Slide 1: Decoding Biology To Radically Improve Lives
Decoding Biology To Radically Improve Lives February 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: 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 4: 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 5: 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 6: The Recursion OS combines many tools to industrialize drug discovery
The Recursion OS combines many tools to industrialize drug discovery 6
Slide 7: In Brief: The Recursion Value Proposition
In Brief: The Recursion Value Proposition 7
Slide 8: 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 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: More than a dozen discovery and research programs
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 Pa
Slide 14: Scientific collaborations span biopharma, tech and 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 for up to 7 oncology programs • Mid single-digit royalties on net sales • Recursion owns all algorithmic i
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: The Future of TechBio
The Future of TechBio 16
Slide 17: 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… 17
Slide 18: 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 Groundbreaking models trained on >1 billion images and hundreds of millions of parameters learn to extract biologically me
Slide 19: Integrating point solutions as modules
To truly industrialize drug discovery, point solutions must be integrated as modules across many diverse steps 19
Slide 20: Each module is complex and continuously improved
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 21: 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 22: Continuously adding new modules to the Recursion OS
We continuously add new modules to improve the Recursion OS 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 supercom
Slide 23: A palette of ever-evolving sophisticated modules
The result is a palette of ever-evolving sophisticated modules 23
Slide 24: Find NCE for known target
We use different modules for different tasks: Find NCE for known target 24
Slide 25: Find novel target and drug it
We use different modules for different tasks: Find novel target & drug it 25
Slide 26: Slide 26
Slide 27: LOWE demo
[ DEMO ] 27 LOWE puts the power of the Recursion OS your fingertips via natural language without any coding expertise required
Slide 28: LOWE demo
[ DEMO ] 28 LOWE puts the power of the Recursion OS your fingertips via natural language without any coding expertise required
Slide 29: Discovery User Interface
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… 29
Slide 30: First-in-Disease Opportunities and Beyond
First-in-Disease Opportunities and Beyond 30
Slide 31: SYCAMORE: REC-994 for CCM
Julia – living with CCM 31 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 32: SYCAMORE trial design and update
32 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 33: POPLAR: REC-2282 for NF2
33 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 34: 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 35: TUPELO: REC-4881 for FAP
35 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 36: TUPELO Part 1 complete, Part 2 expected H1 2024
36 TUPELO Clinical Trial : REC-4881 for FAP Phase 1b/2 Underway Clinical: FAP Part 1 Complete, 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 ampull
Slide 37: REC-4881 for AXIN1 or APC mutant cancers
37 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 38: LILAC 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 39: REC-3964 for recurrent C. difficile
39 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 40: Planned Phase 2 proof of concept design
Screening Randomization & Treatment • NHV DDI study will proceed initiation of Phase 2 POC • Study designed to rapidly demonstrate proof of concept • Phase 2 initiation expected in 2024 Trial Update 40 Planned Proof of Concept Phase 2 Design Clinical: C. Difficile REC-3964 250 mg orally BID REC-3964
Slide 41: RBM39: HR-Proficient Ovarian Cancer and Other Solid Tumors
RBM39: HR-Proficient Ovarian Cancer & Other Solid Tumors 41 Similar Opposite BRCA-proficient ovarian cancer PDX Preclinical: HR-Proficient Ovarian Cancer and Other Solid Tumors Identify potential first-in-class tumor-targeted precision therapeutic NCE with novel MOA capable of potentially treating H
Slide 42: 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 43: Value Driven by Our Milestones and Team
Value Driven by Our Milestones and Team 43
Slide 44: Pipeline, platform and partnership progress
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 45: Potential near-term milestones
• Potential for additional INDs • HR-Proficient Cancers RBM39 in H2 2024 • In-licensed program from Bayer (Target Epsilon) for a novel target in fibrotic diseases now entering IND-enabling studies • Expected Ph2 trial starts • Ph2 FPI for AXIN1 or APC mutant cancers program expected in Q1 2024 • Ph2
Slide 46: 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 47: Leadership team and Board of Directors
Our leadership team brings together experience & innovation to lead TechBio 47 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
Slide 48: Appendix
Appendix © Recursion.
