maximize pipeline and partnership value-drivers Data Strategy Licensing Augment Recursion OS Data *Includes a single oncology indication from our Roche and Genentech collaboration.14
Slide 15: The future of TechBio
The future of TechBio 15
Slide 16: Point solutions in drug discovery: Phenomics
Most BioTech companies have built a point solution - they’ve developed a tool, process, model or analysis to accomplish an important step in drug discovery. This is how we started too. But discovering and developing medicines requires hundreds of steps… Phenomics 16
Slide 17: Phenomics and Phenom-1 foundation model
We manipulate human cells with CRISPR/Cas9- mediated gene knockouts, compounds, and other reagents Phenom-1 Groundbreaking models trained on >1 billion images and hundreds of millions of parameters learn to extract biologically meaningful signals from cell images FOUNDATION MODELS Diverse biological
Slide 18: Integrating point solutions as modules
To truly industrialize drug discovery, point solutions must be integrated as modules across many diverse steps Patient Connectivity & Novelty. Invivomi Prontization Hit Target Validation und Optimization rrr : Clinical Development Cae s Satoh ne ‘Currently being explored 18 @ Recursion
Slide 19: DMPK module
Prioritize compound synthesis for compounds predicted to have high likelihood of suitable pharmacokinetics DMPK In Vivo Validation Establish in vitro-in vivo and in silico-in vivo correlations to minimize experimental toil. ANIMAL PHARMACOKINETICSPre-synthesis Evaluation ENRICH FOR QUALITY A highly
Slide 20: InVivomic prioritization
InVivomic prioritization Digitized data collection yields real-time, continuous, and non-invasive data recorded in the animal’s home cage. Data generates high-dimensional assays, and ML connects studies for productivity. Overall, there is a drastic reduction in time, labor, and cost. Industrialized
Slide 21: Tempus data and BioHive-1 supercomputer
The Tempus data is computed and ML oncology models run on BioHive-1, Recursion’s in-house supercomputer. BioHive-1 will be expanded into a top 50 supercomputer in 2024 in partnership with Nvidia. ML trained on Tempus data BioHive-1 supercomputer COMPUTE The Tempus partnership provides Recursion with
Slide 22: Palette of ever-evolving modules
The result is a palette of ever-evolving sophisticated modules 5 © Phenomics Compound Patient-specific Phenom-1 Chemical InVivomic selection with ML hypotheses tractability prioritization IN gas im ©) &8 Kew LLMs & literature InVivomic Chemical property Predicted target Tempus data Phenomic search e
Slide 23: Modules to find NCE for known target
We use different modules for different tasks: Find NCE for known target Phenomics Compound InVivomic selection with ML prioritization Chemical property Phenomic predictions efficacy @ MatchMaker Digital tolerability @ Recursion
Slide 24: Modules to find novel target and drug it
We use different modules for different tasks: Find novel target & drug it Phenomics Compound InVivomic selection with ML prioritization ess) LLMs & literature Chemical property Phenomic search predictions efficacy Transcriptomics MatchMaker Digital tolerability @ Recursion
Slide 25: Slide 25
Slide 26: LOWE demonstration: target listing
26 Static images taken from live software demonstration LOWE hops you orchestrate complicated workflows using natural language, ‘Try one of the tampates below of entra prompt manually. Listing Known Targets Associated witha Specific Prenotype Ioenttying Top Compounds with Sinilar Phenoprins toa Give
Slide 27: LOWE demonstration: compound ordering
7 Static images taken from live software demonstration O EEE pe moon SD ‘To user nas request to tnd ne top 0 commerciaty aatate compounds Sat gen SMILES string an nen place an oder for $0 wi rt ue the Matimlortyeneh tol ond the op 50 snaar compounds andthe se the OreCampeumds Pal a place nord or the
Slide 28: Discovery User Interface
…it is increasingly integrated and accessible via a Discovery User Interface that can be used by any of our scientists from the comfort of their laptop… 28
Slide 29: 2023 accomplishments
Pipeline • Multiple Phase 2 trials began or continued enrolling patients • Positive C Diff Phase 1 data • Progress against multiple discovery and preclinical NCE programs moving towards the clinic Platform • LLMs deployed to automate significant portions of new program initiation • Creation of Pheno
Slide 30: Expected 2024 milestones
• Potential for additional INDs • HR-Proficient Ovarian Cancer RBM39 in H2 2024 • In-licensed program from Bayer (Target Epsilon) for a novel target in fibrosis • Expected Ph2 Trial starts • Ph2 FPI for AXIN1 or APC mutant cancers program expected in Q1 2024 • Ph2 initiation for C. difficile Infecti
