Century Therapeutics, Inc. · NASDAQ:IPSC
Century Therapeutics — Investor Day (November 2022)
66 slides from Century Therapeutics's investor day presentation, Nov 10, 2022
Slide 1: R&D Day November 11, 2022
R&D DayNovember 11, 2022
Slide 2: Forward-looking statements
2 This presentation contains forward-looking statements within the meaning of, and made pursuant to the safe harbourprovisions of, The Private Securities Litigation Reform Act of 1995. All statements contained in this document, other than statements of historical facts or statements that relate to p
Slide 3: Agenda
3 AgendaDelivering on a Next-Generation iPSC PlatformLalo Flores, PhD, CEONectin-4 directed therapies: Urothelial Cancer and BeyondJonathan Rosenberg, MD, Chief Genitourinary Oncology Service, Division of Solid Tumor Oncology; Enno W. ErcklentzChair, Memorial Sloan Kettering Cancer Center Rationale
Slide 4: Delivering on a Next-Generation iPSC Platform
Delivering on a Next-Generation iPSC PlatformLalo Flores, PhD ǀCEO
Slide 5: Positioned to Deliver Next-Generation Cell Therapies
5 Positioned to Deliver Next-Generation Cell Therapies First IND (CNTY-101) deemed eligible to proceed by FDA, Poised to initiate Phase 1 imminentlyFoundational investment to establish in-house manufacturing Maintaining financial strength with cash runway into 2025 Advances with next generation iNK3
Slide 6: Century's Key Areas of Internal Focus
6 Century’s Key Areas of Internal Focus B cell malignanciesCNTY-101: Lead product candidate, CD19 targeted CAR-iNKCNTY-102: First γδiTcandidate, multi-specific (CD19 + CD79b) CAR-iTDesigned to increase proportion of patients achieving durable responses through multi-dosing regimens enabled by key Al
Slide 7: Leapfrogging the Competition in Lymphoma
7 Leapfrogging the Competition in Lymphoma Leverage iPSC technology to develop products•With multiple enhancements introduced with precision CRISPR gene editing•That can be manufactured at scale with antibody-like COGs•That can realize the durability benefit of repeat dosing because they can resist
Slide 8: Transforming the cell therapy treatment paradigm
8 Transforming the cell therapy treatment paradigm •AUC main predictor of duration of response•Variable cell expansion/exposure drives toxicity and suboptimal responses •Finite repeatdosing regimens have the potential to exceed bar set by autologous cell therapy and deliver more durable responses, i
Slide 9: Advances with iNK and iT Cell Platforms Showcased at SITC
9 Advances with iNKand iTCell Platforms Showcased at SITCEmpowering iPSC-Derived iNKCells with Multiple Gene Edits to Improve Persistence and Anti-Tumor Efficacy (SITC Abstract 265) Multiple Targeting of Solid Tumors with iPSC-derived Gamma Delta CAR T Cells in Combination with Therapeutic Antibodie
Slide 10: Winning in Solid Tumors
10 Winning in Solid Tumors Trafficking and infiltration γδiTcells -tissue homing TME / Immunosuppressive environment Requirement for chemotherapy conditioning Tumor heterogeneity •Novel conditioning regimens•Genetic engineeringChallengesCentury’s Solution Future engineering strategies •Engage endoge
Slide 11: CNTY-107: First in Class Nectin-4 Targeted GD iT Cell Therapy
11 CNTY-107: First in Class Nectin-4 Targeted GD iTCell TherapyNectin-4 has been validated by ADC approaches•Opportunity to address multiple Nectin-4 positive solid tumors•Potential indications include bladder, breast, pancreatic, non-small cell lung cancer, esophageal/gastric, head and neck, and/or
Slide 12: Product candidate pipeline
