Slide 1: Decoding Biology To Radically Improve Lives
Decoding Biology To Radically Improve Lives May 2024
Slide 2: Disclaimers
Disclaimers 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, esti
Slide 3: Recursion Poised to Hit TechBio Escape Velocity from Competition
• Pipeline: We believe we are the 1st TechBio company to create a flywheel of programs and rapid cadence of potential pivotal trial readouts • CCM Ph2 readout expected in Q3 2024 • NF2 Ph2 safety & prelim efficacy expected Q4 2024 • FAP Ph2 safety & prelim efficacy expected H1 2025 • AXIN1 or APC mu
Slide 4: In Brief: The Recursion Value Proposition
In Brief: The Recursion Value Proposition 4
Slide 5: A formula for mapping and navigating complex systems using technology
There is a formula for mapping and navigating complex systems using technology 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.)
Slide 6: Data roadblocks make mapping and navigating biology difficult
Data roadblocks make mapping and navigating biology difficult 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
Slide 7: Recursion OS: 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 8: The Recursion OS combines many tools to industrialize drug discovery
The Recursion OS combines many tools to industrialize drug discovery 8
Slide 9: Failing faster and earlier to spend less and go faster
Screen — Hit ID — Validated Lead — Advanced Candidate — Development Candidate — Industry Recursion Failing faster and earlier to › › spend less › C o st t o IN D ( $ M ) › and go faster 100 80 60 51 80% 75% 85% 100 55 18 55% 32% 62% 7 37% St ag e Ti m e t o V al id at ed L e ad ( m o ) 4 Industry Re
Slide 10: Multi-pronged capital efficient business strategy
We harness value from the Recursion OS with a multi-pronged capital efficient business strategy Pipeline Recursion OS Build internal pipeline in indications with potential for accelerated path to approval Pipeline Strategy Precision Oncology Rare Disease Partnerships Data Partnership Strategy Partne
Slide 11: Pipeline strategy
Build internal pipeline in indications with potential for accelerated path to approval Pipeline Strategy Precision Oncology Rare Disease Pipeline Recursion OS Partnerships Data *Includes a single oncology indication from our Roche and Genentech collaboration. We harness value from the Recursion OS w
Slide 12: Our pipeline reflects the scale and breadth of our approach
12 More than a dozen discovery and research programs in oncology or with our partners – first program optioned by Roche-Genentech in GI-oncology Our pipeline reflects the scale and breadth of our approach All populations defined above are US and EU5 incidence unless otherwise noted. EU5 is defined a
Slide 13: 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 Recursion OS P
Slide 14: Scientific collaborations span biopharma, tech & data
Exciting scientific collaborations span biopharma, tech & data Undruggable oncology targets • $30M upfront and $50M equity investment • Increased per program milestones which may be up to $1.5B in aggregate for up to 7 oncology programs • Mid single-digit royalties on net sales • Recursion owns all
Slide 15: Data strategy
Pipeline Recursion OS 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. We
Slide 16: A new kind of team and culture
Advanced degreesEmployees Team Members >500 What it takes to make this happen – a new kind of team and culture >50% ESG Highlights ✓ ESG reporting on Healthcare and Technology Metrics ✓ 100% of electricity powering our Biohive-1 supercomputer comes from renewable sources ✓ Learn more about Recursion
Slide 17: Our leadership team brings together experience & innovation
Our leadership team brings together experience & innovation to lead TechBio 17 Board of Directors Dean Li, MD PHD Co-Founder of RXRX, President of Merck Research Labs Rob Hershberg, MD PHD Co-Founder, CEO, & Chair of HilleVax, Former EVP, CSO, & CBO of Celgene Blake Borgeson, PHD Co-Founder of RXRX
Slide 18: What to Watch for from Recursion: Potential Near-Term Milestones
• Expected Ph2 readouts for AI-discovered programs • CCM readout expected in Q3 2024 • NF2 safety & prelim efficacy expected Q4 2024 • FAP safety & prelim efficacy expected H1 2025 • AXIN1 or APC mutant cancers safety & prelim efficacy expected H1 2025 • Additional Ph2 trial starts • Ph2 FPI for AXI
Slide 19: The Future of TechBio
The Future of TechBio 19
Slide 20: TechBio Origins: Point Solutions
TechBio Origins: Point Solutions 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… 20
Slide 21: Point solutions evolve in complexity and scale