Slide 31: Recursion
6 Recursion.
Slide 32: Appendix
GRecursion Appendix
Slide 33: Clinical: CCM
Julia – living with CCM 33 Clinical: CCM Symptomatic US + EU5, >1 million patients worldwide live with these lesions today PREVALENCE & STANDARD OF CARE CAUSE LOF mutations in genes CCM1, CCM2 & CCM3, key for maintaining the structural integrity of the vasculature due to unknown mechanisms PATHOPHYS
Slide 34: CCM trial design and update
34 Source: https://www.clinicaltrials.gov/ct2/show/NCT05130866?term=recursion&draw=2&rank=3; https://www.SycamoreCCM.com/ Screening & Randomization 1:1:1 Treatment Follow-up Outcome Measures Enrollment Criteria • MRI-confirmed CCM lesion(s) • Familial or sporadic • Symptoms directly related to CCM •
Slide 35: Clinical: NF2
35 Clinical: NF2 LOF mutations in NF2 tumor suppressor gene, leading to deficiencies in the tumor suppressor protein merlin PATHOPHYSIOLOGY & REASON TO BELIEVE Efficacy in Recursion OS, cellular, and animal models; suppression of aberrant ERK, AKT, and S6 pathway activation in a Phase 1 PD Study in
Slide 36: NF2 Phase 2/3 trial design
Phase 2/3 trial initiated in Q2 2022 Outcome Measures Enrollment Criteria • MRI-confirmed progressive meningioma • Either of the below • Sporadic meningioma with confirmed NF2 mutation • Confirmed diagnosis of NF2 disease • Primary: Safety and tolerability • Progression-free survival • Time to progr
Slide 37: Clinical: FAP
37 Clinical: FAP Polyps Found in Colon and Upper GI Tract Inactivating mutations in the tumor suppressor gene APC PATHOPHYSIOLOGY & REASON TO BELIEVE KEY ELEMENTS • Targeting classical FAP patients (with APC mutation) • MEK inhibitor, small molecule • Oral dosing • FPI for Part 2 expected H1 2024 •
Slide 38: FAP Phase 2 trial design
38 Clinical: FAP Part 2 FPI Expected H1 2024 Outcome Measures Enrollment Criteria • Confirmed APC mutation • ≥ 55 years old • Post-colectomy/proctocolectomy • No cancer present • Polyps in either duodenum (including ampulla of vater) or rectum/pouch • Primary: • Safety & Tolerability • Change from b
Slide 39: Clinical: AXIN1 or APC mutant cancers
39 LOF mutations in AXIN1 or APC tumor suppressor genes PATHOPHYSIOLOGY & REASON TO BELIEVE Alterations in the WNT pathway are found in a wide variety of tumors and confer poor prognosis and resistance to standard of care Substantial need for developing therapeutics for patients harboring mutations
Slide 40: AXIN1 or APC Phase 2 trial design
Expect FPI in Q1 2024 Outcome Measures Enrollment Criteria • Unresectable, locally advanced, or metastatic cancers • ≥ 55 years old • AXIN1 or APC mutation confirmed by NGS (tissue or blood) • CRC patients must be RAS / RAF wildtype • No MEK inhibitor treatment within 2 months of initial dose • ≥ 1
Slide 41: Clinical: C. difficile
41 Colleen – lived with rCDI C. difficile toxins from colonizing bacterium causes degradation of colon cell junction, toxin transit to bloodstream, and morbidity to host PATHOPHYSIOLOGY & REASON TO BELIEVE Highly recurrent infectious disease with severe diarrhea, colitis, and risk of toxic megacolon
Slide 42: REC-3964 extended survival over SOC
REC-3964 significantly extended survival over SOC Clinical: C. difficile 42 • REC-3964 potently inhibits toxin B with residual activity against toxin A, while bezlotoxumab is specific to toxin B. • Significant difference in probability of survival vs bezlotoxumab alone at the end of treatment (p<0.0
Slide 43: REC-3964 Phase 1 topline