12 ProductiPSC PlatformTargetsIndicationsExpected IND SubmissionDiscoveryPreclinicalClinicalCollaboratorCNTY-101iNKCD19B-Cell MalignanciesCleared to proceed 3Q22CNTY-103iNKCD133Glioblastoma2024CNTY-102iT CD19 + CD79bB-Cell Malignancies2024CNTY-104iNK/iTMulti-specificAcute Myeloid Leukemia2024CNTY-10
Slide 13: Anticipated Catalysts Over Next Months
13 Anticipated Catalysts Over Next 12 MonthsUnderpinned by strong balance sheet with platform synergies and operational excellenceCNTY-101•Phase 1 (ELiPSE-1) trial initiation in B-cell malignancies (by YE22)CNTY-101 Follow On (CNTY-102) •Present pre-clinical data at major medical meeting (2H23)CNTY-
Slide 14: Nectin-4 directed therapies: Urothelial cancer and beyond
Nectin-4 directed therapies: Urothelial cancer and beyondJonathan Rosenberg, MDChief, Genitourinary Oncology ServiceMemorial Sloan Kettering Cancer CenterNew York, NY
Slide 15: Landscape of advanced urothelial cancer treatment
Cisplatin eligible Cisplatin ineligible Gemcitabine/carboplatin PDL1 high: Atezolizumab Platinum ineligible Pembrolizumab or atezolizumab Enfortumabvedotin SD/PR/CR:Avelumab maintenance PD: Pembrolizumab Accelerated approval: Sacituzumab govitecanFGFR2/3 mutation: Erdafitinib Metastatic urothelial c
Slide 16: Nectin-4 biology and expression
•Calcium-independent immunoglobulin-like cell adhesion molecule•Nectinsare cell surface protein involved in polarity, proliferation, differentiation, and migration•Expressed during development in multiple cell types (epithelial, immune, neuronal)•Nectin-4 expression is evident in multiple cancers, a
Slide 17: Nectin prevalence in cancer
Nectin - 4 prevalence in cancer Source: https://www.proteinatlas.org/ENSG00000143217-NECTIN4/pathology
Slide 18: Nectin prevalence in cancer
Nectin - 4 prevalence in cancer N%Ab usedRefHead and Neck Squamous cell ancer15913.8% negative53.5% weak 32.7% medium-highAbcam clone EPR15613-68Oncotarget.2022; 13:1166-1173Esophageal cancer9266% H score ≥70AF2659Cancer Cell Int. 2019; 19:106Luminal B Her2 Negative Breast cancer147IRS scores:23.8%
Slide 19: Nectin-4 staining in urothelial cancer
Nectin-4 staining* in urothelial cancer EV 101: J Clin Oncol 2020 38 1041-1049EV 201: J Clin Oncol 2021 39 6_suppl 394*M22-321b41.1 (developed by Agensys, not commercially available)Required in EV-101 (phase I study of EV in urothelial and other Nectin-4 positive cancers)Urothelial cancer: Median H-
Slide 20: Nectin-4: role in cancer
Nectin - 4: role in cancer •Nectin-4 knockdown reduces migration, spheroid formation, cell proliferation•Plays a role in epithelial-mesenchymal transition•Upon association with Afadin, Nectin-4 induces PI3K/AKT activation, and cellular proliferation via PI3K/AKT pathway•Nectin-4 interacts with ERBB2
Slide 21: Enfortumab Vedotin: Nectin-Targeted Therapy
Enfortumab Vedotin : Nectin - 4 Targeted Therapy
Slide 22: Enfortumab vedotin anti-tumor activity
Enfortumab vedotin anti - tumor activity EV-101Phase IORR 43%EV-201Phase 2 ORR 44%
Slide 23: EV-301: EV improves survival compared to chemotherapy
EV - 301: EV improves survival compared to standard chemotherapy Powles, Rosenberg, et al. NEJM2021PFS 5.55 vs. 3.71 months; hazard ratio for progression or death, 0.62; 95% CI, 0.51 to 0.75; P<0.001)EV ORR 40.6%
Slide 24: Common enfortumab vedotin toxicities
Common enfortumab vedotin toxicities include fatigue, rash, neuropathy; hyperglycemia occurs and may be severe Powles and Rosenberg, et al. NEJM2021
Slide 25: MMAE payload-related side effects
MMAE Payload - related side effects Powles and Rosenberg, et al. NEJM2021
Slide 26: Nectin-on-target side effects
Nectin - 4 on - target side effects Powles and Rosenberg, et al. NEJM2021 Overlapping?