As these point solutions evolve they increase in complexity and scale We manipulate human cells with CRISPR/Cas9- mediated gene knockouts, compounds, and other reagents Phenom-1 Models trained on a library of >2 billion images and hundreds of millions of parameters learn to extract biologically mean
Slide 22: Point solutions must be integrated as modules
To truly industrialize drug discovery, point solutions must be integrated as modules across many diverse steps 22
Slide 23: Each module is complex, and we continuously improve them
Each module is complex, and we continuously improve them 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 PHARMACOKINE
Slide 24: Utilizing each module requires specialized teams and expertise
Utilizing each module requires specialized teams and expertise 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 i
Slide 25: We continuously add new modules to improve the Recursion OS
We continuously add new modules to improve the Recursion OS BioHive-2, Recursion’s next generation supercomputer, can analyze Tempus data and run ML oncology models. We believe that BioHive-2’s performance may place it in the top 50 of the next TOP500 list. ML trained on Tempus data BioHive-2 superc
Slide 26: A palette of ever-evolving sophisticated modules
The result is a palette of ever-evolving sophisticated modules 26
Slide 27: Find NCE for known target
We use different modules for different tasks: Find NCE for known target 27
Slide 28: Find novel target & drug it
We use different modules for different tasks: Find novel target & drug it 28
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Slide 30: LOWE demo
[ DEMO ] 30 LOWE puts the power of the Recursion OS your fingertips via natural language without any coding expertise required
Slide 31: LOWE demo
[ DEMO ] 31 LOWE puts the power of the Recursion OS your fingertips via natural language without any coding expertise required
Slide 32: Discovery User Interface for the Recursion OS
The Recursion OS is now more than a collection of point solutions accessible to expert users …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… 32
Slide 33: First-in-Disease Opportunities and Beyond
First-in-Disease Opportunities and Beyond 33
Slide 34: REC-994 for CCM Phase 2: SYCAMORE
Julia – living with CCM 34 SYCAMORE Clinical Trial : REC-994 for CCM Phase 2 Fully Enrolled 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
Slide 35: SYCAMORE Clinical Trial: REC-994 for CCM
35 SYCAMORE Clinical Trial : REC-994 for CCM Phase 2 Fully Enrolled 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 lesi
Slide 36: POPLAR Clinical Trial: REC-2282 for NF2
36 POPLAR Clinical Trial : REC-2282 for NF2 Phase 2 Underway 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
Slide 37: POPLAR trial design and update
POPLAR Clinical Trial : REC-2282 for NF2 Phase 2 Underway 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 an
Slide 38: TUPELO Clinical Trial: REC-4881 for FAP
38 TUPELO Clinical Trial : REC-4881 for FAP Phase 1b/2 Underway 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, smal
Slide 39: TUPELO Part 2 enrollment commenced
39 TUPELO Clinical Trial : REC-4881 for FAP Phase 1b/2 Underway Clinical: FAP Part 2 Enrollment Commenced 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 re
Slide 40: REC-4881 for AXIN1 or APC mutant cancers
40 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 41: LILAC Clinical Trial: REC-4881 Phase 2
FPI achieved 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 p
Slide 42: REC-3964 for recurrent C. difficile infection
42 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 43: Planned Proof of Concept Phase 2 Design
Screening Randomization & Treatment • NHV DDI study will precede initiation of Phase 2 POC • Study designed to rapidly demonstrate proof of concept • Phase 2 initiation expected in 2024 Trial Update 43 Planned Proof of Concept Phase 2 Design Clinical: C. Difficile REC-3964 250 mg orally BID REC-3964
Slide 44: RBM39: Advanced HR-Proficient Cancers
RBM39: Advanced HR-Proficient Cancers 44 Similar Opposite BRCA-proficient ovarian cancer PDX Preclinical: RBM39 Identify potential first-in-class tumor-targeted precision therapeutic NCE with novel MOA capable of potentially treating HR-proficient cancers Inhibition of target RBM39 (previously refer
Slide 45: Target Epsilon: Novel Approach for Fibrotic Diseases
Target Epsilon: Novel Approach for Fibrotic Diseases Preclinical: Undisclosed Indication in Fibrosis Healthy StateDiseased State Reversal of Fibrocyte Differentiation Assay Identify a potential first-in-class therapeutic NCE with a novel MOA capable of reversing disease-related fibrotic processes Re
Slide 46: Appendix
Appendix © Recursion.