43 Trial Design • Randomized, Double-blind Trial Population • Healthy Participants • SAD (n = 48) • 36 participants treated with REC-3964 • 12 participants treated with placebo • MAD (n = 42) • 34 participants treated with REC-3964 • 8 participants treated with placebo Primary Objectives ü Assess th
Slide 44: C. difficile Phase 2 development approach
Development Approach • Initial Phase 2 POC study to evaluate REC-3964 in combination with vancomycin • Focus on subjects at risk for CDI with moderate to severe disease planning to receive SOC therapy • Flexibility to assess effects of REC-3964 on both treatment and reduction of recurrence populatio
Slide 45: Preclinical: HR-proficient ovarian cancer
45 CDK13 RBM39 CDK12 2.5μM RBM39 1.0μM 2.5μM 0.1μM 0.25μM 1.0μM REC-65029 0.1μM 0.25μM CDK13 CDK12 REC-65029 Similar Opposite BRCA-proficient ovarian cancer PDX Preclinical: HR-Proficient Ovarian Cancer Identify potential first-in-class tumor-targeted precision therapeutic NCE with novel MOA capable
Slide 46: RBM39 program overview
46 • Recursion OS identified RBM39 as a novel target capable of mimicking CDK12 biology independent of CDK13 • Lead molecule has demonstrated durable regressions across HRP and HRD cell line and patient derived xenografts • Program advanced from target identification to IND-enabling stages in under
Slide 47: Preclinical: undisclosed indication in fibrosis
Preclinical: Undisclosed Indication in Fibrosis Healthy StateDiseased State Reversal of Fibrocyte Differentiation AssayIdentify a potential first-in-class therapeutic NCE with a novel MOA capable of reversing disease-related fibrotic processes Recursion-generated hits show concentration-dependent re
Slide 48: Value driven by our team and our milestones
Value driven by our team and our milestones GS Recursion
Slide 49: Team members and ESG highlights
Advanced degreesEmployees Team Members >500 >50% ESG Highlights ü ESG reporting on Healthcare and Technology Metrics ü 100% of electricity powering our Biohive-1 supercomputer comes from renewable sources ü Learn more about Recursion’s ESG stewardship: www.recursion.com/esg ~44% Female Male ~55% ~1%
Slide 50: Board of Directors and Executive Team
50 Board of Directors Dean Li, MD PHD Co-Founder of RXRX, President of Merck Research Labs Rob Hershberg, MD PHD Co-Founder/CEO/Chairman of HilleVax, Former EVP/CSO/CBO of Celgene Blake Borgeson, PHD Co-Founder of RXRX Terry-Ann Burrell, MBA CFO & Treasurer, Beam Therapeutics Zavain Dar Co-Founder &
Slide 51: Whole-genome CRISPR knock-out map
This is a whole-genome arrayed CRISPR knock-out Map generated in primary human endothelial cells Every gene is represented in a pairwise way (each is present in columns and rows) Dark Red indicates phenotypic similarity according to our neural networks while Dark Blue indicates phenotypic anti- simi
Slide 52: JAK/STAT pathway clustered by interaction
One such example – the JAK / STAT pathway clustered by strength of interaction, including both similar genes (red) and opposite genes (blue) Can wade into areas of novel biology and chemistry… 52 JAK1 TNKS1BP1 PPP1R9B PHF13 SOCS3 PRKCH MEGF8 ASB7 SLC39A1 DOCK9 ZMYM3 FAM49B STK24 YWHAB IL6ST IL6R STA
Slide 53: Integrator complex map replication
Trademarks are the property of their respective owners and used for informational purposes only. 53 INTS9 INTS11 INTS4 INTS7 INTS2 INTS8 INTS1 INTS6 C7orf26 INTS10 INTS13 INTS14 IN TS 14 IN TS 13 IN TS 10 C7 or f2 6 IN TS 6 IN TS 1 IN TS 8 IN TS 2 IN TS 7 IN TS 4 IN TS 11 IN TS 9 Phenomics TVN (belo