Slide 27: EV-103 Cohort K: EV + pembrolizumab responses
Content of this presentation is copyrightand responsibility of the author. Permission is required for re-use. EV - 103 Cohort K: Enfortumab vedotin + pembrolizumab leads to deep and durable responses in newly diagnosed cisplatin - ineligible patients with advanced urothelial cancer Jonathan E. Rosen
Slide 28: EV+P: Nectin-4 Expression and Best Overall Response
Content of this presentation is copyrightand responsibility of the author. Permission is required for re-use. EV+P: Nectin - 4 Expression and Best Overall Response •Nectin-4 was detected in tumor tissue from 94.6% of patients who had adequate tissue for testingJonathan E. Rosenberg, MDActivity seen
Slide 29: Enfortumab moves to first line
Cisplatin ineligible Gemcitabine/carboplatin PDL1 high: Atezolizumab Enfortumab+ pembrolizumab Metastatic urothelial carcinoma Enfortumab moves to first line: Anticipated accelerated approval with EV - 103 Cohort K ull approval pending results of EV-30 comparing gemcitabine and platinum to enfortuma
Slide 30: Potential mechanisms of resistance to Enfortumab vedotin
Potential mechanisms of resistance to Enfortumab vedotin •Luminal urothelial cancers may have higher Nectin-4 levelsClin Cancer Res. 2021 Sep 15;27(18):5123-5130.•MDR-1/P-glycoprotein overexpression likely leads to MMAE export from cancer cellMol Cancer Ther.(2022) 21 (7): 1227–1235.•Downregulation
Slide 31: Other Nectin-targeted therapies: bicyclic compounds
Other Nectin - 4 targeted thearpies : bicyclic compounds in early phase trials •Constrained bicyclic peptides or “bicycles”•Linear peptide cyclized around a trivalent scaffold•Can be used to deliver cytotoxics, or bind to other proteins/immune molecules•Smaller than ADC’s, more able to penetrate tum
Slide 32: Future landscape for Nectin-4 directed therapy
Future landscape for Nectin-4 directed therapy:Nectin-4 directed therapy moves earlier in the urothelial cancer disease course•EV-103 cohort K and EV-302 seek to move EV to first-line therapy•KN-B15, KN-905 (EV/pembrolizumab) and VOLGA (EV/durva/treme) testing EV in muscle invasive localized disease
Slide 33: Rationale for iPSC-derived γδ CAR-T cells
Rationale for iPSC-derived γδ αǀPresident, R&D
Slide 34: γδ T cells in Homeostasis and Host Defense of Epithelial Barrier Tissues
34 γδ T cells in Homeostasis and Host Defense of Epithelial Barrier TissuesNature Reviews Immunology volume17,pages 733–745 (2017) γδT cells make up between 1-20% of peripheral blood T cells, but comprise the majority ofT cells that reside in tissues
Slide 35: Abundance of γδ T cells in tumors
35 Abundance of γδ Ovarian CancerColorectal Cancer18,000 human tumor samplesacross 39 malignanciesDFS
Slide 36: γδ T cells: At the Interface of Innate and Adaptive Immunity
36 γδ T cells: At the Interface of Innate and Adaptive Immunity Yazdanifaret al Cells2020,9(5), 1305Dranoff , Nature Reviews Cancer, 4, 11-22,2004
Slide 37: γδ TCRs Do Not Recognize Classical HLA And Are Not Alloreactive
37 γδ TCRs Do Not Recognize Classical HLA And Are Not Alloreactive Clinical Evidence •Partial HLA-mismatched allo-HCT with αβT cell depleted grafts showed improved DFS as a function of the number of γδT cells (median 11 x 106/kg) infused with no increase in GVHD1-4•γδT cell enriched donor lymphocyte