Slide 47: Oncology Relevance Score
Oncology Relevance Score RXRX PROPRIETARY DATA O n co lo gy R el ev an ce S co re P U B LI C D A TA Targets with Approved Drugs1 All other Potential Targets HighLow Low High We expect to initiate 300 exploratory programs in 2024 from this space, where our proprietary data provides a distinct arbitra
Slide 48: Whole-genome arrayed 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 49: JAK / STAT pathway clustered by strength of 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… 49 JAK1 TNKS1BP1 PPP1R9B PHF13 SOCS3 PRKCH MEGF8 ASB7 SLC39A1 DOCK9 ZMYM3 FAM49B STK24 YWHAB IL6ST IL6R STA
Slide 50: Recursion OS correctly predicted 9 of 10 clinical trials
Drug Prediction Correct? Hydroxychloroquine Negative ✓ Lopinavir Negative ✓ Ritonavir Negative ✓ Remdesivir Positive ✓ Baricitinib Positive ✓ Tofacitinib Positive ✓ Fostamatinib Positive ✓ Ivermectin* Negative ✓ Fluvoxamine Negative ✓ Dexamethasone Negative x COVID-19 research: Recursion OS correctl
Slide 51: REC-994 for Symptomatic 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 52: Disease Overview: Cerebral Cavernous Malformations
52 • 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 53: CCM patient population and no approved medical therapy
53 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 54: CCM is an Under-Appreciated Orphan Disease
54 Disease Overview : CCM is an Under-Appreciated Orphan Disease 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 fibrosi
Slide 55: Therapeutic Approach to CCM
55 • 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 56: CCM: Applied prototyping of the Recursion OS
CCM – Applied prototyping of the Recursion OS 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 Recu
Slide 57: REC-994 Mechanism of Action
Healthy REC-994 – Mechanism of Action 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 ce
Slide 58: Preclinical Studies Validate Insight
58 Further Confidence : Preclinical Studies Validate Insight 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 les
Slide 59: Clinical Studies Indicate Favorable Safety Profile
Further Confidence : Clinical Studies Indicate Favorable Safety Profile 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
Slide 60: REC-994 Target Product Profile
60 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 61: REC-994 for CCM program overview
61 REC-994 for Cerebral Cavernous Malformations (CCM) • 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 oxidati
Slide 62: REC-2282 for NF2 Mutated 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 63: Disease Overview: Neurofibromatosis Type 2
63 Disease Overview : Neurofibromatosis Type 2 (NF2) 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
Slide 64: NF2 Meningiomas patient population
64 Disease Overview : Neurofibromatosis Type 2 (NF2) Meningiomas • 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 C
Slide 65: REC-2282 Rescued Loss of NF2
65 NF2 knockdown cells Healthy Cells REC-2282 REC-2282 identified as rescuing HUVEC cells treated with NF2 C o n tr o l N F2 s iR N A HUVEC, human umbilical vein endothelial cells; NF2, neurofibromatosis type 2; siRNA, small interfering RNA. Insight from OS : REC-2282 Rescued Loss of NF2 Clinical: N
Slide 66: REC-2282 Mechanism of Action
66 REC-2282 – Mechanism of Action 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;
Slide 67: REC-2282 preclinical in-vivo efficacy
67 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 h an ge in t u m o
Slide 68: Prior Studies of REC-2282 Suggest Therapeutic Benefit
• 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 69: REC-2282 vs Other HDAC Inhibitors
69 REC-2282 Appears Well Suited for NF2 vs Other HDAC Inhibitors 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 in
Slide 70: REC-2282 Target Product Profile
70 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 71: REC-2282 for NF2 program overview
71 REC-2282 for Neurofibromatosis Type 2 (NF2) • 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 mutan
Slide 72: 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 1b/2 Designation(s) Fast Track; US and EU Orphan Drug Source of Insight Recursion OS
Slide 73: Disease Overview: Familial Adenomatous Polyposis
73 Disease Overview : Familial Adenomatous Polyposis 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 polyp
Slide 74: FAP Standard of Care
74 Disease Overview : Familial Adenomatous Polyposis – Standard of Care 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 q
Slide 75: REC-4881 rescued phenotypic defects of APC knockdown cells
75 REC-4881 rescued phenotypic defects of cells with APC knockdown 0.1 µM REC-4881 Insight from OS : Rescued Loss of APC, Inhibited Tumor Growth • Compared to thousands of other molecules tested, REC-4881 rescued phenotypic defects substantially better (including better rescue than other MEK inhibit
Slide 76: REC-4881 Blocks Wnt Mutation Induced MAPK Signaling
76 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 77: Preclinical Reduction in Polyp Count and Dysplasia