Slide 54: MatchMaker computation at scale
54 ~36 Billion Compounds from the Enamine Real Space ~80,000 predicted binding pockets from ~15,000 human proteins ~2.8 Quadrillion potential protein- ligand interactions computed and stored Recursion partnered with to integrate and optimize MatchMaker (acquired via ) for massive scale GPU-based com
Slide 55: CRISPR-Cas9 chromosome arm truncations
• Recursion demonstrated that CRISPR-Cas9 editing induces chromosome arm-scale truncations across the genome • Creates a proximity bias in CRISPR screens which can confound some gene-gene relationships • Recursion demonstrated a correction method leveraging public CRISPR-Cas9 knockout screens to mit
Slide 56: RxRx19 COVID-19 predictions
Drug Prediction Correct? Hydroxychloroquine x ✓ Lopinavir x ✓ Ritonavir x ✓ Remdesivir ✓ ✓ Baricitinib ✓ ✓ Tofacitinib ✓ ✓ Fostamatinib ✓ ✓ Ivermectin* x ✓ Fluvoxamine x ✓ Dexamethasone x x 56https://www.biorxiv.org/content/10.1101/2020.04.21.054387v1 • Recursion conducted several AI-enabled experim
Slide 57: REC-994 for CCM
REC-994 for the Treatment of Symptomatic Cerebral Cavernous Malformations (CCM) Target / MOA Superoxide Scavenger Molecule Type Small Molecule Lead Indication(s) Cerebral Cavernous Malformations Status Phase 2 Designation(s) US & EU Orphan Drug Source of Insight Recursion OS
Slide 58: Unmet need in CCM
58 • Large unmet need for a novel nonsurgical treatment • Vascular malformations (cavernomas) in the brain and spinal cord • High-risk for hemorrhage creates “ticking time bomb” • Progressive increase in CCM size and number over time in those with familial disease • Debilitating symptoms, including
Slide 59: CCM patient population
59 Sources: Angioma Alliance ; Flemming KD, et al . Population-Based Prevalence of Cerebral Cavernous Malformations in Older Adults: Mayo Clinic Study of Aging. JAMA Neurol. 2017 Jul 1;74(7):801-805. doi: 10.1001/jamaneurol.2017.0439. PMID: 28492932; PMCID: PMC5647645 ; Spiegler S, et al Cerebral Ca
Slide 60: Non-oncology orphan indication comparison
60 Non-oncology Orphan Indication Product U.S. + EU5 Prevalence Cerebral cavernous malformation (CCM) REC-994 (Recursion) >1,800,000 (Symptomatic: ~360,000) Idiopathic pulmonary fibrosis (IPF) Esbriet (pirfenidone) >160,000 Cystic fibrosis (CF) VX-669/ VX-445 + Tezacaftor + Ivacaftor - Vertex >55,00
Slide 61: Vascular Stability Hypothesis
61 • Symptoms associated with both increased size of lesions, but also inflammation or activation of lesions within the immunoprivileged environment of the brain • Lesions arise from the capillary bed and are not high-pressure (e.g., the lesion growth is unlikely to be primarily driven by the law of
Slide 62: Identification of REC-994
Clinical: CCM Gibson, et al. Strategy for identifying repurposed drugs for the treatment of cerebral cavernous malformation. Circulation, 2015 siCTRL siCCM2 siCCM2 + Simvastatin siCCM2 + Cholecalciferol siCCM2 + REC-994 Using an early version of our Recursion OS in an academic setting, we identified
Slide 63: REC-994 mechanism of action
Healthy REC-994 ImpactCCM Clinical: CCM • Endothelial cell activation • Smooth muscle proliferation • Leukocyte adhesion • Platelet aggregation By regulating SOD2, CCM1 (KRIT1) & CCM2 suppress: CCM1 or CCM2 loss of function leads to activated endothelium: • Decreased cell-cell junctional integrity a