Slide 38: Multiple Potential Mechanisms for Tumor Recognition
38 Multiple Potential Mechanisms for Tumor Recognition Both Intrinsic and SyntheticBlood(2018) 131 (10): 1063–1072.
Slide 39: Diverse Innate Mechanisms for Tumor Targeting
39 gd TCRCD8aCD16NKG2CNKG2DNKp30NKp44NKp46NKG2A 0255075100 Percent positive (CD3+ cells)Delta 1 Delta 2 Diverse Innate Mechanisms for Tumor TargetingN=13 clinical grade TiPSC lines at T cell stage (post differentiation); All lines are Vγ9
Slide 40: γδCAR-iT cells mediate ADCC
40 γδCAR-iTcells mediate ADCC 020406080 0200000400000600000 8000001000000 Hours Red objects(CD19+ CD20+)Green objects(CD19ko CD20+)Tumor cell death IsoIsoRituxObin 020406080 0100000020000003000000 5×1061×1071.5×1072×107 Hours Anti-CD19 CARCD16 (FcRγRIII)
Slide 41: Key Takeaways
41 Key TakeawaysThe biological properties of γδT cells make them an ideal platform for genetically modified cell therapy of cancers •Innate receptors provide multiple orthogonal mechanisms for tumor recognition•Functional Fc receptors enable combination therapies with monoclonal antibodies•Tissue tr
Slide 42: γδ T Cell Platform
γδT Cell PlatformMark Wallet, PhD ǀVP Immuno-Oncology
Slide 43: iPSC-derived Therapeutics are Developed from Unique Cells and Processes
43 iPSC-derived Therapeutics are Developed from Unique Cells and Processes
Slide 44: iPSC-derived Therapeutics are Developed from Unique Cells and Processes
44 iPSC-derived Therapeutics are Developed from Unique Cells and Processes iPSC-derivedT cells
Slide 45: iPSC-derived Therapeutics are Developed from Unique Cells and Processes
45 iPSC-derived Therapeutics are Developed from Unique Cells and Processes iPSC-derivedT cells1. ReprogrammingγδT cells into TiPSC3. Differentiationof TiPSC into high-yield, high-purityγδCAR-T cells2. Engineering TiPSCfor enhanced fitness4. Pre-clinicalstudies exhibitingpotent activity ofγδCAR-T cel
Slide 46: 1. Reprogramming γδ T cells into TiPSC
46 1. Reprogramming γδT cells into TiPSC Banked cells fromhealthy donors Dozens of TiPSClines for clinical use Narrowed to twolead lines for initialclinical programs TCRs sequenced,cloned, and testedfor allo-reactivity Single blood donationenables developmentan entire platform withmultiple productsV
Slide 47: 1. Reprogramming γδ T cells into TiPSC
47 1. Reprogramming γδT cells into TiPSC Each TiPSC line is clonal-Arises from a single T cell-Carries a single monoclonal TCR gene rearrangement Lead γδTCR lacks allo-reactivity Anti-TCR Pos CTLAllogenic PBMCsAnti-TCR Pos CTLAllogenic PBMCs 02040 6080100 Activation condition% GFP+ (activated)TCR-le
Slide 48: 2. Engineering TiPSC for Enhanced Fitness
48 2. Engineering TiPSCfor Enhanced Fitness + CD19 CAR forPOC studies 0100200300 05×1061×107 Time Elapsed (hours)Tumor growth (red object intensity)γδCAR-T + recombinant IL-15 γδCAR-T Sustained serial killing in presence of recombinant IL-15~ 4 roundsserial killing14+ rounds serial killing
Slide 49: 2. Engineering TiPSC for Enhanced Fitness
49 2. Engineering TiPSCfor Enhanced Fitness + CD19 CAR forPOC studies Sustained serial killing with engineered IL15/IL15RA 05×1061×107 DaysTumor growth (red object intensity)01234567891011121314151617γδ CAR-T CAR-T + engineered IL15/IL15RA Tumor Alone γδ CAR-T + recombinant IL15
Slide 50: 3. Differentiation of TiPSC into High-yield / High-purity T cells
50 3. Differentiation of TiPSCinto High-yield / High-purity T cells γ δ TiPSC w/ IL15 γδ HPC γ δ TiPSC w/o CAR γ δ HPC w/o CAR γ δ TiPSC w/o CAR γ δ HPC w/o CAR EGFR CAR98% 0714212835 02550 75100 Day of Differentiation% Positive EGFR-CARCD3 Yield from batch shown:1 iPSC →281,931 γδCAR-T cells91%IL15
Slide 51: 4. Preclinical Studies Exhibiting Potent Activity of γδCAR-T Cells
51 4. Preclinical Studies Exhibiting Potent Activity of γδCAR-T Cells Against Solid Tumors SKOV-3OVCAR-3 EGFR Solid Tumor Models(Ovarian) 2:11:11:21:4 01020304050607080 90100 % Cytolysis γδ-CAR-T γδT (no CAR) 2:11:11:21:4 01020 30405060708090100 % Cytolysis 2:11:11:21:4Targetonly 0100200300400500 60
Slide 52: Summary