Slide 49: 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 50: 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… 50 JAK1 TNKS1BP1 PPP1R9B PHF13 SOCS3 PRKCH MEGF8 ASB7 SLC39A1 DOCK9 ZMYM3 FAM49B STK24 YWHAB IL6ST IL6R STA
Slide 51: COVID-19 research: Recursion OS 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 52: REC-994 for Cerebral Cavernous Malformations
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 53: Disease overview: Cerebral Cavernous Malformations
53 • 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 54: CCM patient population and no approved therapy
54 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 55: CCM is an under-appreciated orphan disease
55 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 56: Therapeutic approach to CCM
56 • 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 57: 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 58: 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 59: Preclinical studies confirm insight
59 Further Confidence : Preclinical Studies Confirm 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 lesi
Slide 60: Clinical studies confirming safety
Further Confidence : Clinical Studies Confirming 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 Mo
Slide 61: Target product profile: REC-994
61 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 62: REC-994 for CCM program summary
62 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 63: 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 64: Disease overview: Neurofibromatosis Type 2
64 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 65: NF2 meningiomas disease overview
65 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 66: REC-2282 rescued loss of NF2
66 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 67: REC-2282 mechanism of action
67 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 68: REC-2282 preclinical in-vivo efficacy
68 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 69: Prior studies suggest potential 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 70: REC-2282 vs other HDAC inhibitors
70 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 71: Target product profile: REC-2282
71 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 72: REC-2282 for NF2 program summary
72 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 73: REC-4881 for Familial Adenomatous Polyposis
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 74: Disease overview: Familial Adenomatous Polyposis
74 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 75: FAP standard of care
75 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 76: REC-4881 rescued phenotypic defects of APC knockdown
76 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 77: REC-4881 blocks Wnt mutation induced MAPK signaling
77 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 78: Preclinical reduction in polyp count and dysplasia
78 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 79: Clinical data generated by Recursion
79 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 80: Target product profile: REC-4881 FAP
80 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 81: REC-4881 for FAP program summary
81 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 82: 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 83: Disease overview: AXIN1 or APC mutant cancers
83 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 84: Flexible patient selection strategy and study design
84 • 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 85: Novel insight around established MoA
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 86: Preclinical studies confirming insight
-20 0 20 40 60 80 100 Further Confidence : Preclinical Studies Confirming 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 86 AXIN1 or APC wildtype 0 5
Slide 87: Target product profile: AXIN1 or APC mutant cancers
87 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 88: REC-4881 for AXIN1 or APC mutant cancers summary
88 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 89: REC-3964 for 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 90: 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 9
Slide 91: C. difficile disease progression
91 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 92: 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 92 Clinical: C. difficile
Slide 93: REC-3964 superior to bezlotoxumab in hamster model
Further Confidence : Preclinical Studies Confirmed Recursion OS Insight REC-3964 significantly extended survival over SOC Clinical: C. difficile 93 • REC-3964 potently inhibits toxin B with residual activity against toxin A, while bezlotoxumab is specific to toxin B. • Significant difference in prob
Slide 94: Phase 1 study complete
94 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 95: Clinical studies confirming 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 96: 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 97: 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 98: Target product profile: REC-3964
98 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 99: REC-3964 program summary
99 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 100: RBM39 inhibition for HR-proficient ovarian cancer
RBM39 Inhibition for the Treatment of HR-Proficient Ovarian Cancer and Other Solid Tumors Target / MOA RBM39 Molecular Glue Degrader Molecule Type Small Molecule Lead Indication(s) HR-Proficient Cancers Status Pre-IND Source of Insight Recursion OS
Slide 101: RBM39 degradation target product profile
101 RBM39 Degradation for HR-Proficient Ovarian Cancer & Other Solid Tumors 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. P
Slide 102: RBM39 program summary
102 RBM39 Program for HR-Proficient Ovarian Cancer & Other Solid Tumors • 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