Slide 64: REC-994 preclinical mouse model data
64 Source: Data above from Gibson, et al. Strategy for identifying repurposed drugs for the treatment of cerebral cavernous malformation. Circulation, 2015 or Recursion internal data (Ccm1 mouse model) Preclinical Studies: REC-994 reduces lesion burden and ameliorates vascular defects in genetic mou
Slide 65: REC-994 Phase 1 safety
REC-994 Phase 1 Studies - well-tolerated with no dose-dependent adverse events in SAD and MAD Clinical: CCM MAD Study Placebo 50 mg 200 mg 400 mg 800 mg Total Number of TEAEs Total Subjects with ≥ one TEAE 5 4 0 0 10 3 4 3 15 4 Severity Mild Moderate Severe 3 1 0 0 0 0 3 0 0 3 0 0 3 1 0 Relationship
Slide 66: REC-994 Target Product Profile
66 Target Product Profile: Drug-like properties support oral dosing QD. Therapeutic exposures achievable in humans Well-tolerated with no DLTs or SAEs in Phase 1. No treatment-related discontinuations REC-994 for Symptomatic Cerebral Cavernous Malformations (CCM) Differentiated mechanism of action.
Slide 67: REC-994 program overview
67 • First therapeutic candidate advanced to an industry-sponsored Phase 2 trial (SYCAMORE) for CCM • Partnered with leading KOLs at University of Rochester to develop a CCM PRO instrument for clinical trials • Putative MOA decreases ROS and oxidative stress to rescue pathogenetic endothelial dysfun
Slide 68: REC-2282 for NF2 meningiomas
REC-2282 for the Treatment of Progressive Neurofibromatosis Type 2 (NF2) Mutated Meningiomas Target / MOA HDAC Inhibitor Molecule Type Small Molecule Lead Indication(s) NF2 Mutated Meningiomas Status Phase 2/3 Designation(s) Fast Track; US and EU Orphan Drug Source of Insight Recursion OS
Slide 69: NF2 patient population
69 Source: https://rarediseases.org/rare-diseases/neurofibromatosis-2 Patient Population – Large and Diagnosable No Approved Medical Therapy • Rare autosomal dominant tumor syndrome resulting from biallelic inactivation of the NF2 gene which leads to deficiencies in the tumor suppressor protein merl
Slide 70: NF2 meningioma population
70 • Threatens mortality; if amenable, surgical excision is primary intervention • Many patients have multiple meningiomas that exhibit heterogenous behavior and asynchronous growth • Stasis or shrinkage of tumor could improve prognosis Clinical: NF2 ● Most tumors are benign and slow growing but loc
Slide 71: REC-2282 rescue of NF2 knockdown cells
71 NF2 knockdown cells Healthy Cells REC-2282 REC-2282 identified as rescuing HUVEC cells treated with NF2 Co nt ro l N F2 si RN A HUVEC, human umbilical vein endothelial cells; NF2, neurofibromatosis type 2; siRNA, small interfering RNA. Clinical: NF2 71
Slide 72: HDAC inhibitor mechanism in NF2
72 AKT, protein kinase B; eIF4F, eukaryotic initiation factor 4F; HDAC, histone deacetylase; mTor, mammalian target of rapamycin; mTORC1; mammalian target of rapamycin complex 1; NF2, neurofibromatosis type 2; PI3K, phosphoinositide 3-kinase; PP1, protein phosphate 1; Ras, reticular activating syste
Slide 73: REC-2282 preclinical in-vivo efficacy
73 REC-2282 preclinical studies demonstrated clear in-vivo efficacy in multiple NF2 tumor types Shrinks vestibular schwannoma xenografts in nude mice Prevents growth & regrowth of NF2- deficient meningioma model in mice Vehicle % Change tumor vol. REC-2282 % Change tumor vol. % c ha ng e in tu m or
Slide 74: REC-2282 clinical safety and PFS