52 Summary•Century has developed a fully in-house iPSC-derived γδT cell platform•Technical advances have enabled successful proof of concept for pre-clinical utility of γδCAR-T cells for solid tumors•The team is well-positioned to develop a solid tumor program for the clinic
Slide 53: CNTY-107, our γδiT Product Candidate for Nectin-4 Solid Tumors
CNTY-107, our γδiTProduct Candidate for the Treatment of Solid Tumors Expressing Nectin-4Luis Borges, PhD ǀCSO
Slide 54: CNTY-107, Next-Generation Product Candidate For Nectin-4 Expressing Cancers
54 CNTY-107, Next-Generation Product Candidate For The Treatment Of Nectin-4 Expressing Cancers Trafficking and infiltration γ9δ1iT cells, subset of γδT cells that preferentially home to tissues TME / Immunosuppressive environment Sufficient homeostatic cytokine support for enhanced persistence Tumo
Slide 55: Engineering Profile of CNTY-107
55 Engineering Profile of CNTY-107 Tumor cell killing Imaging + Cytokine support + Safety switch Cell Fitness ENGINEERING PROFILEStepGene EditRationale1KOβ2M Allo-EvasionKIHLA-E-2A-HLA-GAllo-Evasion2KONKG2A KO landing pad, potential to block inhibitory signalKIIL15/IL15RαHomeostatic cytokine support
Slide 56: CNTY-107 Has Multiple Built-In Mechanisms for Tumor Killing
56 CNTY-107 Has Multiple Built-In Mechanisms for Tumor Killing PATHWAYS FOR TUMOR KILLING1.CAR-mediated killing2.ADCC (Antibody-dependent cellular cytotoxicity)3.Innate receptors (NCRs, others) mediated killing though recognition of stress ligands 1 2 3
Slide 57: Nectins
57 Nectins Nectins are cell adhesion molecules (CAMs) involved in Ca2+-independent cell-cell interactions The Nectin family includes four Nectins •Nectins 1-3 are enriched in normal adult tissues•Nectin-4 is mostly expressed during fetal development and its expression declines in adult tissues (low
Slide 58: Nectin-4 Expression in Cancer
58 Nectin-4 Expression in Cancer •Nectin-4 is expressed in high frequency in bladder, breast, lung, pancreatic, ovarian, head & neck, and esophageal cancers•The highest levels of expression of Nectin-4 are seen in bladder, breast, lung and pancreatic cancers•Clinical validation of Nectin-4 as a tumo
Slide 59: Nectin-4 Expression Levels On Skin Keratinocytes Lower Than Tumor Cell Lines
59 Nectin-4 Expression Levels On Human Skin Keratinocytes Is Lower Than In Most Tumor Cell Lines JurkatUM-UC-3TCCSUP Human KeratinocytesHeLaT245367SW780A431 HT1197K562OVCAR3CAPAN2OE19RT4T47DHT1376CHO-Nectin4BeadsNectin-4 PE Cell LineOriginRankingUM-UC-3Bladder cancerNegativeTCCSUPBladder cancerJURKA
Slide 60: Selection of VHH Binders to Build Nectin-4 CAR
60 Selection of VHH Binders to Build Nectin-4 CAR VHH LibraryNot for further distributionLlama VHH antibodies Biophysicalanalysis Cell binding (FACS) CAR engineering and selection In vitro and in vivo screens 20 VHH binders identified Tissue specificity (Retrogenix) Final CAR selectionCentury’s Prop
Slide 61: Century's Nectin-4 CARs Distinguish Between Low vs. High Nectin-4 Expression
61 Century’s Nectin-4 CARs Distinguish Between Cells Expressing Low vs. Moderate to High Levels Of Nectin-4 0.00.51.01.52.02.5 0204060 80100 TUCCSUPE:TCytotoxicity (%target killed) 0.00.51.01.52.02.5 020406080100 T24E:TCytotoxicity (%target killed)UTD P2026 P2017 P2117 P3106 P3107 P3108 P3110 P3113
Slide 62: CNTY-107 Nectin-4 CARs Mediate Robust Anti-Tumor Activity In Vivo
62 CNTY-107 Nectin-4 CARs Mediate Robust Anti-Tumor Activity in VivoNovember 8, 2022•5x106OVCAR-3 cells implanted subcutaneously in the right flank •Mice randomized after tumors reached 75-125 mm3•Mice treated with 5x106CAR-T cells Treatment GroupDay 28 % TGIDay 28 P-ValueP3108 -NECM_1780.80.0003P31
Slide 63: CNTY-107 Next Steps and Milestones
63 CNTY-107 Next Steps and Milestones Complete Engineering of the γδ γδ δ βα
Slide 64: CNTY-107 Preliminary Clinical Strategy
64 CNTY-107 Preliminary Clinical Strategy•Initial Phase I clinical study is planned to be run as a basket trial that will include multiple Nectin-4 positive cancers•Cancers under consideration include bladder, breast, pancreatic, non-small cell lung cancer, esophageal, head and neck, and/or ovarian
Slide 65: Thank you
CENTURY Thank you THERAPEUTICS
Slide 66: Century Therapeutics
CENTURY THERAPEUTICS