77 Further Confidence : Preclinical Studies Confirming Reduction in Polyp Count and High-Grade Dysplasia 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 •
Slide 78: Clinical Data Generated by Recursion
78 REC-4881-101: Single-center, double-blind, placebo- controlled, dose-escalation study in healthy volunteers • Group 1 (n=13): Food effect crossover (REC-4881 4 mg/PBO [fed/fasted]), followed by single dose REC-4881 8 mg/PBO [fed] • Group 2 (n=12): Matched single ascending dose (REC- 4881 4 mg/PBO
Slide 79: REC-4881 FAP Target Product Profile
79 Differentiated profile versus other MEKs. Low clearance and minimal hepatic metabolism Acceptable safety profile consistent with 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
Slide 80: REC-4881 for FAP program overview
80 REC-4881 for Familial Adenomatous Polyposis (FAP) • Orally bioavailable, small molecule non-ATP competitive allosteric inhibitor of MEK 1/2 in Phase 1b/2 (TUPELO) • REC-4881 appears more active versus approved MEK inhibitors in disease relevant preclinical models • Fast Track Designation in FAP g
Slide 81: 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 82: Disease Overview: AXIN1 or APC Mutant Cancers
82 Disease Overview : AXIN1 or APC Mutant Cancers • 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 progress
Slide 83: Flexible Patient Selection Strategy and Study Design
83 • 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 84: REC-4881 rescues APC and AXIN1
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 regulators of Wnt signaling • Both proteins for
Slide 85: Preclinical Studies Validate Insight
-20 0 20 40 60 80 100 Further Confidence : Preclinical Studies Validate Insight 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 85 AXIN1 or APC wildtype 0 5 1
Slide 86: REC-4881 AXIN1 or APC Target Product Profile
86 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 87: REC-4881 for AXIN1 or APC Mutant Cancers overview
87 REC-4881 for AXIN1 or APC Mutant Cancers • 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 • Recursion’s first clinical trial in oncol
Slide 88: REC-3964 for Prevention of Recurrent C. difficile Infection
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 89: Disease Overview: C. Difficile Infection
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 8
Slide 90: C. Difficile Infection disease progression
90 Disease Overview : C. Difficile Infection (CDI) 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 Infe
Slide 91: REC-3964 Rescued Cells Treated with C. difficile Toxins
REC-3964 identified as a NCE that demonstrated strong rescue in HUVEC cells treated with C. difficile toxin Insight from OS : REC-3964 Rescued Cells Treated with C. difficile Toxins C. difficile toxin B phenotype Healthy Control Disease State Healthy Cells REC-3964 0.1 µM 91 Clinical: C. difficile
Slide 92: REC-3964 Superior to Bezlotoxumab in Hamster Model
Further Confidence : Preclinical Studies Validate Recursion OS Insight REC-3964 significantly extended survival over SOC Clinical: C. difficile 92 • REC-3964 potently inhibits toxin B with residual activity against toxin A, while bezlotoxumab is specific to toxin B. • Significant difference in proba
Slide 93: REC-3964 Phase 1 study complete
93 Clinical Trial : REC-3964 for C. difficile Phase 1 Study Complete 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 •
Slide 94: Clinical Studies Suggest Favorable Safety Profile
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 95: REC-3964: Selective Inhibitor of C. difficile Toxins
REC-3964 : Selective Inhibitor of C. difficile Toxins 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
Slide 96: REC-3964: Selective Inhibitor of C. difficile Toxins
Adapted from Awad, MM. et al. (2014). Clostridium difficile virulence factors: Insights into an anaerobic spore-forming pathogen. Gut Microbes. 5(5), 579-593. REC-3964 : Selective Inhibitor of C. difficile Toxins 3 1 2 4 REC-3964 binds and blocks catalytic activity of the toxin’s innate glucosyltran
Slide 97: REC-3964 Target Product Profile
97 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 actio
Slide 98: REC-3964 for Prevention of rCDI overview
98 REC-3964 for Prevention of recurrent C. difficile infection (rCDI) • 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 precli
Slide 99: RBM39 Inhibition for Advanced HR-Proficient Cancers
RBM39 Inhibition for the Treatment of Advanced HR-Proficient Cancers Target / MOA RBM39 Molecular Glue Degrader Molecule Type Small Molecule Lead Indication(s) 2L+ HR-Proficient Cancers Status Pre-IND Source of Insight Recursion OS
Slide 100: RBM39 Degradation Target Product Profile
100 RBM39 Degradation for Advanced HR-Proficient Cancers Robust RBM39 degradation correlated with benefit. FIH studies enable rapid clinical path to POC Monotherapy label with combination potential. Acceptable TI in human cancer xenografts Opportunity to address high unmet need. PARP naïve and PARP
Slide 101: RBM39 Program for Advanced HR-Proficient Cancers
101 RBM39 Program for Advanced HR-Proficient Cancers • 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 targ