• Evaluable Patients: CNS Solid Tumors: NF2 N=5; Non-CNS Solid Tumors: N=10 • PFS: CNS solid tumors = 9.1 months; Non-CNS solid tumors = 1.7 months • Best overall response = SD in 8/15 patients (53%; 95% CI 26.6–78.7) • Longest duration of follow-up without progression: > 27 months (N=1) • Most comm
Slide 75: First-in-disease HDAC inhibitor for NF2
75 1 Sborov DW, et al. A phase 1 trial of the HDAC inhibitor AR-42 in patients with multiple myeloma and T- and B-cell lymphomas. Leuk Lymphoma. 2017 Oct;58(10):2310-2318. 2 Collier KA, et al. A phase 1 trial of the histone deacetylase inhibitor AR-42 in patients with neurofibromatosis type 2-associ
Slide 76: REC-2282 Target Product Profile
76 Target Product Profile: Preliminary evidence of PK/PD in Phase 1. First-in-disease potential Differentiated profile versus other HDACs. Low/minimal QTc prolongation observed Well-established safety profile. 50+ patients exposed across 4 ISTs Brain-penetrant and orally bioavailable. Preferential d
Slide 77: REC-2282 program overview
77 • Orally bioavailable small molecule inhibitor of class I and class IIB HDACs in Phase 2/3 (POPLAR) trial • Unique MOA that disrupts PP1-HDAC interface, attenuating pathophysiologic p-AKT without affecting total AKT • Fast Track Designation in NF2 mutant meningioma granted by FDA in 2021 Program
Slide 78: REC-4881 for FAP
REC-4881 for the Treatment of Familial Adenomatous Polyposis (FAP) Target / MOA MEK Inhibitor Molecule Type Small Molecule Lead Indication(s) Familial Adenomatous Polyposis Status Phase 2 Designation(s) Fast Track; US and EU Orphan Drug Source of Insight Recursion OS
Slide 79: FAP patient population
79 Patient Population – Easily Identifiable Clinical: FAP ~50,000 Diagnosed US + EU5 patients • Autosomal dominant tumor predisposition syndrome caused by a mutation in the APC gene • Classic FAP (germline mutation) : • Hundreds to thousands of polyps in colon and upper GI tract • Extraintestinal ma
Slide 80: No approved medical therapy for FAP
80 No Approved Medical Therapy • Standard of care: colectomy during adolescence (with or without removal of rectum) • Post-colectomy, patients still at significant risk of polyps progressing to GI cancer • Significant decrease in quality-of-life post-colectomy: continued endoscopies and surgical int
Slide 81: REC-4881 rescued APC knockdown cells
81 REC-4881 rescued phenotypic defects of cells with APC knockdown 0.1 µM REC-4881 • Compared to thousands of other molecules tested, REC-4881 rescued phenotypic defects substantially better (including better rescue than other MEK inhibitors) for APC specific knockdown • Findings validated in tumor
Slide 82: MEK inhibitor mechanism
82 Jeon, WJ, et al. (2018). Interaction between Wnt/β-catenin and RAS-ERK pathways and an anti-cancer strategy via degradations of β-catenin and RAS by targeting the Wnt/β-catenin pathway. npj Precision Oncology, 2(5). 3 3 REC-4881 inhibits MEK 1/2 and recovers the destabilization of RAS by the β-Ca
Slide 83: In-vivo efficacy in APCmin mouse model
83 APC, adenomatosis polyposis coli; ERK, extracellular signal-regulated kinase; FAP, familial adenomatous polyposis. Clinical: FAP ↓ High-Grade Dysplasia 2• In-vivo efficacy in APCmin mouse model • Apcmin = FAP disease model • Mice treated once daily for 8 weeks After 8 weeks of treatment: ↓ Polyp
Slide 84: REC-4881 healthy volunteer study
84 Note: AE, adverse event; MEK, mitogen-activated protein kinase; NHV, normal healthy volunteer; pERK, phosphorylated extracellular signal-regulated kinase; SAE, serious adverse event. REC-4881-101: Single-center, double-blind, placebo- controlled, dose-escalation study in healthy volunteers • Grou
Slide 85: REC-4881 Target Product Profile
85 Differentiated profile versus other MEKs. Low clearance and minimal hepatic metabolism Acceptable safety profile consistent vs other MEKs. 5 FAP patients treated in Part 1 of TUPELO REC-4881 for Familial Adenomatous Polyposis (FAP) Drug-like properties support oral dosing QD. Target engagement ob
Slide 86: REC-4881 FAP program overview
86 • Orally bioavailable, small molecule non-ATP competitive allosteric inhibitor of MEK 1/2 in Phase 2 (TUPELO) • REC-4881 appears more active versus approved MEK inhibitors in disease relevant preclinical models • Fast Track Designation in FAP granted by FDA in 2022 Program Overview First-in-disea
Slide 87: REC-4881 for AXIN1 or APC mutant cancers
REC-4881 for the Treatment of Solid Tumors with AXIN1 or APC Mutant Cancers Target / MOA MEK Inhibitor Molecule Type Small Molecule Lead Indication(s) Solid Tumors with AXIN1 or APC Mutant Cancers Status Phase 2 Source of Insight Recursion OS
Slide 88: Sustained Wnt signaling in solid tumors
88 • Sustained Wnt signaling is a frequent driver event found across a wide variety of solid tumors • Dysregulation of β-catenin destruction complex due to inactivating mutations in AXIN1 or APC leads to sustained Wnt signaling promoting cancer progression and survival1 • AXIN1 or APC mutant solid t
Slide 89: Patient selection and treatable populations
89 • AXIN1 and APC genes covered by commercially available NGS panels and liquid biopsy detection assays • FDA guidance supports utility of ctDNA as patient selection for the detection of alterations for eligibility criteria and as a stratification factor for trials enrolling marker-positive and mar
Slide 90: REC-4881 rescues APC and AXIN1
AXIN 1 APC 2.5 μM 1.0 μM 0.1 μM 0.2 5μ M REC-4881 Dosage Hypothesis: Rescue of AXIN1 may impact tumor progression and/or restore checkpoint sensitivity in cancers driven by AXIN1 loss Recursion Differentiation: REC-4881 rescues tumor suppressor genes APC and AXIN1 • APC and AXIN1 are negative regula
Slide 91: REC-4881 PDX model efficacy
-20 0 20 40 60 80 100 Clinical: AXIN1 or APC Note: REC-4881 dosed at 3 mg/kg QD for up to 21 days. 3 mice per treatment per model (3 x 3 x 3) design. 1 Wong, H., et al. Clin Cancer Res, 2012, 18:14, pp.3846-3855 91 AXIN1 or APC wildtype 0 5 10 15 20 0.0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1.0 Wildty
Slide 92: REC-4881 Target Product Profile
92 REC-4881 for AXIN1 or APC mutant cancers Drug-like properties support oral dosing QD. Pharmacologically active at low doses Acceptable safety profile versus other MEKs. 51 solid tumor patients treated in Phase 1 Differentiated versus other MEKs. Low clearance and minimal hepatic metabolism Potent
Slide 93: REC-4881 AXIN1 or APC program overview
93 • Orally bioavailable, small molecule non-ATP competitive allosteric inhibitor of MEK 1/2 in Phase 2 (LILAC) • First therapeutic candidate advanced to a Phase 2 signal finding study in AXIN1 or APC mutant cancers • Utilizing Tempus and FMI clinical trial solutions for patient identification and e
Slide 94: REC-3964 for rCDI
REC-3964 for the Prevention of Recurrent C. difficile Infection (rCDI) Target / MOA Selective C. difficile Toxin Inhibitor Molecule Type Small Molecule Lead Indication(s) Prevention of rCDI Status Phase 2 Source of Insight Recursion OS
Slide 95: rCDI patient population and unmet need
Source, CDC *NAAT = Nucleic Acid Amplification Test; **rCDI = recurrent CDI • RCDI** occurs in 20-30% of patients treated with standard of care • 40% of those patients will continue to recur with 2+ episodes • >29,000 patients die in the US each year from CDI • Cost burden of up to $4.8bn annually 9
Slide 96: C. difficile disease progression
96 Disruption of microbiota and colonization of C. diff Release of C. diff toxins Degradation of colon cell junction & toxin transit to bloodstream Source: McCollum, D,, Rodriguez, JM . Detection, Treatment, and Prevention of Clostridium difficile Infection. Clinical Gastroenterology and Hepatology
Slide 97: REC-3964 rescue in HUVEC cells
REC-3964 identified as a NCE that demonstrated strong rescue in HUVEC cells treated with C. difficile toxin C. difficile toxin B phenotype Healthy Control Disease State Healthy Cells REC-3964 0.1 µM 97 Clinical: C. difficile
Slide 98: REC-3964 extended survival over SOC
REC-3964 significantly extended survival over SOC Clinical: C. difficile 98 • REC-3964 potently inhibits toxin B with residual activity against toxin A, while bezlotoxumab is specific to toxin B. • Significant difference in probability of survival vs bezlotoxumab alone at the end of treatment (p<0.0
Slide 99: REC-3964 MAD study safety
MAD Study Placebo (N=8) n ( %) 100 mg (N=10) n ( %) 300 mg (N=8) n ( %) 500 mg (N=8) n ( %) 900 mg (N=8) n ( %) REC-3964 Overall (N=34) n ( %) MAD Overall (N=42) n ( %) Total Number of TEAEs 17 24 5 9 7 45 62 Total Participants with ≥ 1 TEAE 6 ( 75.0) 8 ( 80.0) 4 ( 50.0) 5 ( 62.5) 4 ( 50.0) 21 ( 61.
Slide 100: CDI toxin mechanism
The glucosyltransferase locks Rho family GTPases in the inactive state CDI toxins bind to cell surface receptors and trigger endocytic event 1 Autocatalytic cleavage event releases CDI toxin's glucoyltransferase enzymatic domain into the cytosol of the infected cell 2 3 3 1 2 Inactivation of Rho GTP
Slide 101: REC-3964 blocks toxin glucosyltransferase
Adapted from Awad, MM. et al. (2014). Clostridium difficile virulence factors: Insights into an anaerobic spore-forming pathogen. Gut Microbes. 5(5), 579-593. 3 1 2 4 REC-3964 binds and blocks catalytic activity of the toxin’s innate glucosyltransferase, but not the host's 5 5 REC-3964 is Recursion’
Slide 102: REC-3964 Target Product Profile
102 Target Product Profile: Drug-like properties support oral dosing BID. Therapeutic exposures observed in humans Well-tolerated with no DLTs or SAEs in Phase 1. No treatment-related discontinuations REC-3964 for Prevention of recurrent C. difficile infection (rCDI) Differentiated mechanism of acti
Slide 103: REC-3964 program overview
103 • Orally bioavailable, small molecule C. difficile toxin inhibitor and the first NCE developed by Recursion • Differentiated MOA selectively targets bacterial toxin while sparing the host to minimize adverse events • Robust preclinical efficacy demonstrating superiority vs bezlotoxumab in the go
Slide 104: Oncology target relevance and differentiation
104Sources: Independent cancer gene census dataset COSMIC (738 genes). Open Targets Oncology targets with genetic evidence correlate with stronger biological hypotheses Bi ol og ic al H yp ot he si s Target Relevance Oncology likely causal genes1 Oncology causal genes All genes evaluated by pooled d